Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer)

Abstract

Background

Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC.

Patients and methods

Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m² in Japan, 75 mg/m² at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120 mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2.

Results

A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833–1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm.

Conclusion

S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC.

Clinical trial number

Japan Pharmaceutical Information Center, JapicCTI-101155.

Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

Abstract

Background

Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.

Patients and methods

EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.

Results

Minimum follow-up was 42 months. Kaplan–Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64–1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38–0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70–1.82; P = 0.63) in the RET M918T–negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.

Conclusion

The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.

Trial Registration Number

NCT00704730

A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

Abstract

Background

Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.

Materials and methods

We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours.

Results

A high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4–Q1) 1.37; 95% confidence interval (CI), 1.14–1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI₁₆) (16:1n–7/16:0) [OR (Q4–Q1), 1.28; 95% C, 1.07–1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3–T1)=2.01; 95% CI, 1.03–3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.

Conclusion

These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

The past and future of ‘reported outcomes’ in studies on chemotherapy neuropathy

The manuscript by Park et al. in this issue of Annals of Oncology [1] reports on potential clinical and genetic prognostic factors of chemotherapy-induced peripheral neuropathy (CIPN). Predicting CIPN in individual patients, before symptoms manifest, is a critical goal that has not been achieved in the field. Even at the cohort level (a lesser challenge) available CIPN studies tend to disagree, regarding which predictors (genetic and otherwise) are significant. Therefore, additional clinical data are critically needed. We congratulate Park et al. on achieving this step: to put ICON7, a large, high-quality clinical trial, onto the 'map' of CIPN research.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

Abstract

Background

Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle–drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC.

Patients and methods

Patients with mRCC and 2–3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety.

Results

In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0–4.3) and 3.9 months (95% confidence interval 2.2–5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel–Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified.

Conclusions

Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.

Clinical trial identification

NCT02187302 (NIH).

ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe

Abstract

Background

The availability and affordability of safe, effective, high-quality, affordable anticancer therapies are a core requirement for effective national cancer control plans.

Method

Online survey based on a previously validated approach. The aims of the study were to evaluate (i) the availability on national formulary of licensed antineoplastic medicines across the globe, (ii) patient out-of-pocket costs for the medications, (iii) the actual availability of the medication for a patient with a valid prescription, (iv) information relating to possible factors adversely impacting the availability of antineoplastic agents and (v) the impact of the country's level of economic development on these parameters. A total of 304 field reporters from 97 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer review and amendments have been incorporated into the final report.

Results

Surveys were submitted by 135 reporters from 63 countries and additional peer-review data were submitted by 54 reporters from 19 countries. There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most substantial issues are in lower-middle- and low-income countries. Even among medications on the WHO Model List of Essential Medicines (EML) the discrepancies are profound and these relate to high out-of-pocket costs (in low-middle-income countries 32.0% of EML medicines are available only at full cost and 5.2% are not available at all, and for low-income countries, the corresponding figures are even worse at 57.7% and 8.3%, respectively).

Conclusions

There is wide global variation in formulary availability, out-of-pocket expenditures and actual availability for most licensed anticancer medicines. Low- and low-middle-income countries have significant lack of availability and high out-of-pocket expenditures for cancer medicines on the WHO EML, with much less availability of new, more expensive targeted agents compared with high-income countries.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma

Abstract

Background

In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG₁ 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC.

Patients and methods

We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies.

Results

Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, –34.6%; 1400 mg, –41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response.

Conclusions

These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects.

Clinical trial registration number

NCT01046266 (ClinicalTrials.gov).

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

Abstract

Background

B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Patients and methods

Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m²), then weekly (1-h infusions, 250 mg/m²). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m²; CetCisPac arm: 75 mg/m²) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m²) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy.

Results

A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72–1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53–1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38–1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%).

Conclusion

The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced.

Clinical trial number

EudraCT# 2011-002564-24.

Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools

Abstract

Background

Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma.

Patients and methods

PCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2′-deoxycytidine-mediated demethylation and siRNA-knockdown.

Results

Pemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2′-deoxycytidine overcame resistance.

Conclusions

These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms.

Patients and methods

Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models.

Results

Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177–0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN.

Conclusions

There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Circulating tumor DNA as a novel tool to shape clinical trial designs with the potential to impact outcomes: a focus on PI3K inhibitors

Tumor heterogeneity is a major challenge for drug development, and changes in heterogeneity are thought to contribute to anticancer treatment resistance. However, the standard diagnostic approach in clinical trials relies on analysis of a single (usually archival) sample from the primary tumor [1]. This provides limited characterization of a single tumor at initial diagnosis that is not necessarily representative of current disease status [1]. Recent studies have also highlighted challenges with intratumoral heterogeneity in advanced cancers [2, 3]. The success of targeted therapies is closely associated with identification of the target within a tumor sample. However, most tumors develop resistance due to intratumoral heterogeneity, clonal evolution, and selection pressure [1–4].

De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR− phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel

Abstract

Background

Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR− trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy.

Patients and methods

Female patients with HER2+/HR− EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m². Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients.

Results

From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population.

Conclusion

Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR− EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol

Abstract

Background

Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC.

Patients and methods

Genetic profile of 146 BC patients' tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in >3% of the tumours were selected.

Results

A total of 193 genomic rearrangements were identified, and 16 were observed in >3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6 years was reported for PIK3CA mutation carriers (n = 31, 21.2%) versus 9.9 years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12–0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09–0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS.

Conclusion

PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative for FLT3 -ITD, NPM1- or biallelic CEBPA mutations

Abstract

Background

The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML) in first complete remission (CR1).

Patients and methods

We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML subgroup comprised 497 patients, aged 18–60 years.

Results

In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3–0.9, P = 0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3–1.1, P = 0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37–0.9, P = 0.02) and relapse-free survival (HR 0.51, 95% CI 0.34–0.76; P = 0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer.

Conclusion

Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1^mut-neg/CEBPA^dm-neg/FLT3-ITD^neg AML in CR1.

Cinicaltrials.gov identifier

NCT00180115, NCT00180102

Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer

Abstract

Background

Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.

Patients and methods

Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer.

Results

At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%).

Conclusions

GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.

Anti-Desmoglein 1 IgG/IgA-Pemphigus in Verbindung mit einem Thymom

Virusreaktivierung täuscht Rezidiv des Pemphigus vulgaris bei einer immunsupprimierten Patientin vor

Dr. Christian Posch – Preisträger des Österreichischen Wissenschaftspreis der ÖGDV

Schwimmflossen-Vakuumversiegelung zur Behandlung plantarer Exzisionsdefekte

Ist eine komplette Lymphknotendissektion beim malignen Melanom mit positivem Sentinel notwendig?

Leserbrief zu Ebrahimi-Fakhari D et al. Dermatologische Manifestationen der tuberösen Sklerose (TSC). J Dtsch Dermatol Ges 2017; 15(7): 695–701.

Delayed-type hypersensitivity to oral and parenteral drugs

Summary

Adverse drug reactions of the delayed type rank among the most common dermatoses and are predominantly characterized by exanthematous macular or maculopapular eruptions. However, approximately 2 % of affected individuals develop severe or even life-threatening systemic immune reactions associated with organ involvement, requiring immediate diagnosis and treatment. Numerous drugs are capable of eliciting delayed-type hypersensitivity reactions, with antibiotics, anticonvulsant drugs, and the xanthine oxidase inhibitor allopurinol being the most common. Apart from genetic susceptibility, predisposing factors for the development of drug hypersensitivity reactions include high drug doses, polypharmacy, long treatment duration, female gender, as well as acute or chronic infections.

