Medicine by Alexandros G. Sfakianakis: 10/02/17

Δευτέρα 2 Οκτωβρίου 2017

Veliparib With Temozolomide or Carboplatin/Paclitaxel Versus Placebo With Carboplatin/Paclitaxel in Patients With BRCA1/2 Locally Recurrent/Metastatic Breast Cancer: Randomized Phase II Study

Abstract

Background

Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, which interfere with DNA damage repair. Veliparib, a potent PARP inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.

Patients and methods

Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and overall response rate (ORR).

Results

Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively (hazard ratio [HR], 0.789; 95% CI, 0.536–1.162; P=0.227), interim median OS 28.3 and 25.9 months (HR, 0.750; 95% CI, 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR, 1.858; 95% CI, 1.278–2.702; P=0.001), interim median OS 19.1 months (HR, 1.483; 95% CI, 1.032–2.131; P=0.032), and ORR 28.6% (P<0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.

Conclusion

Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared to PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.Clinical trial information: NCT01506609.

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

Abstract

Background

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

Patients and methods

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

Results

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

Conclusion

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

Clinical trial number

Japan Pharmaceutical Information Center, JapicCTI-101155

Surgery for patients with ‘lower grade’ glioma: putting assumptions, beliefs and convictions into perspective

Annals of Oncology 2017:00:1-2. doi:10.1093/annonc/mdx295

Citizenship for children: By soil, by blood, or by paternalism?

Abstract

Do states have a right to exclude prospective immigrants as they see fit? According to statists the answer is a qualified yes. For these authors, self-determining political communities have a prima facie right to exclude, which can be overridden by the claims of vulnerable groups such as refugees and children born in the state's territory. However, there is a concern in the literature that statists have not yet developed a theory that can protect children born in the territory from being excluded from the political community. For if the self-determining political community has the right to decide who should form the self in the first place, then that right should count against both newcomers by immigration and newcomers by birth. Or so the concern goes. In this essay, I defend statism against this line of criticism and provide a liberal justification for the inclusion of children born within the state's borders. My account leads to some surprising implication for citizenship law, as well as immigration arrangements in the area of asylum and unauthorized immigration.

Biochemical and histopathological changes of subacute cadmium intoxication in male rats

Abstract

Biochemical and histopathological effects of subacute intoxication of rats with cadmium (Cd) were studied in rats. Twenty adult healthy male albino rats were randomly divided into two duplicate groups (five rats in each cage); (1) control group where rats were provided with standard diet and water ad-libitum, (2) Cd group where rats were subjected to freshly prepared Cd chloride solution (CdCl2) 200 mg/l in drinking water daily for 8 weeks, the whole duration of experiment. Blood samples were obtained after 4 weeks, via retro-orbital bleeding for separation of serum. Five rats were killed, each sacrifice by decapitation for collection of kidneys and heart. Disturbed renal and cardiac functions were achieved after 4 weeks as indicated by the increase of most biochemical parameters measured in the serum, renal, and cardiac tissues. Histopathological examination of kidneys and hearts showed pathological alterations in Cd-intoxicated rats after 4 and 8 weeks with hematoxylin and eosin (H&E) and Masson trichrome stains. It was concluded that subacute exposure of rats to Cd (200 mg/l) in drinking water daily induced glomerular shrinkage, focal renal, and cardiac fibrosis at 4 and 8 weeks.

Evaluation of fibroblast growth factor activity exerted by placental extract used as a cosmetic ingredient

Summary

Background

The biological activities claimed for placental extract (PE) in its medical and cosmetic applications are largely assumed to be the combined effects of its various signaling molecules and nutritional constituents. But there are considerable uncertainties about this assumption.

Aims

To determine the specific biological activity of PE at a molecular level.

Methods

Fibroblast growth factor (FGF) activity was assessed based on the ability to induce proliferation of FGF receptor (FGFR)-overexpressing BaF3 cells.

