Upregulation of inhibitory immune checkpoints is critical for the control of T-cell activation in order to prevent autoimmunity and tissue damage. It is now clear that tumors can hijack immune checkpoint mechanisms as protection against the anticancer T-cell response. Blockade of the PD-1/PD-L1 immune checkpoint pathway has created a revolution in the treatment of melanoma, lung cancer and several other cancer types. In metastatic breast cancer patients, the response rates to PD-1 blocking antibodies are modest (4%–25%), but durable responses are seen [1–7]. Given that the majority of patients do not have clinical benefit, there is an urgent need to improve immunotherapy for breast cancer patients. This optimization is not a paved road and requires the integration of different parallel approaches, such as the search for predictive biomarkers [8], combination treatment with conventional therapies [9, 10], strategies to convert cold tumors into hot tumors [4, 11] and development of novel immunomodulatory compounds.
Παρασκευή 8 Δεκεμβρίου 2017
Incremental improvement in osteosarcoma chemotherapy?
Osteosarcoma is one of the first solid cancers for which a survival benefit from adjuvant chemotherapy was established [1, 2]. After decades of clinical research to improve on results obtained in the 1980s, the long-standing chemotherapy regimen of doxorubicin and cisplatin with or without methotrexate remains a standard treatment of osteosarcoma, resulting in a 5-year survival rate of more than 60% in patients with localized disease [3, 4]. In patients with metastatic osteosarcoma at diagnosis, or with distant disease relapse after treatment of localized disease, the long-term survival rate is <20%, and new therapies are much needed for this group of patients [5]. Neither the intensification of chemotherapy by adding ifosfamide and etoposide nor the use of muramyl tripeptide or traztuzumab has improved the survival of patients with metastatic osteosarcoma [6–8]. However, cure can be achieved in patients with metastatic osteosarcoma who undergo metastasectomy [5, 9].
Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer
Abstract
Background
Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies. Patients and methods
All data are from 2009 to 2014, including 13 089 people ages 20–69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer. Results
Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20–69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will 'ever' develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had 'elevated risk' (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2–4 partners or did not smoke and had ≥5 partners) had 'medium risk' (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was 'low' among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%). Conclusions
Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains low.Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: an overview of the current landscape and challenges ahead
Abstract
Advances in the last decade in genomic profiling and the identification of druggable targets amenable to biological agents have transformed the management and survival of a subgroup of patients with brain metastasis in non-small-cell lung cancer. In parallel, clinicians have reevaluated the role of whole brain radiotherapy in selected patients with brain metastases to reduce neurocognitive toxicity. Continual progress in this understudied field is required: optimization of the sequence of schedules for therapies in patients with brain metastases of differing genomic profiles, focusing on new strategies to overcome mechanisms of biological resistance and increasing drug penetrability into the central nervous system. This review summarizes the field to date and possible treatment strategies based on current evidence.Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial
Abstract
Background
The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described. Methods
We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial. Results
TF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen. Conclusion
MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.DPYD genotype-guided fluoropyrimidines dose: is it ready for prime time?
For over 50 years, fluoropyrimidines have been the cornerstone of anticancer drugs for various types of solid cancers. Treatment with these drugs—5-fluorouracil (FU) and its oral prodrugs, capecitabine and tegafur—is generally well-tolerated, except in a small proportion of patients who develop severe and life-threatening early toxicity. This toxicity is mainly associated with a deficiency of the primary fluoropyrimidine detoxifying enzyme, dihydropryrimidine dehydrogenase (DPD) [1]. The drug labels of FU and capecitabine state DPD deficiency as a contraindication, but they give no warning for the 3%–8% of the population who are partially DPD deficient.
SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer
Abstract
Background
Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods
Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. Results
A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. Conclusion
The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. Trial identifier
Clinicaltrials.gov NCT01750281.Gougerot-Sjogren-like syndrome under PD-1 inhibitor treatment
A 36-year-old female patient with no significant medical history except hypothyroidism was diagnosed with left parotid acinic cell carcinoma that was treated by radical parotidectomy followed by adjuvant radiotherapy (50 Gy) in 2004. Seven years after the initial diagnosis, the patient developed histologically confirmed metastases on the left adrenal gland and the lung, for which systemic therapy was indicated. The patient participated in two successive studies and received lapatinib and then an EZH-2 inhibitor. In March 2016, the patient's adrenal lesion progressed, and she started treatment with pembrolizumab, 200 mg, every 3 weeks. At the time of the 11th injection, the patient experienced a retinal detachment that was linked to her myopia. The detachment was treated by surgery and amoxicillin for 7 days. Subsequently, the patient developed an oral candidiasis that was treated with systemic fungizone. At the time of the 13th injection, in December 2016, the patient experienced a debilitating grade 2 dry-eye syndrome that was associated with grade 1 conjunctival hyperemia, grade 2 xerostomia, and grade 1 skin rash on both hands. Therefore, serum protein electrophoresis (SPEP) and determination of antinuclear antibodies (ANA) [particularly Sjogren's syndrome A/Sjogren's syndrome B (SSA/SSB)] were carried out. A salivary gland biopsy could not be conducted because of the patient's radiation history. The SPEP and the ANA were normal. Concomitantly, the CT-scan showed a stable disease using the RECIST criteria v1.1.
Molecular Tumor Boards: current practice and future needs
Abstract
Background
Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date. Methods
Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation. Results
Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community. Conclusions
This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.Clinical and molecular characterization of patients with cancer of unknown primary in the modern era
Abstract
Background
On the basis of historical data, patients with cancer of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than 1 year. Treatment is typically cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next-generation sequencing in the evaluation and treatment of patients with CUP. Patients and methods
Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent 2-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next-generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment. Results
We identified 333 patients with a diagnosis of CUP evaluated at our institution from 1 January 2014 through 30 June 2016. Of these patients, 150 had targeted next-generation sequencing carried out on available tissue. Median overall survival in this cohort was 13 months. Forty-five of 150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15 of 150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21 of 150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco. Conclusions
Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next-generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.Clinical benefit of systemic treatment in patients with advanced pancreatic and gastrointestinal neuroendocrine tumours according to ESMO-MCBS and ASCO framework
Abstract
Background
Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks. Methods
The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed. Results
The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F. Conclusion
The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS)
Abstract
Background
Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. Patients and methods
A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. Results
Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3–4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. Conclusion
Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors
Abstract
Background
Novel immune checkpoint blockade strategies are being evaluated in clinical trials and include targeting the lymphocyte activation gene 3 (LAG-3) checkpoint, alone or in combination with PD-1/PD-L1 blockade. We investigated LAG-3 expression and its prognostic value in a large series of breast cancer patients, and correlated LAG-3 expression with key biomarkers including PD-1 and PD-L1. Experimental design
LAG-3 expression was evaluated by immunohistochemistry on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N = 330 in the training and N= 3992 in the validation set) linked to detailed clinicopathologic, biomarker and long-term clinical outcome data. PD-1 and PD-L1 expressions were also evaluated by immunohistochemistry. Stromal or intra-epithelial tumor infiltrating lymphocytes (sTILs or iTILs) expressing LAG-3 or PD-1 were assessed by absolute count. PD-L1 expression was evaluated as the percentage of positive carcinoma cells per core. Kaplan–Meier curves and Cox proportional hazard models were used for survival analyses. Results
After locking down interpretation cut-offs on the training set, LAG-3+ iTILs were found in 11% of cases in the validation set. In both sets, LAG-3+ iTILs were significantly associated with negative prognostic factors: young age, large tumor size, high proliferation, HER2E and basal-like breast cancer subtypes. In multivariate analyses, breast cancer patients with LAG-3+ iTILs had a significantly improved breast cancer-specific survival [hazard ratio (HR): 0.71, 95% CI 0.56–0.90], particularly among estrogen receptor-negative patients (HR: 0.50, 95% CI 0.36–0.69). Furthermore, we found that 53% of PD-L1+ and 61% of PD-1+ cases were also positive for LAG-3+ iTILs. Concurrent infiltration of LAG-3+ and CD8+ iTILs was significantly associated with increased breast cancer-specific survival (HR: 0.49, 95% CI 0.32–0.74). Conclusion
LAG-3+ iTILs are enriched in estrogen receptor-negative breast cancers and represent an independent favorable prognostic factor. In addition, a high proportion of PD-1/PD-L1+ tumors are co-infiltrated with LAG-3+ TILs, supporting potential immune checkpoint blockade combination strategies as a treatment option for breast cancer patients.The antibody–drug conjugate target landscape across a broad range of tumour types
Abstract
Background
Antibody–drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods
PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical trials. Gene expression profiles of 18 055 patient-derived tumour samples representing 60 tumour (sub)types and 3520 healthy tissue samples were collected from the public domain. Next, we applied Functional Genomic mRNA-profiling to predict per tumour type the overexpression rate at the protein level of ADC targets with healthy tissue samples as a reference. Results
We identified 87 ADCs directed against 59 unique targets. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high-incidence tumour types like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumour types we observed, amongst others, a predicted overexpression rate of 55% of samples for CD22 and 55% for ENPP3 in adrenocortical carcinomas, 81% for CD74 and 81% for FGFR3 in osteosarcomas, and 95% for c-MET in uveal melanomas. Conclusion
This study provides a data-driven prioritization of clinically available ADCs directed against 59 unique targets across 60 tumour (sub)types. This comprehensive ADC target landscape can guide clinicians and drug developers which ADC is of potential interest for further evaluation in which tumour (sub)type.Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study
Abstract
Background
Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. Patients and methods
We conducted this multicentre, prospective, case–control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Results
Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). Conclusion
The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.Response to ‘Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest’
We thank Farkhad Manapov and Chukwuka Eze [1] for their interest in our phase III trial of etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small-cell lung cancer [2]. We have addressed here, and hope to clarify, a few points that they raised in their letter.
Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508)
Abstract
Background
Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. Methods
Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). Results
Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4–7.1) in arm A versus 7 months (95% CI 5.7–7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65–1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. Conclusions
The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. ClinicalTrials.gov Identifier
NCT00955305Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000–2013
Abstract
Background
We sought to evaluate the impact of adjuvant chemotherapy on overall survival (OS) in patients with stage I endometrioid epithelial ovarian cancer (EEOC) or ovarian clear cell cancer (OCCC) using a national database. Patients and methods
The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I EEOC or OCCC from 2000 to 2013. We sought to identify predictors of chemotherapy use and to assess the impact of chemotherapy on OS in these patients. OS was compared using the log-rank test and the Cox proportional hazards model. Results
In all, 3552 patients with FIGO stage I EEOC and 1995 patients with stage I OCCC were identified. Of the 1600 patients (45%) with EEOC who underwent adjuvant chemotherapy, the 5-year OS rate was 90%, compared with 89% for those who did not undergo adjuvant chemotherapy (P = 0.807). Of the 1374 (69%) patients with OCCC who underwent adjuvant chemotherapy, the 5-year OS rate was 85%, compared with 83% (P = 0.439) for those who did not undergo adjuvant chemotherapy. Chemotherapy use was associated with younger age, higher substage, and more recent year of diagnosis for both the EEOC and OCCC groups. Only in the subgroup of patients with FIGO substage IC, grade 3 EEOC (n = 282) was chemotherapy associated with an improved 5-year OS—81% compared with 62% (P = 0.003) in untreated patients (HR: 0.583; 95% CI: 0.359–0.949; P = 0.030). In patients with OCCC, there was no significant effect of adjuvant chemotherapy on OS in any substage. Conclusions
Adjuvant chemotherapy was associated with improved OS only in patients with substage IC, grade 3 EEOC. In stage I OCCC, adjuvant chemotherapy was not associated with improved OS.Trastuzumab use in patients with durable complete response in HER2-amplified metastatic breast cancer: to continue or not to continue
Exceptional response to trastuzumab, a monoclonal antibody against human epidermal growth factor receptor-2 (HER2/ERBB2), as manifested by prolonged absence of radiographic evidence of disease (durable complete response, DCR) is uncommon.
Role of adjuvant chemotherapy in early-stage endometrioid and clear-cell ovarian cancer
With more than 200 000 new cases annually worldwide [1], ovarian cancer represents the sixth most common cancer among women and the most lethal gynecologic malignancy.
Association of HLA-DQB1*03:03 with pityriasis rosea in Chinese patients
Summary
Background
The association of human leucocyte antigen (HLA) with a variety of diseases has been described, especially with various autoimmune diseases. However, there are few studies on the association between HLA and pityriasis rosea (PR).
Aim
To investigate the relevance of HLA II alleles with the development of PR.
Methods
Typing for HLA-DRB1, HLA-DQA1 and HLA-DQB1 typing was performed in 55 patients with PR and 90 healthy controls (HCs), using sequence-based typing (SBT) and PCR with sequence-specific primers (PCR-SSP), respectively.
Results
We found that the frequency of HLA-DQB1*03:03 was significantly higher in the PR compared with the HC group [P = 0.001; relative risk (RR) = 2.24; 95% CI 1.38–3.6], while suggestive evidence for a protective effect of HLA-DQB1*06:06 was observed in the study cohort (P < 0.02; RR = 0.40; 95% CI 0.17–0.90).
Conclusions
The HLA-DQB1*03:03 allele may be a susceptible factor in patients with PR. In addition, the association of HLA-DQB1*03:03 with PR suggests participation of immunity in the pathogenesis of PR.
Effect of age and body mass index on the yield of stromal vascular fraction
Summary
Objective
The aim of this study was to determine the influence of age, body mass index, and site of liposuction on the cell yield of SVF.
Methods
A prospective study was performed on 58 patients. The average age was 39 years old, with BMI ≤ 25 or BMI ≥ 25. Fat tissue was harvested from the abdominal region, flanks, or thighs and SVF was isolated.
Results
The yield of viable SVF was evaluated by trypan blue, and the markers of stem cells were evaluated by flow cytometry. The cells were positive for stem cells markers, the age, sex of the patient had no impact on SVF cell yield with an average of 1.17 × 10^8. However, the BMI > 25 had resulted in higher cell numbers, and the harvest site had a significant impact on cell yield with abdomen being the site of interest.
Conclusion
These data demonstrate that the age of the person does not affect the cell yield of SVF; nevertheless, the donor site and BMI might be important factors in affecting cell number.
Results of a systematic literature review of treatment modalities for jugulotympanic paraganglioma, stratified per Fisch class
Abstract
Objective
Key for successful jugulotympanic paraganglioma management is a personalized approach aiming for the best practice for each individual patient. To this end, a systematic review is performed, evaluating the local control- and complication rates for the different treatment modalities stratified by the broadly accepted Fisch classification.
Design
A systematic literature review according to the PRISMA statement was performed. A detailed overview of individual treatment outcomes per Fisch class is provided.
Main outcome measures
local control, cranial nerve damage, complications, function recovery.
Results
Eighteen studies were selected, resembling 83 patients treated with radiotherapy and 299 with surgery. Excellent local control was found post surgery for class A and B tumours and risk of cranial nerve damage was <1%. For class C1-4 tumours, local control was 80-95% post surgery (84% post radiotherapy) and, cranial nerve damage was found in 71-76% (none post radiotherapy; p < 0.05). There was no difference in treatment outcomes between tumours of different C class. For class C1-4De/Di tumours, local control was 38-86% (98% post radiotherapy; p < 0.05), cranial nerve damage/complication rates were 67-100% (3% post radiotherapy; p < 0.05). C1-4DeDi tumours showed lesser local control and cranial nerve damage rates when compared to C1-4De tumours.
Conclusions
An individual risk is constituted for surgery and radiotherapy, stratified per Fisch class. For class A and B tumours surgery is a suitable treatment option. For class C and D tumours radiotherapy results in lower complication rates and similar or better local control rates when compared to the surgical group.