75 years after Erich Wagner's doctoral dissertation: “A Contribution to the Issue of Tattooing” – scientific misconduct in Nazi Germany

Off-Label-Use und Entscheidungen über Anträge auf Kostenübernahme in Deutschland – eine retrospektive Analyse

Zusammenfassung

Hintergrund und Zielsetzungen

Mit dem Begriff „Off-Label-Use" (zulassungsüberschreitende Anwendung) wird die Verordnung pharmazeutischer Präparate außerhalb ihrer zugelassenen Anwendungsgebiete beschrieben. Für seltene Krankheiten sind häufig keine oder kaum zugelassene Therapiealternativen verfügbar. Die Kosten für eine Off-Label Verordnung werden von der Gesetzlichen Krankenversicherung (GKV) nur unter bestimmten, gesetzlich geregelten Voraussetzungen übernommen. Um Regressforderungen durch die Kostenträger zu vermeiden, kann vor Verordnung ein Antrag auf Kostenübernahme ('Off-Label Antrag') gestellt werden.

Patienten und Methoden

Es wurde eine retrospektive Auswertung von Off-Label Anträgen, die im Zeitraum 2010-2012 in zwei Sprechstunden einer dermatologischen Hochschulambulanz gestellt wurden, durchgeführt (Autoimmun-Sprechstunde, Urtikaria-Sprechstunde). Krankenkassen, Bewilligungsraten, Gründe für Ablehnungen und die Bearbeitungsdauer wurden ausgewertet.

Ergebnisse

Die Auswertung ergab, dass 56,8 % der eingeschlossenen Off-Label Anträge (n = 44) initial bewilligt wurden. Nach bis zu zweimaligem Widerspruch gegen die Ablehnung einer Kostenübernahme betrug die Bewilligungsrate insgesamt 75 %. Die Dauer zwischen Antragstellung und Bescheid durch die Kostenträger betrug 49 Tage (Median). Bei positivem Bescheid erfolgte die Therapieeinleitung 92 Tage (Median) nach Antragstellung.

Schlussfolgerungen

Die vorliegende Fallserie zeigt, dass die Kostenträger den beantragten Kostenübernahmen für Off-Label Therapien im überwiegenden Teil der betrachteten Fälle zustimmten. Ob die identifizierten Probleme durch die gegenwärtigen Veränderungen der gesetzlichen Rahmenbedingungen (GKV-Versorgungsstrukturgesetz, Patientenrechtegesetz) adäquat adressiert werden, sollte in einer prospektiven Studie untersucht werden.

Dr. Kurt und Eva Herrmann-Stipendium in Höhe von 10.000 Euro für junge Dermatologinnen/Dermatologen

Rasche Entwicklung bilateraler Nekrosen der oberen Extremität

Sweet-Syndrom: Revision der diagnostischen Kriterien

Zusammenfassung

Die Diagnose des Sweet-Syndroms (SS) gründet sich auf eine Reihe von Kriterien, von denen mindestens zwei Haupt- und zwei Nebenkriterien erfüllt sein müssen. In einigen Fällen ist die Diagnose aufgrund des Fehlens bestimmter Kriterien jedoch nicht so einfach. Ziel der vorliegenden Studie war es, die klinischen, histopathologischen und Labormerkmale der aktuellen Diagnosekriterien für das SS zu überprüfen und ihre Aussagekraft anhand der publizierten Fälle sowie bei 40 in unserem Institut behandelten Patienten zu beurteilen. Unsere umfassende Prüfung der aktuellen Kriterien für das SS ergab, dass seit seiner Erstbeschreibung im Jahr 1964 die beiden Hauptkriterien bei allen Fällen – einschließlich unserer – durchweg vorhanden waren. Andererseits gab es hinsichtlich der Nebenkriterien deutliche Unterschiede zwischen den verschiedenen Studien und bei vielen Patienten war die Bedingung, dass zwei Nebenkriterien vorhanden sein müssen, nicht erfüllt. Wir schlagen hier zwei Gruppen von revidierten Diagnosekriterien für das SS vor. Dies geschieht mit dem Ziel, die Diagnose zu vereinfachen, Fehldiagnosen zu vermeiden und eine sofortige Behandlung zu ermöglichen. Die erste Gruppe umfasst konstante klinische und histopathologische Merkmale, die vorhanden sein müssen und die per se für die Diagnose eines SS ausreichen. Die zweite Gruppe enthält veränderliche Merkmale, deren Fehlen es nicht erlaubt, ein SS auszuschließen.

Penile ulcer in a 58-year-old HIV-positive patient after local injection of methamphetamine (crystal meth)

Kongresskalender 2017

Genitales Ulkus am Penis eines 58-jährigen HIV-positiven Patienten nach lokaler Injektion von Methamphetamin (Crystal Meth)

Quality of life assessment in patients with nonmelanoma skin cancer – psychometric validation of the EORTC QLQ-C30 questionnaire

Summary

Background

Nonmelanoma skin cancer (NMSC) is a chronic and sometimes difficult-to-treat condition affecting the quality of life (QL). The present study was conducted to investigate whether the European Organization for Research and Treatment of Cancer (EORTC) core QL Questionnaire – Cancer (QLQ-C30) is a suitable tool for the assessment of QL in patients with NMSC.

Patients and methods

In order to define the psychometric properties of the questionnaire, the QLQ-C30 and the Dermatology Life Quality Index (DLQI) were handed out to 172 patients of the Department of Dermatology at the University Hospital Regensburg, Germany.

Results

Internal consistencies of all multi-item scales (except one) were acceptable, with Cronbach's alpha ranging from 0.71 to 0.93. The hypothesized scale structure was supported by item/scale and interscale correlations within the QLQ-C30. Related scales of the QLQ-C30 and the DLQI correlated significantly, thus establishing construct validity. At the same time, the proportion of substantial correlations (6 % ≥ 0.40) indicated that the two questionnaires assessed distinct components of QL. The QLQ-C30 significantly differentiated between clinically distinct patient groups, indicating that severe clinical conditions were associated with greater impairment in physical, role, and cognitive functioning (p ≤ 0.030).

Conclusions

These results confirm the QLQ-C30 to be a suitable tool for the assessment of QL in patients with NMSC.

Wege zum Verständnis neutrophiler Dermatosen

Beurteilung der Lebensqualität bei Patienten mit nicht-melanozytärem Hautkrebs – psychometrische Validierung des EORTC QLQ-C30-Fragebogens

Zusammenfassung

Hintergrund

Nicht-melanozytärer Hautkrebs (NMSC, nonmelanoma skin cancer) ist eine chronische und mitunter schwierig zu behandelnde Erkrankung, die die Lebensqualität (LQ) beeinträchtigt. Die vorliegende Studie wurde durchgeführt um zu prüfen, ob der Kernfragebogen Quality of Life Questionnaire - Cancer (QLQ-C30) der European Organization for Research and Treatment of Cancer (EORTC) ein geeignetes Instrument für die Beurteilung der LQ bei NMSC-Patienten ist.

Patienten und Methoden

Zur Bestimmung der psychometrischen Eigenschaften des Fragebogens wurden der QLQ-C30 und der Dermatology Life Quality Index (DLQI) an 172 Patienten der Klinik und Poliklinik für Dermatologie des Universitätsklinikums Regensburg, Deutschland, ausgegeben.

Ergebnisse

Die interne Konsistenz aller Multi-Item-Skalen (außer einer) war akzeptabel, wobei Cronbachs Alpha-Koeffizient zwischen 0,71 bis 0,93 lag. Die angenommene Skalenstruktur wurde durch Korrelationen zwischen Items und Skalen sowie Korrelationen zwischen Skalen innerhalb des QLQ-C30 bestätigt. Verwandte Skalen des QLQ-C30 und des DLQI korrelierten signifikant und belegten damit die Konstruktvalidität. Gleichzeitig wies der Anteil substanzieller Korrelationen (6 % ≥ 0,40) darauf hin, dass mit den beiden Fragebogen unterschiedliche Aspekte der LQ beurteilt werden. Der QLQ-C30 differenzierte signifikant zwischen Patienten mit verschiedenen Erkrankungsgraden. Eine schwere Erkrankung ging mit stärkeren Beeinträchtigungen der Körperlichen, Rollen- und Kognitiven Funktion einher (p ≤ 0,030).