Results

Porcine PE (PPE), an ingredient in numerous cosmetics, activated proliferation of BaF3 cells overexpressing FGFR subtypes 1c, 2c, 2b, 3c, or 4, that is, all the major FGFR subtypes. The effect was suppressed largely or partially when the cells were treated with a FGFR inhibitor PD173074, and the FGFR-negative BaF3 parent cells exhibited minimal growth promotion as compared to the FGFR-expressing BaF3 cells. The high (>10 kDa) and low (<3 kDa) molecular weight fractions of PPE were effective activators of FGFR signaling. PPE was found to contain sulfated glycosaminoglycans, including heparin/heparan sulfate and chondroitin sulfate, which serve as both structural stabilizers of FGFs and indispensable cofactors for FGF-FGFR signaling.

Conclusions

These results indicate that PPE is capable of evoking FGF signaling in cells via FGFRs. Given that recombinant FGFs have proven useful for medical/cosmetic purposes, our results suggest that the medical/cosmetic utility of PPE is provided at least partly through the activation of FGF signaling in epidermal, dermal, and subdermal tissues.

Pial Artery Supply as an Anatomic Risk Factor for Ischemic Stroke in the Treatment of Intracranial Dural Arteriovenous Fistulas [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Although intracranial dural arteriovenous fistulas are principally supplied by dural branches of the external carotid, internal carotid, and vertebral arteries, they can also be fed by pial arteries that supply the brain. We sought to determine the frequency of neurologic deficits following treatment of intracranial dural arteriovenous fistulas with and without pial artery supply.

MATERIALS AND METHODS:

One hundred twenty-two consecutive patients who underwent treatment for intracranial dural arteriovenous fistulas at our hospital from 2008 to 2015 were retrospectively reviewed. Patient data were examined for posttreatment neurologic deficits; patients with such deficits were evaluated for imaging evidence of cerebral infarction. Data were analyzed with multivariable logistic regression.

RESULTS:

Of 122 treated patients, 29 (23.8%) had dural arteriovenous fistulas with pial artery supply and 93 (76.2%) had dural arteriovenous fistulas without pial arterial supply. Of patients with pial artery supply, 4 (13.8%) had posttreatment neurologic deficits, compared with 2 patients (2.2%) without pial artery supply (P = .04). Imaging confirmed that 3 patients with pial artery supply (10.3%) had cerebral infarcts, compared with only 1 patient without pial artery supply (1.1%, P = .03). Increasing patient age was also positively associated with pial supply and treatment-related complications.

CONCLUSIONS:

Patients with dural arteriovenous fistulas supplied by the pial arteries were more likely to experience posttreatment complications, including ischemic strokes, than patients with no pial artery supply. The approach to dural arteriovenous fistula treatment should be made on a case-by-case basis so that the risk of complications can be minimized.

Efficacy and Safety of Ethanol Ablation for Branchial Cleft Cysts [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Branchial cleft cyst is a common congenital lesion of the neck. This study evaluated the efficacy and safety of ethanol ablation as an alternative treatment to surgery for branchial cleft cyst.

MATERIALS AND METHODS:

Between September 2006 and October 2016, ethanol ablation was performed in 22 patients who refused an operation for a second branchial cleft cyst. After the exclusion of 2 patients who were lost to follow-up, the data of 20 patients were retrospectively evaluated. All index masses were confirmed as benign before treatment. Sonography-guided aspiration of the cystic fluid was followed by injection of absolute ethanol (99%) into the lesion. The injected volume of ethanol was 50%–80% of the volume of fluid aspirated. Therapeutic outcome, including the volume reduction ratio, therapeutic success rate (volume reduction ratio of >50% and/or no palpable mass), and complications, was evaluated.