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A qualitative study of the experience of lower extremity wounds and amputations among people with diabetes in Philadelphia
Abstract
The purpose of this study was to explore perceptions among people with type 2 diabetes about foot ulcers and lower extremity amputations. This was a qualitative observational study utilizing open-ended, semistructured interviews of 39 people with diabetes who were purposively selected because they had either a foot ulcer (n = 19) or a lower extremity amputation (n = 20). Interviews were audio-recorded, deidentified, and entered into NVivo 10.0 for coding and analysis. Our integrated analytic approach combined inductively and deductively derived codes that were applied to all transcripts. Coded data were summarized and examined for patterns. Participants' description of the relationship between diabetes and their foot ulcer or amputation revealed a limited understanding of the disease process. Disruption and loss of independence was expressed whether the person had a foot ulcer or an amputation. Treatment recommendations for foot ulcers were viewed by most as extremely difficult. Amputation was a feared outcome, but some learned to adapt and, at times felt that the amputation enhanced their quality of life. Clinicians have assumed that a focus on limb salvage is preferred over a major amputation. However, because of the complexity of care requiring frequent healthcare provider visits, the frequency of care failure, the frequency of recurrence, and mortality associated with having had a foot ulcer, it may be more appropriate for clinicians to prioritize quality-of-life salvage. Foot ulcer treatment failure may be due to a lack of providers' understanding of the impact of treatment on a patient's life.
Elevated levels of the antimicrobial peptide LL-37 in hidradenitis suppurativa are associated with a Th1/Th17 immune response
Summary
Hidradenitis suppurativa (HS) is an inflammatory skin disease with poorly understood immunopathogenic mechanisms. LL-37 is an antimicrobial peptide, which is transcribed from the CAMP (cathelicidin antimicrobial peptide) gene. Previous reports showed upregulated levels of CAMP and LL-37 in HS lesions and therefore the aim of this study was to compare levels of LL-37 in HS to other inflammatory skin diseases and to establish immunomodulatory functions of LL-37 in HS. We confirm an upregulation of the LL-37 peptide in lesional HS skin with comparable levels as in psoriasis patients and are able to positively correlate the presence of LL-37 in HS with the presence of T cells, macrophages, neutrophils, IFNγ, IL-17, IL-23, TNFα, IL-32 and IL-1β. Mechanistically, LL-37 boosts the proliferation of unspecifically activated CD4+ T cells via an increased calcium signalling independent of antigen presenting cells. Targeting LL-37 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease, but it has to be kept in mind that LL-37 also has an antimicrobial function.
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The effect of melasma on self-esteem: A pilot study
Melasma is a common disorder of hyperpigmentation characterized by tan or brown macules and patches affecting sun-exposed areas, particularly the face. Melasma has been shown to have a significant impact on the quality of life and self-esteem of those affected. We interviewed six patients who were diagnosed with moderate-to-severe melasma with regard to the effect of their disorder on their self-esteem. All patients reported a significant negative effect on their quality of life and self-esteem.
Fast, Cheap, and Unethical? The Interplay of Morality and Methodology in Crowdsourced Survey Research
Abstract
Crowdsourcing is an increasingly popular method for researchers in the social and behavioral sciences, including experimental philosophy, to recruit survey respondents. Crowdsourcing platforms, such as Amazon's Mechanical Turk (MTurk), have been seen as a way to produce high quality survey data both quickly and cheaply. However, in the last few years, a number of authors have claimed that the low pay rates on MTurk are morally unacceptable. In this paper, I explore some of the methodological implications for online experimental philosophy research if, in fact, typical pay practices on MTurk are morally impermissible. I argue that the most straightforward solution to this apparent moral problem—paying survey respondents more and relying only on "high reputation" respondents—will likely increase the number of subjects who have previous experience with survey materials and thus are "non-naïve" with respect to those materials. I then discuss some likely effects that this increase in experimental non-naivete will have on some aspects of the "negative" program in experimental philosophy, focusing in particular on recent debates about philosophical expertise.
Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features
Anti-MDA5 dermatomyositis exhibits unique clinical features including mucocutaneous ulceration, palmar papules, non-scarring alopecia, panniculitis, arthritis, and interstitial lung disease.Early intervention may reduce disease-related morbidity and improve survival in affected individuals.Knowledge of the salient features of anti-MDA5 dermatomyositis enhances its recognition and facilitates treatment.
Merkel Cell Carcinoma: an Update and Review Part 1. Pathogenesis, Diagnosis, and Staging
Capsule Summary: word count not required for CME articles; please note that bulleted points appear at the start of each section but are not included in the total word count
Merkel Cell Carcinoma: An Update and Review. Part II: Current and Future Therapy
Capsule Summary: word count not required for CME articles as these appear before each section and are included in the text word count
Correctness of Self-Reported Task Durations: A Systematic Review
Abstract
Objectives
Duration of tasks in a job is an essential interest in occupational epidemiology. Such duration is frequently measured using self-reports, which may, however, be associated with both bias and random errors. The present systematic literature review examines the correctness of self-reported durations of tasks, i.e. the extent to which they differ from more valid reference data due to either systematic or random errors, and factors influencing this correctness, with particular emphasis on the assessment of exposures of relevance to musculoskeletal disorders. Methods
The search for relevant studies included the databases ISI Web of Science, MEDLINE, EBSCO HOST, Proquest, and Psycnet. Results
Thirty-two articles were identified; of which, 23 examined occupational tasks and 9 examined non-occupational tasks. Agreement between self-reports and a more correct reference was reported for, in total, 182 tasks. Average proportional errors were, for most tasks, between −50% (i.e. underestimations) and +100%, with a dominance of overestimations; 22% of all results considered overestimations of 100% or more. For 15% of the 182 reported tasks, the mean difference between the self-reported and the reference duration value was <5%, and 20% of the 182 mean differences were between 5 and 20%. In general, respondents were able to correctly distinguish tasks of a longer duration from shorter tasks, even though the actual durations were not correct. A number of factors associated with the task per se appeared to influence agreement between self-reports and reference data, including type of task, true task duration, task pattern across time (continuous versus discontinuous), and whether the addressed task is composed of subtasks. The musculoskeletal health status of the respondent did not have a clear effect on the ability to correctly report task durations. Studies differed in key design characteristics and detail of information reported, which hampers a formal aggregation of results. Conclusions
The correctness of self-reported task durations is, at the best, moderate at the individual level, and this may present a significant problem when using self-reports in task-based assessment of individual job exposures. However, average self-reports at the group level appear reasonably correct and may thus be a viable method in studies addressing, for instance, the relative occurrence of tasks in a production system. Due to the disparity of studies, definite conclusions on the quantitative effect on agreement of different modifiers are not justified, and we encourage future studies specifically devoted to understanding and controlling sources of bias in self-reported task durations. We also encourage studies developing decision support for when to apply or avoid self-reports to measure task durations, depending on study purpose and occupational setting.Harnessing the Power of Data in Facial Plastic and Reconstructive Surgery
The widespread use of electronic health records (EHRs) has created unprecedented opportunities to apply meaningful clinical data for quality improvement. Through machine learning, large data sets of patient clinical information gathered through routine clinical encounters can be analyzed for risk prediction and treatment algorithms. Although randomized clinical trials remain the criterion standard study type to show causality, the use of big data is showing promise as an alternative for discovery. This alternative is of particular significance in surgery, where randomized clinical trials are not feasible or likely.
Recreational Activity and Facial Trauma Among Older Adults
This database analysis uses the National Electronic Injury Surveillance System to collect data to evaluate the incidence of recreational activity–associated facial fractures among older adults and to further delineate injury characteristics including demographics, fracture location, and activities.