Schlussfolgerungen

Diese Ergebnisse bestätigen, dass der QLQ-C30 ein geeignetes Instrument für die Beurteilung der LQ bei NMSC-Patienten darstellt.

Kopfhautnekrose an Stirn und Schläfe

Flächige Hyperpigmentierungen im Gesicht einer philippinischen Patientin

EXTH-15. RADIATION-INDUCED LATE MALIGNANT MENINGIOMA TRANSFORMATION: CDK 4/6 INHIBITOR THERAPY

Abstract

Meningiomas are the most common primary brain tumor reported in the United States each year and account for approximately 30% of primary neoplasms. Though in most cases the etiology of meningiomas is unclear, prior exposure to radiation is responsible for a subset of meningiomas. Some have speculated that there may be a relationship between pretreatment characteristics and radiotherapy parameters in the development of radiation-induced meningiomas (RIM). Compared with their sporadic counterparts, currently, the clinical treatment involves is similar with radiation used as a first line therapy. Novel therapeutic agents being investigated in the treatment of these tumors, rely on the direct or cell cycle-mediated induction of DNA damage to promote cellular apoptosis. Our pre-clinical data showed that disruption of p16INK4a-Cdk4-Rb (retinoblastoma) pathways plays a significant role in the development of RIM in Rb+ low-gradelow-grade meningioma cells. These observations highlight the critical role of the p16INK4a-Cdk4-Rb pathway in RIM and suggest that targeting this pathway might be a promising strategy to improve the therapeutic efficacy among RIM patients. Pretreatment characteristics and radiotherapy parameters which may influence the time interval for development of radiation-induced Rb+ meningiomas (RIM) were identified. Our results also demonstrated that CDK 4/6 Inhibitor, significantly suppresses radiation induced malignant transformation and prolonged survival in a cell-free, slice culture model and xenograft model of meningioma. Success of the proposed therapeutic strategies in both in vitro and in vivo models may form the basis for future research.

ACTR-02. DCC-2618, A NOVEL pan-KIT AND PDGFRa KINASE SWITCH CONTROL INHIBITOR, SHOWS ENCOURAGING SIGNAL IN A PATIENT (PT) WITH GLIOBLASTOMA (GBM)

Abstract

BACKGROUND

Non-clinical data suggest that PDGFRa plays an important role in the development and progression of human gliomas. To date, few PDGFRa inhibitors with CNS activity have been available. DCC-2618 was designed to potently inhibit the broadest range of mutations (mut) in KIT & PDGFRa kinases that emerge during tumor progession or on treatment.

METHODS

In a dose-escalation study (NCT# 02571036) of oral DCC-2618 (QD or BID q28 days), pts with advanced malignancies with a molecular rationale for activity were eligible. MRI scans were performed initially every 2 cycles then every 3 cycles.

RESULTS

We enrolled 4 GBM pts and 1 anaplastic astrocytoma (AA) pt with PDGFRa muts/ amplifications who had progressed after standard temozolomide chemoradiation (GBM) or temozolomide only (AA) and had received 0 to 5 salvage therapies. Three pts (2 GBM and 1 AA) had a triple amplification of PDGFRa, KIT and KDR (4q12 amplicon). Two GBM pts had activating PDGFRa mutations. Pts were treated at 20 mg (1 pt), 50 mg BID (2 pts) or 100 mg QD (2 pts). The per-protocol population (N=48) received doses up to 200 mg BID and DCC-2618 was well tolerated. One GBM pt with mut PDGFRa progressed after 6 weeks and one stopped treatment due to a tumor-related hemaorrhage on C1D12. Two of the three pts with triple amplifications progressed after 2 cycles while the third pt (GBM, 20 mg BID) achieved a PR per RANO after 9 cycles. This pt is currently in cycle 20 with a remarkable 94% tumor reduction.

CONCLUSIONS

The durable partial response of >18 months in a GBM patient (94% tumor reduction) warrants further evaluation of DCC-2618 in gliomas. An expansion cohort for pts with KIT- and PDGFRa driven tumors was initiated to be able to better select the patient population with a likely benefit.

SCDT-20. NEW THERAPEUTIC APPROACH FOR BRAINSTEM GLIOMA: INTRANASAL DELIVERY OF NANOLIPOSOMAL SN-38

Abstract

INTRODUCTION

Children with diffuse intrinsic pontine gliomas (DIPGs) die within 2 years after initial diagnosis. The infiltrative nature and anatomic location of DIPGs in an eloquent area of the brain preclude surgical resection, and the blood-brain barrier (BBB) reduces the availability of systemically administered agents. In order to improve outcomes for patients with DIPG, new drug delivery approach circumventing the BBB are greatly needed. Intranasal delivery (IND) is a practical, noninvasive method to deliver therapeutic agents into the brain along with the olfactory and trigeminal nerves pathway. With the advantages of reducing systemic side effects and convenient self-administration for patients, IND is an alternative to systemic (intravenous) and/ or direct invasive (intraparechymal) drug delivery.

METHODS

Two human DIPG cell lines were treated with hydrophobic fluorophore (DiI)-labeled nanoparticle liposomes containing CPT-11 (nanoliposomal CPT-11) and SN-38. Cell viability was determined by MTS assay and intracellular localization was imaged by confocal microscopy. For in vivo study, mice bearing human brainstem gliomas were randomly assigned to 3 groups: 1. empty nanoliposomes, 2. nanoliposomal CPT-11, 3. nanoliposomal SN-38, administrating by IND for 3 weeks. In vivo distribution was determined by DiI-labeled nanoliposomal SN-38 into the tumor bearing mice. Tumor growth and response to therapy were quantitatively measured by bioluminescence imaging, and efficacy was assessed by survival analysis.

RESULTS

DiI-fluorescence were detected at 30 minutes and peaked at 24 hours following treatment with DiI nanoliposomal SN-38. Nanoliposomal SN-38 induced dose dependent inhibition of the growth of DIPG cells, that is greater inhibition than nanoliposomal CPT-11. IND of nanoliposomal SN-38 showed significant reduction of the growth rate in compared to IND of empty nanoliposome. Results from animal survival will be reported at the meeting.

ACTR-03. INDUCING FACTORS OF MALIGNANT RECURRENCE IN LOW-GRADE GLIOMA

Abstract

Low-grade glioma patients have relatively long life expectancy for gliomas, but once they recur in malign, their prognosis can be poor. We analyzed factors corresponding to malignant recurrence by uni- and multi-variate analysis applying their treatment backgrounds. SUBJECTS: 261 newly diagnosed WHO grade 2 adults gliomas in 2004 to 2014. Malignant recurrence was determined by pathological diagnosis if the patient had a surgery (69% of the recurrent patients), otherwise contrast T1WI or 11C- methionine PET images if the patient was unable to undergo any surgery or biopsy.

RESULTS

Age average 41 years old, the 10-year survival rate in all patients was 75%, and the mean of progression-free survival time was 7.8 years. Relapse event occurred in 115 cases (44%), and 67 % of them developed malignant glioma sometime. The 10-year survival rate for the patients who relapsed in malign was 37%, on the contrary, the patients who had recurrence but staying in low grade was 71% (p=0.0389). When they were categorized by 1p19q deletion and IDH1 mutation status, IDH wild type diffuse astrocytoma patients had significantly developed malignant glioma compared to oligodendroglioma and IDH mutant type diffuse astrocytoma (p<0.0001). The factors related to malignant progression were extracted as; recurrence in 2 years, 6% and over in MIB-1 index, no intervention longer than 18 months since the disease revealed, 1p19q non-co-deletion, less than 90% of tumor resection rate, and IDH wild type. In the 1p19q non-deletion patients, who were provisionally defined as diffuse astrocytoma patients here, the factors were resection rate, MIB-1 index, and duration between discovered the disease and the first surgery, but not the IDH mutant status (p＜0.0001, p=0.0015, p=0.0478 respectively).