In Memoriam: Gary Burget, MD (1941-2017)
Facial plastic surgery recently lost a dear friend, teacher, and colleague on May 31, 2017, with the passing of Gary Burget, MD. Dr Burget was born in Toledo, Ohio, on April 20, 1941, the second child of Dean E. and Marie A. Burget. His parents were schoolteachers who had grown up on small working farms in southern Ohio near West Virginia near the Appalachian foothills. His parents obtained schoolteaching jobs in the Toledo, Ohio, public school system after graduating from Bowling Green State University at the height of the Great Depression. Dr Burget attended Thomas A. DeVilbiss High School and served as president of the student council his senior year. He attended Yale University and graduated with a BA in English and then followed his older brother, Dean, to Yale Medical School, which he completed in 1967. During his fourth year of medical school, he arranged a surgical clerkship in Edinburgh, Scotland, under the direction of Andrew Logan, MD, which increased his interest in surgery. Following medical school, he pursued an internship at Columbia University College of Physicians and Surgeons in New York City and spent much of his time at Harlem Hospital. He then went to Jackson Memorial Hospital at the University of Miami as a resident in general surgery, followed by a residency in plastic surgery under D. Ralph Millard, Jr, MD. He was influenced by his older brother, Dean, who preceded him into a career in plastic surgery. Following completion of his plastic surgery residency, he was invited to join Dr Millard as an associate partner in his private practice. While honored, Dr Burget decided to enter private practice with Walter Garst, MD. After several years, Dr Burget struck out on his own and opened a practice in Miami. Henry W. Menn, MD, an early Mohs surgeon, referred a large number of patients with difficult facial defects to Dr Burget. It was during these years that Dr Burget realized the importance of the aesthetic units of the face and the need to sometimes remove additional tissue to move scars into favorable positions.
Teaching Photographic Nasal Analysis
This study evaluates the common pitfalls exhibited by otolaryngology residents in performing photographic nasal analysis and a systematic approach model for teaching photographic nasal analysis.
Partial Cost Cartilage Harvest for Rhinoplasty
To the Editor The article by Nelson and Gaball, "Technique to Reduce Time, Pain, and Risk in Costal Cartilage Harvest," recently published in JAMA Facial Plastic Surgery, nicely describes a surgical technique to harvest only the anterior two-thirds of a donor rib when autologous costal cartilage is necessary for reconstructive rhinoplasty.
Simulation Course for Evaluation and Treatment of Facial Fractures
This study assesses the value of a novel facial trauma simulation course requiring residents to practice advanced decision making.
Teaching Rhinoplasty
Rhinoplasty is considered by many to be the most challenging operation that otolaryngologists do. Teaching rhinoplasty is even more challenging. In this issue of JAMA Facial Plastic Surgery, Robitschek and colleagues provide a combination of rhinoplasty analysis, science, and teaching our younger colleagues. Their study is a well-designed, prospective look at the effect of a simple teaching tool (a 10-minute slide presentation) and the thoroughness with which otolaryngology residents analyze the nose from patient photographs. The study concludes that 10 weeks after the teaching session, residents continue to perform better at rhinoplasty analysis, especially in terms of describing the position of the caudal septum.
Bony Batten Grafting to Correct Caudal Septal Deviation in Septoplasty
This cohort study evaluates the surgical outcomes of bony batten grafting for the management of caudal septal deviation in patients undergoing endonasal septoplasty.
The Columella Retraction Suture
This report presents the columella retraction suture as a way to control dead space after correction of the nasolabial and columella-tip complex.
Perception of Permanent Unilateral Facial Paralysis
This cohort study compares multiple domains of casual observer and expert perception with the actual experience of patients with permanent unilateral facial paralysis.
Review of Facial Plastic and Reconstructive Surgery
In 2001, Raza Pasha, MD, edited and published Otolaryngology–Head and Neck Surgery: A Clinical Reference Guide. This resource is currently in its fourth print edition and is ubiquitous in residency programs around the United States. The success of this book is due to its concise format and excellent overview of the specialty of Otolaryngology. Shaun Desai, MD, has borrowed some of this format for his text, Facial Plastic and Reconstructive Surgery: Clinical Reference Guide, and replicates this success with a narrower focus on the subspecialty of facial plastic and reconstructive surgery.
Costal Cartilage Warping Using Oblique Split vs Concentric Carving
This in vitro cadaveric study assesses whether the 30-degree oblique split method of preparing costal cartilage grafts produces less warping of the graft than the current standard of harvesting the central segment of a rib using the concentric carving method.
Algorithm-Based Levator Aponeurectomy in Ptosis Surgery
This cohort study investigates the postoperative success of an algorithmic external levator aponeurosis resection technique in patients with aponeurotic ptosis and good levator function.
Training Current and Future Residents in Facial Plastic Surgery
In this issue of JAMA Facial Plastic Surgery, Christophel et al assess the value of a novel facial trauma simulation course given to 30 residents from 2 institutions. During this 1-day course, an impactor delivered a measurable force to create facial fractures in fresh frozen cadaver heads, which were then scanned with high-resolution computed tomography. Using each specimen's unique findings, a pair of trainees formulated and presented their theoretical treatment plan, which included airway management, fracture type, surgical approach, and type of fracture repair. Finally, the authors measured the improvement in the trainees' knowledge after the course with the Accreditation Council for Graduate Medical Education otolaryngology facial trauma residency milestone scale. This milestone is a national metric measure to monitor the resident's progress of learning; it uses a disease-based format for patient care and medical knowledge during training.
Complete Philtrum Reconstruction on the Partial-Thickness Cross-Lip Flap
This study describes the reconstruction of the philtrum in the cross-lip flap transfer using nasolabial muscle tension line group reconstruction.
Data Collection Integration to Optimize Clinical Outcomes Research
This Special Communication describes a method for prospective periodic evaluation of patients undergoing elective functional septorhinoplasty with data collection embedded into an electronic health record.
Electrochemical Therapy of Porcine Skin
This study examines the changes in optical, mechanical, and acoustic impedance properties in porcine skin after electrochemical therapy.
The Twisted Nose
A young man had functional nasal obstruction after facial trauma resulted in fractured nasal bones, had undergone a closed nasal fracture reduction but obstructive symptoms persisted, also expressed dissatisfaction with the appearance of his nose. What would you do next?
Lateral Crural Overlay Technique and Strength of Lower Lateral Cartilages
This cadaver study measures the difference in lateral crural strength and resilience after performing lateral crural overlay procedures using 2 different techniques.
Interleukin-21 receptor signaling is not critically required for imiquimod-induced psoriasiform dermatitis in mice
Abstract
Psoriasis is largely mediated by interleukin (IL)-23/ T helper (Th) 17 axis, and IL-21 is a pleiotropic cytokine expressed by Th17 cells. Despite previously reported possible pathogenic roles of IL-21 in human psoriasis, we found that IL-21 receptor (IL-21R) signaling was not crucial for imiquimod-induced psoriatic inflammation, using IL-21R−/− mice. The severity of imiquimod-induced psoriatic manifestation and pro-inflammatory Th17 cytokine levels, IL-17A-producing γδ T cells and CD4+ T cells, and in vitro IL-17A production by γδ T cells after IL-23 stimulation was comparable between wild-type and IL-21R−/− mice. Collectively, IL-21R signaling was not critically involved in IMQ-induced psoriatic inflammation despite an increased IL-21 expression in the IMQ-treated mouse skin. Our data may represent the significant differences between human psoriasis and murine psoriasis model, and further studies using other models will be required to elucidate the role of IL-21 in psoriasis pathogenesis.
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A randomized phase II study evaluating different maintenance schedules of nab-Paclitaxel in the first-line treatment of metastatic breast cancer: final results of the IBCSG 42-12/BIG 2-12 SNAP trial
Abstract
Background
The phase II SNAP trial was designed to evaluate the efficacy of alternative chemotherapy schedules for prolonged administration in HER2-negative metastatic breast cancer (MBC), after a short induction at conventional doses. Methods
Between April 2013 and August 2015, 258 women untreated with chemotherapy for MBC were randomly assigned to receive three different maintenance chemotherapy schedules after three cycles of identical induction chemotherapy: Arm A, nab-Paclitaxel 150 mg/m2 days 1,15 Q28; Arm B, nab-Paclitaxel 100 mg/m2 days 1,8,15 Q28; Arm C, nab-Paclitaxel 75 mg/m2 days 1,8,15,22 Q28. Induction was three cycles nab-Paclitaxel 150/125 mg/m2, days 1,8,15 Q28. The primary objective was to evaluate the efficacy of each maintenance schedule, in terms of progression-free survival (PFS), as compared to the historical reference of 7-month median PFS reported by previous studies with first-line docetaxel. One-sample, one-sided log-rank tests were utilized. Quality-of-life evaluation was performed, global indicator for physical well-being was defined as the primary endpoint; completion rates of quality-of-life forms were >90%. Results
255 patients were evaluable for the primary endpoint. After 18.2 months median follow-up, 182 PFS events were observed. Median PFS was 7.9 months (90%CI 6.8-8.4) in Arm A, 9.0 months (90%CI 8.1-10.9) in Arm B and 8.5 months (90%CI 6.7-9.5) in Arm C. PFS in Arm B was significantly longer than the historical reference of first-line docetaxel (P=0.03). Grade≥2 sensory neuropathy was reported in 37.9%, 36.1% and 31.2% of patients in Arm A, Arm B and Arm C, respectively (Grade≥3 in 9.1%, 5.6% and 6.6% of patients, respectively). Noteworthy, the quality-of-life scores for sensory neuropathy did not worsen with prolonged nab-Paclitaxel administration in any of the maintenance arms. Conclusion
The SNAP trial demonstrated that alternative nab-Paclitaxel maintenance schedules with reduced dosages after a short induction at conventional doses are feasible and active in the first-line treatment of MBC. Registration
ClinicalTrials.gov NCT01746225Analysis of Angiogenesis Biomarkers for Ramucirumab Efficacy in Patients with Metastatic Colorectal Cancer from RAISE, a Global, Randomized, Double-Blind, Phase III Study
Abstract
Background
The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo+FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods
Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1:1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1:2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were performed using exploratory assays to assess the correlations of baseline marker levels (VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 [plasma], and VEGFR-2 [tumor tissue]) with clinical outcomes. Cox regression analyses were performed for each candidate biomarker with stratification factor adjustment. Results
Biomarker results were available from >80% (n=894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/mL was appropriate for high/low subgroup analyses. Evaluation of the combined ME+MC populations found that the median OS in the ramucirumab+FOLFIRI arm compared with placebo+FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup (13.9 months [95% CI 12.5–15.6] versus 11.5 months [95% CI 10.1–12.4], respectively), and a decrease of 0.5 month in the low VEGF-D subgroup (12.6 months [95% CI 10.7–14.0] versus 13.1 months [95% CI 11.8–17.0], respectively). PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions
The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration
NCT01183780Title: Rituximab: A Benchmark in the Development of Chemotherapy-free Treatment Strategies for Follicular Lymphomas
Abstract
Background
With the introduction of the anti-CD20 antibody rituximab, the outcomes of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Maintenance strategies with rituximab have also improved on clinical endpoints. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion: We provide data that supports the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy
Abstract
Background
Diagnosis of mesothelioma based on death certificate is subject to misclassification, which may bias the results of epidemiology studies. A high proportion of mesothelioma harbor mutations in the BRCA1-associated protein 1 (BAP1) gene. Methods
We searched medical and pathology records and specimens for 127 workers from a textile- asbestos factory in Italy who died during 1963-2013 with a diagnosis of pleural or peritoneal neoplasm or mesothelioma on death certificate, to confirm the diagnosis with immunohistochemistry (IHC) markers. We calculated the odds ratio (OR) of confirmation by selected characteristics and asbestos exposure variables. When sufficient pathology material was available, we analyzed BAP1 protein expression. Results
The diagnosis of mesothelioma was histologically confirmed for 35 cases (27.6%); 5 cases were classified as non-mesothelioma (3.9%), for 33 cases a mention of mesothelioma was found on record but no sufficient material was available for revision (26.0%); no records were available for 54 cases (death- certificate-only 42.5%). Diagnostic confirmation was not associated with sex, location of the neoplasm, age, or duration of employment; however, there was a significant association with time since first employment (p for linear trend 0.04). An association between duration of employment and time since first employment was observed for confirmed cases but not for death-certificate-only cases. BAP1 protein was lost in 18/35 cases (51.4%), without an association with sex, location, age, indices of asbestos exposure, or survival. Conclusions
We were able to confirm by IHC a small proportion of mesothelioma diagnoses on certificates of deceased asbestos workers, and confirmation correlated with latency of asbestos exposure but not other characteristics. BAP1 protein loss is a frequent event in mesothelioma of asbestos-exposed workers, but does not correlate with exposure.Progestin-associated shift of meningioma mutational landscape
Abstract
Background
Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods
We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing in order to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results
Compared to the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas (19/40(48%) vs. 25/530 (5%), p < 10−12) and located at the skull base (46/72 (64%) vs. 241/481 (50%), p = 0.03). We found a higher frequency of PIK3CA mutations (14/40 (35%) vs. 18/530 (3%), p < 10−8) and TRAF7 mutations (16/40 (40%) vs. 140/530 (26%), p < 0.001) and a lower frequency of NF2-related tumors compared to the control population of meningiomas (3/40 7.5% vs. 169/530 32%, p < 0.001). Conclusion
This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.Skin Cancer Prevention Campaign in Childhood: Survey based on 3,676 children in Brazil
Abstract
Background and Objectives
Primary skin cancer prevention campaigns are essential and more effective among children, not only because of the importance of sun exposure effects during this period, but also because at this age is when individuals are developing behaviors. The Brazilian Society of Dermatology - Regional State of Sao Paulo developed and conducted, the program named "The Sun, Friend of Childhood", a school health education and disease prevention project for children and parents. Our objective was to evaluate the cognitive and behavioral effects of the children and parents before and after an education model-based intervention of sun protection.
Methods
We carried out a study on a school population of Social Service of Industry – Regional State of São Paulo, from the first to the fifth years of the regular course (6-10 years). Our educational project was planned to be based on two children's learning tools (comic magazine and a DVD cartoon). Questionnaires in relation to habits and knowledge in sun exposure where applied to the children (3,776) before and (2,748) after the intervention. A questionnaire was applied to 3,663 parents regarding personal details and habits of their children.
Results
According to the McNemar′s statistical test, all changes in the children in acquire new knowledge about good practices for sun exposure were statistically significant.
Conclusions
Educative sun exposure programs in childhood are a relevant tool to modify the history of life for next generations, to concern the skin cancer and good health practices.
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Safety and Efficacy of Apremilast Through 104 Weeks in Patients With Moderate to Severe Psoriasis Who Continued on Apremilast or Switched From Etanercept Treatment: Findings From the LIBERATE Study
Abstract
Background
Apremilast, an oral phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate to severe psoriasis.
Objective
To evaluate long-term efficacy and safety of apremilast in biologic-naive patients with moderate to severe plaque psoriasis and safety of switching from etanercept to apremilast in the phase 3b LIBERATE trial.
Methods
Two hundred fifty patients were randomized to placebo, apremilast 30 mg BID, or etanercept 50 mg QW through Week 16; thereafter, all patients continued or switched to apremilast through Week 104 (extension phase). Skin, scalp, and nail involvement at Weeks 16, 52, and 104 were assessed using the Psoriasis Area and Severity Index (PASI; 0–72), Scalp Physician Global Assessment (ScPGA; 0–5), and Nail Psoriasis Severity Index (NAPSI; 0–8); patient-reported outcomes (PROs) were assessed using the Dermatology Life Quality Index (DLQI; 0–32) and pruritus visual analog scale (VAS; 0–100 mm).
Results
The apremilast-extension phase (Weeks 16–104) included 226 patients in the placebo/apremilast (n=73), apremilast/apremilast (n=74), and etanercept/apremilast (n=79) groups, and at Week 104, 50.7%, 45.9%, and 51.9% of these patients, respectively, maintained ≥75% reduction from baseline in PASI score (based on last observation carried forward analysis). Across treatment groups, ScPGA 0 (clear) or 1 (minimal) was achieved by 50.0%–59.2% of patients; NAPSI mean change from baseline was −48.1% to −51.1%; DLQI score ≤5 was achieved by 66.0%–72.5% of patients; and pruritus VAS mean change from baseline was −24.4 to −32.3. AEs in ≥5% of patients (diarrhea, nausea, nasopharyngitis, upper respiratory tract infection, and headache) did not increase with prolonged apremilast exposure.