CONCLUSION

Recurrence in malign form low-grade glioma can be avoided by early intervention in 18 months from diagnosis and resection over 90% of volume of the tumor.

SURG-28. KYPHO-IORT: A NEW TREATMENT PARADIGM FOR PATHOLOGICAL FRACTURES

Abstract

OBJECTIVE

This is a prospective single institution study to assess the safety and efficacy of Kypho-intraoperative radiation therapy (Kypho-IORT) for potentially mechanically unstable metastatic disease to the spine in reducing pain.

METHODS

Patients with symptomatic osteolytic vertebral body metastasis underwent Kypho-IORT: kyphoplasty procedures and intraoperative radiotherapy with the ZEISS INTRABEAM System followed by cement augmentation. Tumors were limited to vertebral body using the International Spine Radiosurgery Consortium (ISRC) anatomic classification system, SINS scores of 7-12 (potentially unstable), and Bilsky grade 0. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR delineation were done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to a distance from the source tip to the distal boundary. The prescription was limited by a maximum dose limit to the spinal cord of 12 Gy. Preoperative and postoperative pain scores were assessed with the numerical rating pain scale (NRPS). The involved spine will be imaged at 3-month intervals up to one year.

RESULTS

7 vertebral levels were treated. All patients were discharged home within 12 hours of the Kypho-IORT procedure. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57 ± 2.82 preoperative versus 4.00 ± 2.16 postoperatively; p=0.0349). After 3 months, one patient with metastatic rectal cancer suffered local progression. No patients experience neurological deterioration postoperatively.

CONCLUSIONS

Kypho-IORT is a safe treatment option for potentially unstable spinal metastases. Patient reported pain scores significantly improve within two weeks, enhancing the patient's quality of life. Long-term follow up is necessary to further evaluate efficacy.

ACTR-44. AUTOPSY STUDY ON THE EFFECTS OF TUMOR TREATMENT FIELDS IN RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS AND TRIAL DESIGN

Abstract

BACKGROUND

Optune therapy with tumor treatment fields (TTFields) is approved for the treatment of recurrent glioblastoma due to a recent clinical trial that showed better quality of life and comparable overall survival to conventional therapy. In the newly diagnosed setting, the addition of TTFields to standard therapy consisting of surgery, radiation and temozolomide has also been shown to prolong tumor progression and improve overall survival. TTFields are low-intensity, alternating frequency electric fields that have been shown to disrupt cell division and subsequently tumor growth. Apoptosis and cell cycle arrest have been seen in vitro, and shown in mice and rabbit tumor models. Though preclinical studies are ongoing, glioblastoma patients who have undergone TTFields therapy have not yet been assessed at autopsy to determine both the pathological signature of TTFields therapy, and the pattern of failure.

METHODS

Whole brain samples were acquired and analyzed pathologically from two recurrent GBM patients at autopsy. One patient served as a control and one considered a test patient who had undergone TTFields therapy. Tissue samples were acquired from regions suspicious of tumor and treatment effects. Samples were paraffin embedded and hematoxylin and eosin (H&E) stained, and pathologically reviewed by a board certified pathologist. Samples were then compared.

RESULTS

The patient who underwent TTFields therapy showed regions of necrosis and increased cellular debris compared to the control patient who had pseudo-palisading and radiation necrosis.

CONCLUSION

These findings suggest there is increased apoptosis in patients treated with TTFields compared to those on chemoradiation alone. Recruitment is ongoing for expansion of this study to include 10 patients treated with TTFields at recurrence and 10 at treated at initial diagnosis. Patients will be recruited from brain donation. Pathology will be compared to control patients naïve of TTFields therapy.

CMET-47. PRECLINICAL VALIDATION OF NOVEL THERAPEUTICS TARGETING A BMIC POPULATION IN HUMAN BRAIN METASTASES

Abstract

Brain Metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring at a rate 10 times greater than that of primary brain cancers. Despite the prevalence and severe lethality of BM, therapeutic strategies remain limited. Advancements in in vivo modelling of metastasis presents a useful platform to aid in the advance and screening of novel targeting therapeutics, though currently few models exist that properly recapitulate the clinical progression of brain metastasis. Utilizing primary patient samples of BMs, we have characterized a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. Through injections of BMICs isolated from lung BMs into NOD-SCID mice, we have generated a novel patient-derived xeno-transplantation (PDXT) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain. We then expanded our model to incorporate BMICs derived from breast and melanoma BMs. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify metastatic and tissue-specific gene signatures. BMICs were found to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases, exhibiting dysregulated expression in over 13,000 genes, including those involved in stem cell, epithelial-to-mesenchymal transition, and quiescence properties. In silico analysis was used to generate a list of therapeutics targeting this unique BMIC population. In vitro and in vivo screening has identified a subset of compounds with no previously known efficacy in cancer treatment that inhibits BMIC growth and metastasis. Ultimately, we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

ACTR-45. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM)

Abstract

Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ -- an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma preclinical activity -- is being evaluated in ndGBM patients (NCT02903069). The phase 1 study (MRZ at 0.55, 0.7, 0.8, 1.0, and 1.2 mg/m²) is accruing in separate concomitant (MRZ+TMZ+RT) and adjuvant (MRZ+RT) treatment cohorts (3 + 3 design), followed by dose-expansion at the recommended phase 2 dose in concomitant followed by adjuvant treatment cohorts. Concomitant treatment (42 days (D)): MRZ (10 min IV infusion) D1, 8, 15, 29, 36; RT total dose 60 Gy; TMZ (75 mg/m², PO QD). Adjuvant treatment (28D-cycle): MRZ D1, 8, 15; TMZ (150–200 mg/m², PO QDX5). Tumor response (RANO criteria) measured at beginning and end of concomitant treatment, and every other cycle during adjuvant treatment; MRZ and TMZ PK in concomitant treatment D1-2, 8–9. Mean age 55 yrs (60% male) for 20 patients in 14Apr2017 interim analysis (cohorts 1–3 have completed accrual in concomitant treatment, cohorts 1 and 2 have completed accrual and 2 patients are enrolled in adjuvant cohort 3); one DLT (fatigue) in the 0.7 mg/m² adjuvant cohort. Most common treatment-related AEs (≥4 pts): fatigue, nausea, vomiting, decreased appetite, dizziness, hallucination; three Grade 3 SAEs (fatigue, hallucination, vomiting; all MRZ-related); two Grade 2 SAEs (nausea, confusional state, MRZ-related). Seventeen of the 20 patients included in this interim analysis remain on study: 7 of 9 concomitant patients are continuing in adjuvant treatment (longest beginning adjuvant cycle 7); of 11 adjuvant pts, two beginning cycle 9. The study is ongoing at 1.0 mg/m² for both concomitant and adjuvant dose-escalation cohorts. Together the data demonstrate that the combination of MRZ with standard of care in ndGBM is well tolerated and may provide novel therapeutic benefit in this unmet need.