Conclusions
Apremilast demonstrated significant and sustained improvements in skin, scalp, nails, and PROs (pruritus and quality of life) over 104 weeks in patients with moderate to severe plaque psoriasis. Safety was consistent with the known safety profile of apremilast.
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Consensus on the management of patients with psoriatic arthritis in a dermatology setting
Abstract
Background
Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis (PsO). Early diagnosis and prompt therapeutic intervention are crucial for limiting PsA progression and prevention of disability. Dermatologists are in a privileged position to detect early PsA. The management of patients with PsA in the dermatology setting is widely variable.
Objective
To provide practical recommendations for the management of patients with PsA in the dermatology setting including early diagnosis and treatment.
Methods
A consensus document was written by an expert panel composed by dermatologists (n=12) and rheumatologists (n=6). Eleven highly relevant questions were selected and elaborated with answers/statements based on a narrative literature review. The resulting document was discussed in a face-to-face meeting adopting a nominal group technique to reach consensus (i.e. 100% agreement) by using the Delphi method.
Results
A consensus was achieved in defining the following: the clinical characteristics differentiating inflammatory and non-inflammatory signs and symptoms of joint disease; the most important differential diagnoses of PsA in clinical practice; the most useful screening questionnaires, serum laboratory tests and imaging techniques for the detection of early PsA; the criteria for dermatologist to refer patients with PsO to rheumatologist; the criteria for the diagnosis of PsA; the selection of the indices that the dermatologist could use for measuring the activity and severity of PsA in clinical practice; when systemic steroids and/or intra-articular steroid injections are indicated in the treatment of PsA. Finally, systemic treatments including synthetic and biological disease modifying anti rheumatic drugs to be considered for the treatment of PsA have been reported.
Conclusions
The implementations of these practical recommendations could be very helpful for the management of patients with PsA in the dermatology setting including early diagnosis and treatment.
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Early stage mycosis fungoides screening investigations: a retrospective analysis of 440 cases
Abstract
Early stages of mycosis fungoides (MF stages IA and IB) carry similar long-term life expectancies as an age-, sex-, and race- matched control population (1-3). Despite this, the ten-year disease progression risk in stage IA and IB MF has been reported to be between 10% and 39% (4); hence, investigative screening is frequently performed at presentation. We conducted a retrospective chart review of screening investigations performed on 440 patients with stage T1/IA (52%) and T2/IB (48%) MF.
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Reflectance Confocal Microscopy evaluation of Trichobacteriosis Axilaris
Abstract
We read with great interest the paper by Navarrete-Dechent et al recently published on the Journal of European Academy of Dermatology1, in which the authors detail the dermoscopic findings of trichobacteriosis and highlight the importance of dermoscopy in these cases. We present the case of a 44-year-old man, who emanated an unpleasant axilary odor during a routine check-up. Close examination of the axillary hair shafts showed soft, brown to yellow irregular masses adherent to the central segment of the hairs, suggesting the diagnosis of trichobacteriosis axilaris (TA).
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Response to “Does Stromal Vascular Fraction Supplementation Improve Facial Lipotransfer?”
In response to the previous letter written by Dr. Swanson,1 we are very grateful for his interest in our paper and for spending the time to analyze and comment on it. We appreciate the opportunity to clarify our arguments and ideas that, we hope, can contribute to science and to plastic surgery practices.
Does Stromal Vascular Fraction Supplementation Improve Facial Lipotransfer?
Gontijo-de-Amorim et al1 claim that fat enriched with the stromal vascular fraction (SVF) improves volume retention after facial lipotransfer. The authors describe a comparison of 5 patients injected with enriched fat vs 5 patients injected without SVF supplementation using computed tomography (CT). The authors report that the enriched fat group lost only 9.6% of its volume vs 24% in the untreated group.1 The authors simply centrifuge the lipoaspirate rather than separating it enzymatically using collagenase to isolate adipose-derived stem cells.1 Whether the cell pellet left at the bottom of the tube after centrifugation truly represents the SVF is open to question.2
Rejuvenating the Face: An Analysis of 100 Absorbable Suture Suspension Patients
Abstract
Background
Absorbable suture suspension (Silhouette InstaLift, Sinclair Pharma, Irvine, CA) is a novel, minimally invasive system that utilizes a specially manufactured synthetic suture to help address the issues of facial aging, while minimizing the risks associated with historic thread lifting modalities. Objectives
The purpose of the study was to assess the safety, efficacy, and patient satisfaction of the absorbable suture suspension system in regards to facial rejuvenation and midface volume enhancement. Methods
The first 100 treated patients who underwent absorbable suture suspension, by the senior author, were critically evaluated. Subjects completed anonymous surveys evaluating their experience with the new modality. Results
Survey results indicate that absorbable suture suspension is a tolerable (96%) and manageable (89%) treatment that improves age related changes (83%), which was found to be in concordance with our critical review. Conclusions
Absorbable suture suspension generates high patient satisfaction by nonsurgically lifting mid and lower face and neck skin and has the potential to influence numerous facets of aesthetic medicine. The study provides a greater understanding concerning patient selection, suture trajectory, and possible adjuvant therapies. Level of Evidence: 4
Immunotherapy and Overall Survival in Elderly Patients With Melanoma
This cohort study evaluates if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for `metastatic melanoma.
Practicing Safe Dermatology—Screening Out Liability
The article "Characteristics of Medical Liability Claims Against Dermatologists From 1991 Through 2015" by Kornmehl and colleagues is a welcome addition in our quest to understand how to reduce dermatology practice risk. The study confirms much of what we already knew or suspected but also provides some new interesting insights. It is reassuring to see that most malpractice cases against dermatologists are "abandoned, withdrawn or dismissed." Similarly, it is comforting to know that there has been a net reduction of 29.2% in paid claims for dermatologists. Is this secondary to improved patient care? The changing landscape of tort reform? Or both?
Trends in Medical Liability Claims Against Dermatologists
This study analyzes 24 years of data through 2015 from a nationally representative liability claims registry to compare the medical liability claims against dermatologists vs nondermatologists.
Optical Coherence Tomography Features of Dermatophytoma
This case report illustrates the optical coherence tomography features of dermatophytoma.
Knowledge to Detect Scalp and Neck Melanoma
This study tests the association between a video intervention and hairdresser knowledge of melanoma and self-confidence in skin lesion detection.
Preference-Based QOL Measures for Economic Evaluations in Early Melanoma
This study uses randomized clinical trial data to compare utility scores from the AQoL-8D and the FACT-M and evaluate the sensitivity of both instruments in identifying the influence of fear of cancer recurrence on health-related quality of life in patients with early-stage melanoma.
Topical Tacalcitol for a Family With Follicular Keratosis of the Chin
This case report describes the use of topical tacalcitol to treat follicular keratosis of the chin in 2 brothers.
Allergen Concerns and Popular Skin Care Products—Reply
In Reply We thank Hamann and Thyssen, as well as Harview and Hsiao, for their interest in our work and thoughtful commentaries. We agree that the safety and affordability of cosmetics and personal care products explicitly marketed toward the pediatric population is important to public health. In a recent publication of all adverse events (AE) submitted to the US Food and Drug Administration surrounding cosmetics and personal care products from 2004 to 2016, baby products were associated with the highest percentage of self-reported serious AEs (eg, death, serious injury, or hospitalization).
Allergen Concerns and Popular Skin Care Products
To the Editor We read with great interest the Original Investigation by Xu et al titled "Consumer Preferences, Product Characteristics, and Potentially Allergenic Ingredients in Best-Selling Moisturizers" and published in a recent issue of JAMA Dermatology. In discussions with dermatology colleagues regarding this article, we noticed another disturbing marketing trend: the labeling of skin care products marketed for babies.
Laboratory Monitoring During Systemic Terbinafine Therapy for Pediatric Onychomycosis
This retrospective medical record review examines the prevalence of laboratory monitoring and laboratory abnormalities during systemic terbinafine therapy in pediatric onychomycosis.
Dermatologist Density and Volume and Costs of Dermatology Procedures
This cross-sectional study uses the 2013 Medicare Provider Utilization and Payment Database to characterize the effect of geographic variations in dermatologist density on the provision of dermatology procedures within Medicare.