STEM-11. A MAPK-DRIVEN miR-124-SOX9 AXIS IS CRITICAL FOR STEM CELL MAINTENANCE, PROGRESSION, AND THERAPY-RESISTANCE IN GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. Genetic alterations in growth factor signaling pathways are found in 90% of GBMs. Advances in developmental and glioma biology suggest that common down-stream effector molecules in growth factor signaling pathways are critical for stem cell maintenance in the normal brain and GBM cells. It remains unclear whether differentiation therapies will be of therapeutic value for GBM patients. Here, we demonstrate that constitutive mitogen activated protein kinase (MAPK) activation in stem cells drives GBM formation and blocks neurogenesis in mice. Pharmacological inhibition of MAPK signaling restored neurogenesis in vivo and induced neuronal differentiation in GBM tumorspheres cultures established from murine GBMs and patient-derived tumors. Inhibition of MAPK signaling depleted SOX9 protein expression, and to a lesser extent SOX9 mRNA levels, in GBM cells. MicroRNA profiling experiments demonstrated that MAPK signaling regulates genome-wide expression of miRNAs, including the neuronal determinant miR-124. Pharmacological inhibition of MAPK signaling increased miR-124 levels in SOX9-expressing GBMs, but not SOX10-expressing proneural tumors. Using a doxycycline-inducible approach in vitro and in vivo, we demonstrated that miR-124 overexpression blocks SOX9 expression and induces neuronal differentiation in an EGFRvIII-driven GBM model and patient-derived xenografts. Neuronal differentiation resulted in apoptosis, reduced DNA repair capacity, and radiosensitized GBM cells. Doxycycline-mediated miR-124 overexpression resulted in complete regression for 1/3 of patient-derived xenografts. Mechanistic studies showed that SOX9 was a direct target of miR-124 and a major regulator of stem cell maintenance in GBM. Preliminary data showed that MAPK activation regulates transcriptional networks in SOX10-expressing proneural glioma, suggesting that distinct miRNAs regulate glioma aggressiveness in a subtype-specific manner. In conclusion, our results provide a mechanistic explanation for MAPK-dependent expansion of the stem cell pool during GBM initiation and demonstrate that enforcing neuronal differentiation represents a viable therapeutic strategy in glioma.

ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION

Abstract

INTRODUCTION

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population.

METHODS

Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0–1, no surgery/radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum.

RESULTS

As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1–2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3–4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4–25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented.

CONCLUSIONS

AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.

TMOD-04. A COMPREHENSIVE GENOMIC LANDSCAPE OF GLIOMA SPHEROID CULTURES RECAPITULATES THE HETEROGENEITY OF GLIOBLASTOMA AND IDENTIFIES DNA METHYLATION PREDICTORS OF RADIOTHERAPY RESPONSE

Abstract

Glioma sphere-forming cells (GSCs) are important in glioblastoma (GBM) initiation, maintenance, and treatment resistance. We performed whole exome and transcriptome sequencing, DNA methylation profiling, DNA copy number determination, and functional characterization of 43 GSCs and matching tumors. Comparative analyses revealed that GSCs recapitulate the molecular landscape of GBM and provide a unique means for discovering the inter- and intra-tumor heterogeneity of GBM. We performed clonogenic assays to explore the relationship between methylation status and radiation response in twelve IDH wild type GSCs irradiated with 2-, 4-, and 6-Gy ionizing radiation. The survival fraction at 4Gy and 6Gy (SF4 and SF6, respectively) were used to dichotomize GSCs as either radiation-sensitive or resistant. DNA CpG methylomes of the GSCs were profiled using Infinium 450K methylation beadchip arrays. We observed that 304,458 out of 465,844 methylation probes (65.4%) showed increased methylation in radiation-resistant relative to radiation-sensitive GSCs (Fisher's Exact Test, p < 1e-15). Using GSEA, we observed that fifteen of sixteen oxidative stress genes were methylated in radiation-resistant GSCs (p-value=0.019), suggesting an association between radiation-resistance and reactive oxygen species metabolism (ROS). To validate our finding, we derived a methylation signature differentiating the two GSC radiation response groups and used this to classify TCGA cases that received radiotherapy into a responder and non-responder group. We found that survival was significantly different between the two groups (median survival 84 vs. 61 weeks; HR 1.64 adjusting for patient age, p-value<0.008), suggesting that the methylation signature predicts clinical response to radiation treatment. This study identified a novel predictor of radiation response and confirms that the genomic landscape of GSCs can be used to determine clinical and functional properties of GBM.

GENE-36. ACCURATE DETECTION OF TERT PROMOTER MUTATION IN GLIOMAS USING INFINIUM DNA METHYLATION ARRAYS IDENTIFIES NOVEL EPIGENETIC ASSOCIATION

Abstract

The telomere reverse transcriptase promoter (TERTp) is frequently mutated in malignant gliomas, particularly glioblastomas (GBM, 85%), and is involved in maintaining telomere length. TERTp mutations are prognostic for patient survival. Given the evolving use of Infinium DNA methylation arrays in assaying biomarkers in glioma, we aimed to develop an accurate predictor of TERTp mutations in gliomas using this platform. We analyzed TCGA lower grade glioma (LGG) and GBM available with both TERTp sequencing and Infinium 450k data. Samples were split into training and testing set to determine predictor accuracy. Probes with potential quality issues were excluded and probe selection performed using an elastic net algorithm. Probes were selected across the genome, not limited to the TERTp locus. A logistic regression model with binomial distribution was built using the final optimized model, constructed based on 1000 CpG probes, all distinct from TERTp. Prediction accuracy was 100% (179/179, AUC=1) in the training set and 97.5% (116/119) in the test set. Comparison of the normalized frequency of selected probes by chromosome revealed enrichment for chromosomes 20 (0.4987%) and 18 (0.4859%). The majority of probes enriched in CpG islands (53.6%), followed by open sea (22.9%), shore (17.4%), and shelf (6.1%). Relative to known genes, probe enrichment occurred predominantly near transcriptional start sites (within 200–1500 bp, 31.0%), followed by gene bodies (26.3%) and intergenic regions (18.3%). Quite unexpectedly, probes within the predictor do not map near TERT or other telomere maintenance factors nor fell within known methylation signatures, such as G-CIMP, suggesting that TERTp mutation is associated with novel epigenetic changes. Moreover, this biomarker permits rapid and cost effective detection of TERTp mutation using the widely used Infinium platform.

CBIO-12. GTP METABOLIC SWITCH LEADS TO NUCLEOLAR TRANSFORMATION AND MALIGNANT GROWTH OF GLIOBLASTOMA

Abstract

Nucleolar mass is frequently increased in malignant cells, pointing to a prominent role for aberrant rRNA transcription in highly anabolic cells. ATP and GTP, fundamental energy currencies and building blocks for DNA and RNA, are synthesized by the energy-efficient salvage pathway and energy-demanding de novo pathway. While purine nucleotide biosynthesis is upregulated in malignant cancers, distinctive role(s) of de novo ATP and GTP biosynthesis in cancer cell proliferation remains elusive. Here, we show that the highly lethal brain cancer glioblastoma rewires purine metabolism to activate de novo GTP biosynthesis for rRNA transcription and nucleolar transformation, whereas de novo ATP biosynthesis is commonly utilized in glioblastoma and primary glial cells. Transcriptome screening followed by two cohort analyses identified upregulation of inosine monophosphate dehydrogenase-2 (IMPDH2) in glioblastoma patients. Pharmacological and genetic inhibition of IMPDH2 abolished de novo GTP biosynthesis and growth of glioblastoma cells in vitro and in vivo without affecting de novo ATP biosynthesis. This GTP metabolic switch in glioblastoma cells is critical for enhanced RNA Pol I-dependent nucleolar transcription, but not for RNA Pol II and Pol III transcription. Increased IMPDH2 expression correlates with enlarged nucleoli in human glioma patients, and inhibition of IMPDH2 leads to decreased nucleolar mass. Abnormal nucleolar morphology in many cancer types has long been recognized by pathologists and de novo purine biosynthesis was discovered in 1885. Our data connect these dots of long observed features in cancer by demonstrating a glioblastoma-specific shift in glucose flux to increase de novo GTP biosynthesis, which is required for enhanced ribosome biosynthesis and growth of tumor cells. Our results propose new strategies for the detection and treatment of the incurable glioblastoma, and perhaps other tumors, with minimum impact on normal tissues.

GENE-37. PATHWAY ANALYSIS OF RADIATION-INDUCED MENINGIOMAS REVEALS THAT TUMOURS WITH NF2-FUSION HAVE UPREGULATION OF INFLAMMATORY PATHWAYS

Abstract

INTRODUCTION

As more pediatric cancer patients are surviving into adulthood from improved oncological therapy there is an increase in the long-term sequelae of treatment. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate significantly different biology than sporadic meningiomas (SMs) and demonstrate clinically more aggressive behaviour. RIMs have been shown to not harbor mutations in common SM associated driver genes, such as NF2, TRAF7, KLF4, PIK3CA and SMO; however, a subset of RIMs have genomic rearrangements with NF2 gene fused to a reciprocal gene, which was previously not seen in SMs. We aimed to compare and contrast the gene expression in RIMs with and without the NF2-fusion event.

METHODS

A primary cohort of 7 RIMs with NF2-fusion and 12 RIMs with wildtype NF2 had RNA sequencing performed using the Illumina HiSeq platform. RNA-Seq expression profiles were analyzed using edgeR, available through BioConductor. Gene Set Enrichment Analysis was performed using Cytoscape®.

RESULTS

Principle component analysis of the RNA-Seq data showed that 5/7 RIMs with NF2-fusion were similar to one another. One of the outliers was the only NF2-fusion RIM without a 1p chromosomal arm loss. Significant differentially expressed genes included IGF-1 (log2 of fold change or logFC = 4.14, p=2.65E-05), MME (logFC = 3.03, p = 3.56E-03) and MMP16(logFC = 2.47, p=8.14E-03). Notably, the pathway analysis demonstrated that there was an upregulation of immune/inflammation pathways involving PD-1, STAT-4, IGF-1 and other genes in RIMs with NF2-fusion compared to RIMs with NF2 wildtype.

CONCLUSION

RIMs with the NF2-fusion event have a distinct gene expression profile, with upregulation of inflammatory pathways. Further studies need to be performed to validate these findings using immunohistochemistry. These results suggest that NF2-fusion RIMs may be candidates for immunotherapy.

DDIS-15. SYNERGISTIC INHIBITION OF GLIOMA CELL PROLIFERATION BY WITHAFERIN A AND TUMOR TREATING FIELDS

Abstract

BACKGROUND

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain cancer. Standard therapies are non-specific and often of limited effectiveness; thus, efforts are underway to uncover novel, unorthodox therapies against GBM. In previous studies, we investigated Withaferin A, a steroidal lactone from Ayurvedic medicine that inhibits proliferation in cancers including GBM. Another novel approach, tumor treating fields (TTFields), is thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cells. We hypothesized that combining TTFields with Withaferin A would synergistically inhibit proliferation in glioblastoma.

METHODS

Human glioblastoma cells (GBM2, GBM39, U87-MG) and human breast adenocarcinoma cells (MDA-MB-231) were isolated from primary tumors. The glioma cell lines were genetically engineered to express firefly luciferase. Proliferative potential was assessed either by bioluminescence imaging or cell counting via hemocytometer.

RESULTS

TTFields (4 V/cm) significantly inhibited growth of the four cancer cell lines tested (n=3 experiments per time point, 4 measurements per sample, p<0.02 at least; 2-way ANOVA, control vs. treatment). The combination of Withaferin A (10–100 nM) with TTFields significantly inhibited the growth of the glioma cells to a degree beyond that of Withaferin A or TTFields alone. The interaction of the Withaferin A and TTFields on glioma cells was found to be synergistic in nature (p<0.01, n=3 experiments). These findings were validated by both bioluminescence and hemocytometric measurements.

CONCLUSIONS

The combination of Withaferin A with TTFields represents a novel approach to treat GBM in a manner that is likely better than either treatment alone and that is synergistic.

GENE-38. DISRUPTED ENDOTHELIAL CELL GENE EXPRESSION PROFILE PREDICTS GBM CLINICAL RESPONSE TO ANTI-ANGIOGENIC THERAPY

Abstract

Glioblastoma (GBM) is one of the most aggressive adult brain tumors, with the histopathologic hallmark of increased abnormal vasculature. While anti-angiogenesis therapy had shown value in pre-clinical and early clinical studies, in particular targeting vascular endothelial growth factor (VEGF), the durability of response to anti-angiogenic therapy varies and hence efficacy remains a limitation. There is data to suggest that certain subtypes of GBM however have a more effective response to anti-angiogenic therapy. Therefore, there is a need to identify prognostic markers that can determine the subpopulation of GBM patients that response to AA therapy. We established five genetic expression profiles (group A~E) by stimulating endothelial cells (ECs) with different combinations of ionizing radiation (IR) and mesenchymal stem cells (MSCs) before performing angiogenesis array analysis. Bioinformatics analysis of Group A~E identified the combination of HGF and CXCL10 alterations as the differentiators that separated the AVAglio patients into 3 groups (group 1~3). We found that GBM patients with high HGF and low CXCL10 levels had the worst clinical response to AA therapy. Further qPCR analysis of gene expression levels among different cell types revealed that GBM cells have the highest expression of HGF and the lowest expression of CXCL10 relative to ECs. Similar trend were detected in MSCs relative to ECs but to a lesser degree. Thus we propose that such genetic parameter in GBM could potentially be a prognostic marker for AA therapy.

ACTR-42. INITIAL EXPERIENCE OF BLOOD-BRAIN BARRIER OPENING FOR CHEMOTHERAPEUTIC-DRUG DELIVERY TO BRAIN TUMOURS BY MR-GUIDED FOCUSED ULTRASOUND

Abstract

INTRODUCTION

Magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly open the blood-brain barrier (BBB) for targeted drug delivery. Animal models have shown the feasibility of BBB opening for delivery of a broad range of compounds. We describe the first experience of focused ultrasound mediated BBB opening in malignant brain tumours.

METHODS

This phase-one clinical trial was approved by Health Canada and our Research Ethics Board. A modified clinical MRgFUS brain system was used with a 3T MR scanner. Prior to BBB opening patients received a single dose of IV liposomal doxorubicin (N=1) or temozolomide (N=2). Patients were positioned in the FUS array with a stereotactic frame. Two targets close to the posterior margin of the tumor were chosen based on T2 images. A bolus injection of Definity microbubbles was applied simultaneously with each sonication. Post sonication, Gd-enhanced images were acquired to verify BBB openings, and T2*-weighted GRE images were collected to detect hemorrhage.

RESULTS

All patients tolerated FUS procedures and BBB opening well, with no adverse events. T2* images demonstrated a small degree of RBC extravasation, with no overt hemorrhage on standard T1, no edema on T2 or DWI changes on treatment or follow-up scans. BBB was successfully opened in all patients at each targeted location, with clear Gd enhancement. All patients underwent safe maximal surgical resection at 24 hours post-sonication.

DISCUSSION

Our initial experience of FUS-mediated BBB opening in high-grade glioma demonstrates the safety and feasibility of this emerging adjuvant modality. We were able to open the BBB, as demonstrated with Gd enhancement, in several discrete brain regions surrounding the tumour, without adverse events. Patients tolerated the procedure well. Next steps will include sonication of larger tumour volumes, done in conjunction with standard of care prescriptions of chemotherapeutic agents, for which the BBB is a major challenge.

GENE-39. UNANTICIPATED GERMLINE CANCER SUSCEPTIBILITY MUTATIONS IDENTIFIED DURING ROUTINE NEXT GENERATION SEQUENCING OF PRIMARY CNS NEOPLASMS

Abstract

INTRODUCTION

Tumor genomic profiling is routinely performed on primary brain tumors to identify somatic mutations. Such testing may also identify clinically significant germline mutations. Several syndromes (neurofibromatosis, Li Fraumeni, Von Hippel Lindau and Turcot) are well known causes of primary CNS neoplasms but there is limited data on other germline cancer susceptibility mutations in CNS tumor patients. After a somatic mutation was unexpectedly found to be germline, we interrogated our database of somatic CNS tumor mutations.