Allergen Concerns and Popular Skin Care Products
To the Editor We read with great interest the article by Xu et al published in a recent issue of JAMA Dermatology highlighting the high prevalence of contact allergens in common moisturizers. Their data mirror similar results in our recent study investigating contact allergens in pediatric personal care products marketed as hypoallergenic, dermatologist recommended and/or tested, fragrance free, or paraben free. Similar to the study by Xu et al, which found that 88% of common moisturizers contained at least 1 common contact allergen, we found that 167 of 187 of our selection of pediatric products (89%) contained at least 1 allergen.
A NF-κB signature predicts low-grade glioma prognosis: a precision medicine approach based on patient-derived stem cells
Abstract
Background
While recent genome wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived stem cells representative of the glioma microenvironment. Methods
By next generation sequencing, we analyzed the transcriptional profile of GASC derived from patients that underwent anaplastic transformation either within 48 months (GASC-BAD) or ≥7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of an NF-κB signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-κB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGG. Results
The key elements differentiating the transcriptome of GASC isolated from LGG with different prognosis were mostly related to hallmarks of cancer (e.g. inflammatory/immune process, and NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the TCGA dataset. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression free survival in 146 grade II LGG. Conclusion
This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG, and it outlines the role of patient-based stem cell models as a tool for precision medicine approaches.ICON Intimidation and Predatory Behavior: From Hollywood, “to the Newsroom,” to the Halls of Congress
Violence and Gender , Vol. 0, No. 0.
Efficacy and Safety of Titanium Miniplates in Septorhinoplasty
This case series evaluates the efficacy and safety of titanium miniplates for cartilaginous graft fixation in patients undergoing septorhinoplasty.
Hybrid Cartilage-Modifying Otoplasty Technique and Outcomes
This observational study compares preoperative and postoperative measurements of the ears of patients who underwent hybrid cartilage-modifying otoplasty.
Blast SMS and Enrollment for Cleft Lip and Cleft Palate Surgery in Zimbabwe
This study tested the effectiveness of a "blast" short message service text message to facilitate enrollment with a visiting surgical team in Zimbabwe.
Characteristics, Diagnosis, and Management of Ehlers-Danlos Syndromes
This review summarizes characteristics, assessment, and management of Ehlers-Danlos syndromes, which can be associated with surgical complications and should be identified preoperatively to facilitate optimal treatment.
Opioid Use After Rhinoplasty
This case series examines patient use of an opioid-based drug after rhinoplasty to establish an optimal pain management regimen that also mitigates the misuse or diversion of physician-prescribed opioid medications.
Glutamate residues at positions 162nd and 164th influence the beta-lactamase activity of SHV-14 obtained from Klebsiella pneumoniae
Abstract
Extensive production of SHV-14 beta-lactamase makes Klebsiella pneumoniae resistant to beta-lactams. The presence of omega-loop has been reported to influence the beta-lactamase activity, which is also present in SHV-14. Its omega-loop has three glutamates in nearly alternating positions, 162, 164 and 167 but their concise role on the behaviour of SHV-14 is unknown. To uncover the influence of each glutamate on SHV-14, we replaced glutamates with alanine and estimated the effect of each mutation by assessing the change in beta-lactam sensitivities in the surrogate Escherichia coli cells and catalytic efficiencies for hydrolysis with the purified proteins. Upon expression, the clone of wild-type SHV-14 aggravated the resistance of host by 60–500 folds against penicillin and cephalosporin groups of antibiotics. However, the expression of mutated enzymes (especially E164A) substantially reduced the resistance level as compared to the wild-type, and the results were in synchrony with the estimated enzymatic efficiencies of wild-type and mutated proteins. Therefore, with further support from the in silico analysis, we hypothesize that mutation at the glutamate residues in the omega-loop of SHV-14 can considerably modulate the beta-lactam sensitivity and hydrolysis; thus, revealing the importance of such glutamates as the target for inhibitor design in future.Microbial carbon dioxide fixation: new tricks for an old game
Abstract
The exploitation of petroleum as energy and material source opened unprecedented possibilities for the development of our human societies, but only now we realize that the use of fossil resources comes at devastatingly high environmental costs. Consequently, our efforts to tap other carbon sources are steadily increasing. Industrial microbiology has the potential to use carbon dioxide directly as carbon source, thereby converting a foe into a friend. This thematic issue of FEMS Microbiology Letters sheds some light on recent developments for the understanding of microbial pathways for carbon dioxide fixation and on strategies for their industrial exploitation.Extracellular nucleic acids of the marine bacterium Rhodovulum sulfidophilum and recombinant RNA production technology using bacteria
Abstract
Extracellular nucleic acids of high molecular weight are detected ubiquitously in seawater. Recent studies have indicated that these nucleic acids are, at least in part, derived from active production by some bacteria. The marine bacterium Rhodovulum sulfidophilum is one of those bacteria. Rdv. sulfidophilum is a non-sulfur phototrophic marine bacterium, which is known to form flocs, structured communities of cells, and to produce extracellular nucleic acids in culture media. Recently, it has been revealed that this bacterium produces gene transfer agent-like particles and that this particle production may be related to the extracellular nucleic acid production mechanism. This review provides a summary of recent physiological and genetic studies of these phenomena and also introduces a new method for extracellular production of artificial and biologically functional RNAs using this bacterium. In addition, artificial RNA production using Escherichia coli, which is related to this topic will also be described.Rapid screening method for detecting highly pathogenic Streptococcus intermedius strains carrying a mutation in the lacR gene.
Abstract
Streptococcus intermedius is a member of the normal human commensal flora and secretes a human-specific cytolysin intermedilysin (ILY) as a major virulence factor. Expression of ily is repressed by LacR and loss-of-function mutations of LacR are observed in many ILY high-producing strains isolated from deep-seated abscesses, suggesting that high ILY production is necessary for increased virulence. However, because ILY exhibits no β-hemolysis on animal blood agar plates, differentiating ILY high- and low-producing strains using conventional laboratory methods is not possible. Interestingly, S. intermedius also produces glycosidases, including MsgA and NanA, which exhibit N-acetyl-β-d-glucosaminidase and neuraminidase activities, respectively. Moreover, MsgA expression, but not NanA, is negatively regulated by LacR. Here we measured the activities of MsgA, NanA and ILY in strains isolated from clinical specimens and dental plaque to determine the correlation between these glycosidase activities and ILY hemolytic activity. Hemolytic activity showed a strong positive correlation with MsgA and a weak negative correlation with NanA activities. Therefore, we calculated the ratio of MsgA and NanA activity (M/N ratio). This value showed a stronger positive correlation (r = 0.81) with ILY hemolytic activity and many strains with high M/N ratios ( > 2) were ILY high-producers with loss-of-function mutations in LacR.The impact of environmental factors on CO2 fixation by microalgae
Abstract
Microalgae are among the most productive biological systems for converting sunlight into chemical energy which is used to capture and transform inorganic carbon into biomass. The efficiency of CO2 capture depends on the cultivation system configuration (photobioreactors or open systems) and can vary according to the state of the algal physiology, the chemical composition of the nutrient medium and environmental factors, such as irradiance, temperature and pH. This mini-review is focused on some of the most important environmental factors determining photosynthetic activity, CO2 biofixation, cell growth rates and biomass productivities by microalgae. These include CO2 and O2 concentrations, light intensity, cultivation temperature, nutrients, etc. Finally, a review on operation of microalgae cultivation systems in outdoors is presented as an example of the impact of environmental conditions on biomass productivity and CO2 fixation.Poly(3-hydroxybutyrate) hyperproduction by a global nitrogen regulator NtrB mutant strain of Paracoccus denitrificans PD1222
Abstract