METHODS

This IRB approved retrospective study reviewed patients at the Texas Oncology-Austin Brain Tumor Center from May 2013 through April 2017. Tumors underwent genomic profiling using a commercially available test which evaluates 315 genes using next generation sequencing. Patients' whose tumors carried a mutation which was concerning for a germline variant were tested further.

RESULTS

Tumor genomic profiling was performed on 291 CNS tumor patients. Five patients were found to carry unexpected germline variants (1.7%). Two patients had glioblastoma: 1 BRCA2 pathogenic mutation, 1 MLH1 variant of uncertain significance; 2 anaplastic astrocytomas: 1 BRCA2 pathogenic mutation, 1 with pathogenic APC and ATM mutations; 1 atypical meningioma: 1 BRCA2 pathogenic mutation. Median age was 42.2 (range 33–53). As a result of the incidental findings, medical management was altered and testing of numerous family members was recommended. Complete tumor genomic profiles, pedigrees, and additional pending germline testing will be presented.

CONCLUSIONS

In this series of primary brain tumor patients whose tumors were sequenced, unexpected germline variants were identified in the genes: BRCA2, MLH1, APC and ATM for an incidence of at least 1.7%. These results had life-saving implications for these patients and their families. This data is reasonably extrapolated to the brain tumor population at large and warrants further scrutiny of systematic approaches for identifying patients as candidates for germline testing based on tumor genomic profiling.

STEM-41. A SUBSET OF GBM BRAIN TUMOR STEM CELL LINES ARE UNIQUELY DEPENDENT ON GLUTAMINE METABOLISM FOR AMINO ACID SYNTHESIS

Abstract

Glioblastoma multiforme (GBM) is the most aggressive adult primary brain tumor. Despite a treatment regimen involving surgical resection, chemotherapy, and radiation, GBM patients have a median survival of approximately 15 months. This poor outcome highlights the need for improved therapeutic approaches for GBM patients. A subpopulation of cells that exhibit stem cell properties, termed brain tumor stem cells (BTSCs), are hypothesized to be the source of recurrence and resistance due to their inherent ability to resist treatment, invade into normal tissue, and re-populate a tumor. We have recently found that a subset of BTSC lines are uniquely dependent on glutamine metabolism for survival and maintenance of their stem cell properties. This dependence on glutamine differs from the more conventional view that cancer cells rely on increased glucose metabolism. Inhibiting glutamine metabolism in the sensitive subset of BTSC lines, by targeting the enzyme glutaminase (GLS) that deaminates glutamine to produce glutamate, results in decreased growth, viability, and self-renewal. We have found that inhibition of GLS decreases intracellular glutamate levels and leads to amino acid depletion. Replenishing the amino acid pool using bovine serum albumin rescues the decrease in BTSC growth following GLS inhibition. Intriguingly, the sensitive subset of BTSC lines have low expression of the glutamate transporter termed excitatory amino acid transporter 2 (EAAT2), limiting their glutamate uptake. We are exploring the relationship between reduced glutamate uptake and glutamine dependence; specifically, by asking whether GLS inhibition-resistant BTSC lines become glutamine-dependent after exposure to glutamate transport inhibitors. Taken together, our findings point to a unique dependence on glutamine metabolism for amino acid synthesis, in a subset of BTSC lines. Our long-term goal is to pursue this glutamine dependence as a novel therapeutic strategy to target the cells at the root of this aggressive and lethal disease.

GENE-40. CIRCULATING TUMOR DNA ANALYSIS IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA

Abstract

Extracellular tumor-derived DNA in body fluids (also known as circulating tumor DNA or ctDNA) is being widely studied for noninvasive tumor genotyping, tracking clonal evolution, monitoring treatment response and early detection of cancer. In patients with glioblastoma (GBM), ctDNA is more readily detectable in cerebrospinal fluid as compared to blood plasma. In literature, sensitivity for mutation detection in DNA from CSF is ~60% compared to ~10% in plasma DNA. However, CSF is difficult to sample and other body fluids need to be studied carefully. To develop new strategies for plasma ctDNA detection and increase tumor DNA shedding into plasma in patients with GBM, we sought to utilize body fluid samples form patient derived xenograft (PDX) models. In this context, any human DNA detectable in mouse plasma is derived from the tumor xenograft. Hence, we developed a human-specific multiplexed droplet digital PCR assay to detect and accurately quantify plasma ctDNA in PDX models derived from patients with GBM. This assay is composed of 8 paired primer/probe sets, fluorescently labeled, with careful design accounting for unique diploid amplification, variable regions, cross amplification between species, and most common genomic aberrations in GBM. We will share results demonstrating the analytical validity of the assay as well as utility in testing approaches for increasing ctDNA yield and shedding from GBM tumors.

Prevalence and clinicopathologic characteristics of multiple myeloma with cutaneous involvement: A case series from Korea

Publication date: Available online 6 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Yu Ri Woo, Jong Sic Kim, Ji Hong Lim, Sewon Hwang, Miri Kim, Jung Min Bae, Young Min Park, Chang-Ki Min, Dong-Wook Kim, Hyun Jeong Park
BackgroundMultiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood.ObjectiveThe aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement.MethodsThe medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings.ResultsPatients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction.LimitationsThe retrospective design and the small sample size are the limitations.ConclusionCutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival.

Depressive symptoms, depression, and the effect of biologic therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR)

Publication date: Available online 6 November 2017
Source:Journal of the American Academy of Dermatology
Author(s): Bruce Strober, Melinda Gooderham, Elke M.G.J. de Jong, Alexa B. Kimball, Richard G. Langley, Nikita Lakdawala, Kavitha Goyal, Fabio Lawson, Wayne Langholff, Lori Hopkins, Steve Fakharzadeh, Bhaskar Srivastava, Alan Menter
BackgroundPatients with psoriasis are at an increased risk for depression. However, the impact of treatment on this risk is unclear.ObjectiveEvaluate the incidence and impact of treatment on depression among patients with moderate-to-severe psoriasis.MethodsWe defined a study population within the Psoriasis Longitudinal Assessment and Registry and measured the incidence of depressive symptoms (Hospital Anxiety and Depression Scale–Depression score ≥8) and adverse events (AEs) of depression within cohorts receiving biologics, conventional systemic therapies, or phototherapy. Patients were evaluated at approximately 6-month intervals. Multivariate modeling determined the impact of treatment on risk.ResultsThe incidence rates of depressive symptoms were 3.01 per 100 patient-years (PYs) (95% confidence interval [CI], 2.73-3.32), 5.85 per 100 PYs (95% CI, 4.29-7.97), and 5.70 per 100 PYs (95% CI, 4.58-7.10) for biologics, phototherapy, and conventional therapy, respectively. Compared with conventional therapy, biologics reduced the risk for depressive symptoms (hazard ratio, 0.76; 95% CI, 0.59-0.98), whereas phototherapy did not (hazard ratio, 1.05; 95% CI, 0.71-1.54). The incidence rates for AEs of depression were 0.21 per 100 PYs (95% CI, 0.15-0.31) for biologics, 0.55 per 100 PYs (95% CI, 0.21-1.47) for phototherapy, and 0.14 per 100 PYs (95% CI, 0.03-0.55) for conventional therapy; the fact that there were too few events (37 AEs) precluded modeling.LimitationsIncomplete capture of depression and confounders in the patients on registry.ConclusionCompared with conventional therapy, biologics appear to be associated with a lower incidence of depressive symptoms among patients with psoriasis.

Pediatric severity of alopecia tool

Abstract

The Severity of Alopecia Tool serves as a tool for alopecia research and a clinical guideline for following progression of disease. The original Severity of Alopecia Tool score does not take into account pediatric age groups. As new clinical trials for alopecia areata include more children, a more accurate tool should be available for this population. By collecting images from patients 2-21 years of age and aligning the hair-bearing regions of the scalp, we created an adaptation of the Severity of Alopecia Tool for scoring hair loss percentage of the top, parietal, and occipital scalp in individuals 2-5, 6-11, and 12-21 years of age.

Wound culture isolated antibiograms and caregiver-reported skin care practices in children with epidermolysis bullosa

Abstract

Background/Objectives

Many patients with epidermolysis bullosa (EB) require intensive daily wound care and individualized treatment plans. Understanding patient's home skin care routines and emerging antibiotic resistance patterns in EB wounds is necessary to optimize treatment recommendations. The objective was to identify patterns of antimicrobial resistance in EB wounds and characterize patient's home practices of skin care and bathing.

Methods

This was an observational study of 23 children with EB at an outpatient pediatric dermatology practice in New York City from 2012 to 2014. Information on individual bathing and skin care practices and wound cultures was collected as part of routine examinations and an institutional review board–approved antibiogram protocol.

Results

Sixty wound cultures were collected from 23 patients. Eleven organisms were isolated, most commonly methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Streptococcus species, and Pseudomonas aeruginosa. Six patients (26%) were colonized with methicillin-resistant S. aureus. Over the course of the study, 13 patients (56%) were found to have mupirocin-resistant S. aureus. More than half of participants reported mupirocin or bacitracin use. Fewer than half indicated that they regularly used dilute bleach or dilute vinegar as part of their bathing routine.

Conclusion

Numerous organisms, including resistant bacteria, are known to colonize the wounds of individuals with EB. Mupirocin resistance was prevalent and more than half of the participants reported its use. Testing for mupirocin resistance may be considered for certain patients. These observations may help guide questions for future longitudinal multicenter studies with the goal of optimizing EB wound care recommendations.

Do body build and composition influence striae distensae occurrence and visibility in women?

Summary

Background

Striae have been reported to be one of the most common skin changes and a commonly encountered esthetic problem.

Objectives

To analyze risk factors of striae not associated with pregnancy and verify if body build and composition influence striae distensae (SD) occurrence and visibility.

Methods

Eighty female students (40 with striae (the mean age 23.9 years, SD 2.05 years) and 40 without these lesions (24.7 years, SD 6.2 years)) were included in the study. The subjects were asked to fill out a questionnaire including questions concerning risk factors of SD. Body build and composition were examined using Tanita SC-331S Body Composition Analyzer.

Results

Women without striae more often reported a history of intended weight loss (P < .0001), less frequently had a history of contraceptives intake (P < .001) and more often their family history of striae was negative or unknown (P = .01). Multivariate analysis including body build and composition parameters indicated BMI as risk factor of SD (P = .021; OR =1.155, 95% CI 1.006; 1.325).

Conclusions

History of contraceptives intake and a family history of striae are risk factors of SD occurrence, while weight loss can reduce the risk of these lesions. BMI appeared to be the risk factor of striae visibility, especially in abdomen, but not on the buttocks. Further clinical researches are needed to examine the pathophysiology of this condition and to inform patients about the possibility to reduce the risk of striae occurrence.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: Results of NRG Oncology RTOG 0913

Abstract

Background

This Phase II study was designed to determine the efficacy of the mTOR inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma.

Methods

Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities.

Results

A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced both a significant increase in Grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared to control (median PFS time: 8.2 vs. 10.2 months, respectively; p=0.79). OS for patients randomized to receive everolimus was inferior to the control patients (median survival time (MST): 16.5 vs. 21.2 months, respectively; p=0.008). A similar trend was observed in both 06-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylated and unmethylated tumors.

Conclusion

Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and did not improve PFS in patients with newly diagnosed glioblastoma. Although the MST in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Highly specific determination of IDH status using edited in vivo magnetic resonance spectroscopy

Abstract

Background

Mutations in the isocitrate dehydrogenase (IDH) enzyme affects 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG), and to compare performance of these methods with DNA sequencing and tissue 2HG analysis.

Methods

Twenty-four subjects with suspected diagnosis of low grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3 T using two MRS methods, edited MRS using MEGA-PRESS sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by combination of automated immunohistochemical analysis (IHC) and Sanger sequencing. 2HG levels in tissue samples measured by gas chromatography-mass spectrometry (GC-MS) were compared to those estimated by MRS.

Results

Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings.

Conclusions

Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.

Eat this Book: A Carnivore’s Manifesto Taste as Experience. The Philosophy and Aesthetics of Food

Eat This Book: A Carnivore's Manifesto

Strange Tools: Art and Human Nature

Strange Tools: Art and Human Nature

Digging out the evidence – how strong is the IDSA recommendation against antibiotic prophylaxis in basilar skull fracture and cerebrospinal fluid leakage?

Reply to Kuehl et al.

What’s New in Imaging for Gynecologic Cancer?

Abstract

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

Abstract

Background

Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS) II prevention and Ductal Carcinoma in Situ (DCIS) trials, and its association with early symptoms.

Patients and methods

In the prevention trial, 3864 postmenopausal women were randomized to placebo vs. anastrozole. 2980 postmenopausal women with DCIS were randomized to tamoxifen vs. anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided.

Results

In the prevention trial, adherence was 65.8% (anastrozole (65.7%) vs. placebo (65.9%); HR = 0.97 (0.87-1.09), p=0.6). Adherence was lower for those reporting arthralgia in the placebo group (p=0.02) or gynecological symptoms in the anastrozole group (P=0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% (anastrozole (67.5%) vs. tamoxifen (65.8%); HR = 1.06 (0.94-1.20), p=0.4). Hot flashes were associated with greater adherence in the anastrozole arm (p=0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.

Conclusions

In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

Impact of Neoadjuvant Chemoradiotherapy on Health Related Quality of Life In Long-Term Survivors of Esophageal or Junctional Cancer: Results from the Randomized Cross Trial

Abstract

Background

Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone.

Patients and methods

Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared to pre-treatment and 12-months-postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary endpoints. Predefined secondary endpoints were global quality of life and fatigue (both QLQ-C30).

Results

After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL-endpoints were found between both groups. Compared to one-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared to pre-treatment levels, eating problems had improved (Cohen's d -0.37, p = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pre-treatment levels in both groups (Cohen's d -0.56 and 0.51, resp., both p < 0.001).

Conclusion(s)

Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared to patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care.

CLINICAL TRIALS NUMBER

Trial registration number: Netherlands Trial Register NTR487

Infant Group B Streptococcal Disease Incidence and Serotypes Worldwide: Systematic Review and Meta-analyses

Abstract

Background

Group B Streptococcus (GBS) remains a leading cause of neonatal sepsis in high-income contexts, despite declines due to intrapartum antibiotic prophylaxis (IAP). Recent evidence suggests higher incidence in Africa, where IAP is rare. We investigated the global incidence of infant invasive GBS disease and the associated serotypes, updating previous estimates.

Methods

We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data regarding invasive GBS disease in infants aged 0–89 days. We conducted random-effects meta-analyses of incidence, case fatality risk (CFR), and serotype prevalence.

Results

We identified 135 studies with data on incidence (n = 90), CFR (n = 64), or serotype (n = 45). The pooled incidence of invasive GBS disease in infants was 0.49 per 1000 live births (95% confidence interval [CI], .43–.56), and was highest in Africa (1.12) and lowest in Asia (0.30). Early-onset disease incidence was 0.41 (95% CI, .36–.47); late-onset disease incidence was 0.26 (95% CI, .21–.30). CFR was 8.4% (95% CI, 6.6%–10.2%). Serotype III (61.5%) dominated, with 97% of cases caused by serotypes Ia, Ib, II, III, and V.

Conclusions

The incidence of infant GBS disease remains high in some regions, particularly Africa. We likely underestimated incidence in some contexts, due to limitations in case ascertainment and specimen collection and processing. Burden in Asia requires further investigation.