Paracoccus denitrificans PD1222 accumulates short-length polyhydroxyalkanoates, poly(3-hydroxybutyrate), under nitrogen deficient conditions. Polyhydroxybutyrate metabolism requires the 3-ketoacyl-CoA thiolase PhaA, the acetoacetyl-CoA dehydrogenase/reductase PhaB, and the synthase PhaC for polymerization. Additionally, P. denitrificans PD1222 grows aerobically with nitrate as sole nitrogen source. Nitrate assimilation is controlled negatively by ammonium through the two-component NtrBC system. NtrB is a sensor kinase that autophosphorylates a histidine residue under low nitrogen concentrations and, in turn transfers a phosphoryl group to an aspartate residue of the response regulator NtrC protein, which acts as a transcriptional activator of the P. denitrificans PD1222 nasABGHC genes. The P. denitrificans PD1222 NtrB mutant was unable to use nitrate efficiently as nitrogen source when compared to the wild-type strain, and it also overproduced poly(3-hydroxybutyrate). Acetyl-CoA concentration in the P. denitrificans PD1222 NtrB mutant strain was higher than in the wild-type strain. The expression of the phaC gene was also increased in the NtrB mutant when compared to the wild-type strain. These results suggest that accumulation of poly(3-hydroxybutyrate) in the NtrB mutant strain of PD1222 responds to the high levels of acetyl-CoA that accumulate in the cytoplasm as consequence of its inability to efficiently use nitrate as nitrogen source.Relationship between Escherichia coli growth rate and bacterial susceptibility to ciprofloxacin
Abstract
The effect of Escherichia coli growth rate on its susceptibility to ciprofloxacin was investigated using bacteria grown on different carbon sources and harboring mutations in genes encoding tricarboxylic acid cycle enzymes. A 1-h treatment of the wild type (wt) grown on glucose, succinate, malate, α-ketoglutarate or acetate with 0.3 μg ml–1 ciprofloxacin decreased the number of surviving cells (CFU ml–1), 560, 110, 74, 62 and 5 times, respectively. Among the mutants tested, sucB strain, which grew 1.75 times slower than wt, was 7.4-fold more tolerant to 0.3 μg ml–1 of ciprofloxacin than wt. Strong inverse correlations between log(CFU ml–1) after 1-h exposure to 0.3 and 3.0 μg ml–1 ciprofloxacin and the specific growth rate prior to antibiotic treatment (r = − 0.93 and − 0.96, respectively) were observed. Data from the current and previous studies on the inhibitory effect of ciprofloxacin on cultures exhibiting a wide range of growth rates (0.01–1.3 h–1) were collated. Statistical analysis revealed a significant inverse correlation between log(CFU ml–1) after exposure to 3.0 μg ml–1 of ciprofloxacin and the specific bacterial growth rate prior to antibiotic exposure (r = − 0.92). These data may be used in a design of antibiotic treatment protocols.Biotransformation of trinitrotoluene by Citrobacter sp. YC4 and evaluation of its cyto-toxicological effects
Abstract
Trinitrotoluene (TNT) is an explosive chemical generally used for military, civil and industrial purposes. Therefore, TNT residue can be found in soil and ground water as an environmental pollutant. The environmental control of TNT pollution has become a critical issue because of its potential toxicity and carcinogenicity. The aim of this study is to evaluate the cyto-toxicological effects of TNT after bioremediation. Citrobacter sp. YC4 is able to utilize TNT as a sole nitrogen source. Citrobacter sp. YC4 cells grown in medium with TNT as the sole nitrogen source (TNT-N) were able to rapidly degrade TNT, in contrast to cells grown in Luria Bertani medium as determined by resting cell suspension. The concentration of TNT decreased from 100 ppm to 0 ppm within 10 hours in the solution containing TNT mixed with TNT-N-grown YC4. The cytotoxicity of TNT and its degradation products generated by TNT-N grown YC4 were assessed by WST-1-based cell cytotoxicity assays. Our results showed that the cytotoxic potential of solutions containing TNT decreased almost to the level of the control after a one-hour incubation with TNT-N grown YC4 cells. The rapid conversion of TNT into possibly less toxic products by Citrobacter sp. YC4 proposes a bioremediation prospection.The promises of microalgae – still a long way to go
Abstract
Over the past decades, interest in microalgae has grown exponentially. Especially industrial applications, such as biodiesel production from microalgae were hyped in the early 2000s. But since the first attempts to commercialize microalgae derived products for energy applications, only a few developments made it to the market. What is hindering the full exploitation of this valuable resource for food, feed, and energy applications? This opinion paper reflects on the state of the art of industrial microalgae culturing and the knowledge gaps that still need to be filled jointly by academia and industry.Assessing the diversity of the g23 gene of T4-like bacteriophages from Lake Baikal with high-throughput sequencing
Abstract
Based on second generation sequencing (MiSeq platform), we determined the genetic diversity of T4-like bacteriophages of the family Myoviridae by analysing fragments of the major capsid protein gene g23 in the plankton of Lake Baikal. The sampling depth in our study was significantly higher than in those obtained by the Sanger method before. We obtained 33701 sequences of the g23 gene fragments, 141 OTUs of which were identified. 86 OTUs (60.9%) had the closest relatives from lakes Bourget and Annecy, and 28 OTUs (19.8%) had the highest identity with the Baikal g23 clones, which had been previously identified in the northern and southern basins of the lake by the Sanger method. The remaining OTUs were similar to the clones from other ecosystems. We showed a high genetic diversity of T4-type bacteriophages and a genetic difference with the phage communities from other ecosystems.Mating-type switching in CBS 732T derived sub-cultures unveils potential genetic and phenotypic novelties in haploid Zygosaccharomyces rouxii
Abstract
In haploid Saccharomyces cerevisiae, a complex recombination system regulates mating-type switching and requires one MAT expression locus, two donor cassettes (HML and HMR) and the HO endonuclease that catalyses gene conversion. Zygosaccharomyces rouxii is the most distant species from S. cerevisiae with a functional HO, but with a poorly understood mating-type switching. Here, we described that two sub-cultures of the type strain CBS 732T underwent the α to a genotype switching leading to mixed MATα and MATa populations. Remarkably, during this event the donor cassette was copied into the MAT locus, except for its own 3' end, resulting in a new MATa2 gene copy different from the silenced HMRa copy. Moreover, CBS 732T cells bypassed the cell-cycle control, which oversees HO transcription in S. cerevisiae, and expressed HO at the stationary phase. Despite HO dysregulation, mating-type switching seemed to occur rarely or belatedly during CBS 732T colony formation in most of the tested conditions. When morphology and mating behaviour were analysed, two sub-cultures displayed distinct outcross fertility responses. Overall, our data support that mating-type switching causes genotype instability and phenotypic novelties in CBS 732T and open the question whether this mechanism is shared by other Z. rouxii haploid homothallic strains.Gram-scale production of recombinant microbial enzymes in shake flasks
Abstract
Heterologous production of recombinant proteins is a cornerstone of microbiological and biochemical research as well as various biotechnological processes. Yields and quality of produced proteins have a tremendous impact on structural and enzymology studies, development of new biopharmaceuticals and establishing new biocatalytic processes. Majority of current protocols for recombinant protein expression in Escherichia coli exploit batch cultures with complex media, often providing low yields of the target protein due to oxygen transfer limitation, rapid depletion of carbon sources, and pH changes during the cultivation. Recently introduced EnBase technology enables fed-batch-like cultivations in shake flasks with continuous glucose release from a soluble starch. In this study, we critically compare the yields of fourteen model enzymes in E. coli cultured in a novel semi-defined medium and in a complex medium. Significant improvements of the volumetric yields 2–31 times were observed for all tested enzymes expressed in enzymatic fed-batch-like cultures with no adverse impact on enzyme structure, stability, or activity. Exceptional yields, higher than one gram of protein per litre of culture, were obtained with six enzymes. We conclude that the novel semi-defined medium tested in this study provides a robust improvement of protein yields in shake flasks without investment into costly bioreactors.
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Publication date: Available online 25 July 2018 Source: Journal of Photochemistry and Photobiology B: Biology Author(s): Marco Ballestr...
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Editorial AJR Reviewers: Heartfelt Thanks From the Editors and Staff Thomas H. Berquist 1 Share + Affiliation: Citation: American Journal...
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Publication date: Available online 28 September 2017 Source: Actas Dermo-Sifiliográficas Author(s): F.J. Navarro-Triviño