RESULTS:

The mean index volume of the cysts was 26.4 ± 15.7 mL (range, 3.8–49.9 mL). After ablation, the mean volume of the cysts decreased to 1.2 ± 1.1 mL (range, 0.0–3.5 mL). The mean volume reduction ratio at last follow-up was 93.9% ± 7.9% (range, 75.5%–100.0%; P < .001). Therapeutic success was achieved in all nodules (20/20, 100%), and the symptomatic (P < .001) and cosmetic (P < .001) scores had improved significantly by the last follow-up. In 1 patient, intracystic hemorrhage developed during the aspiration; however, no major complications occurred in any patient.

CONCLUSIONS:

Ethanol ablation is an effective and safe treatment for patients with branchial cleft cysts who refuse, or are ineligible for, an operation.

Initial Investigation into Microbleeds and White Matter Signal Changes following Radiotherapy for Low-Grade and Benign Brain Tumors Using Ultra-High-Field MRI Techniques [ADULT BRAIN]

BACKGROUND AND PURPOSE:

External beam radiation therapy is a common treatment for many brain neoplasms. While external beam radiation therapy adheres to dose limits to protect the uninvolved brain, areas of high dose to normal tissue still occur. Patients treated with chemoradiotherapy can have adverse effects such as microbleeds and radiation necrosis, but few studies exist of patients treated without chemotherapy.

MATERIALS AND METHODS:

Ten patients were treated for low-grade or benign neoplasms with external beam radiation therapy only and scanned within 12–36 months following treatment with a 7T MR imaging scanner. A multiecho gradient-echo sequence was acquired and postprocessed into SWI, quantitative susceptibility mapping, and apparent transverse relaxation maps. Six patients returned for follow-up imaging approximately 18 months following their first research scan and were imaged with the same techniques.

RESULTS:

At the first visit, 7/10 patients had microbleeds evident on SWI, quantitative susceptibility mapping, and apparent transverse relaxation. All microbleeds were within a dose region of >45 Gy. Additionally, 4/10 patients had asymptomatic WM signal changes evident on standard imaging. Further analysis with our technique revealed that these lesions were venocentric, suggestive of a neuroinflammatory process.

CONCLUSIONS:

There exists a potential for microbleeds in patients treated with external beam radiation therapy without chemotherapy. This finding is of clinical relevance because it could be a precursor of future neurovascular disease and indicates that additional care should be taken when using therapies such as anticoagulants. Additionally, the appearance of venocentric WM lesions could be suggestive of a neuroinflammatory mechanism that has been suggested in diseases such as MS. Both findings merit further investigation in a larger population set.

Does the Addition of a "Black Bone" Sequence to a Fast Multisequence Trauma MR Protocol Allow MRI to Replace CT after Traumatic Brain Injury in Children? [PEDIATRICS]

BACKGROUND AND PURPOSE:

Head CT is the current neuroimaging tool of choice in acute evaluation of pediatric head trauma. The potential cancer risks of CT-related ionizing radiation should limit its use in children. We evaluated the role of MR imaging, including a "black bone" sequence, compared with CT in detecting skull fractures and intracranial hemorrhages in children with acute head trauma.

MATERIALS AND METHODS:

We performed a retrospective evaluation of 2D head CT and brain MR imaging studies including the black bone sequence of children with head trauma. Two experienced pediatric neuroradiologists in consensus created the standard of reference. Another pediatric neuroradiologist blinded to the diagnosis evaluated brain MR images and head CT images in 2 separate sessions. The presence of skull fractures and intracranial posttraumatic hemorrhages was evaluated. We calculated the sensitivity and specificity of CT and MR imaging with the black bone sequence in the diagnosis of skull fractures and intracranial hemorrhages.

RESULTS:

Twenty-eight children (24 boys; mean age, 4.89 years; range, 0–15.5 years) with head trauma were included. MR imaging with the black bone sequence revealed lower sensitivity (66.7% versus 100%) and specificity (87.5% versus 100%) in identifying skull fractures. Four of 6 incorrectly interpreted black bone MR imaging studies showed cranial sutures being misinterpreted as skull fractures and vice versa.

CONCLUSIONS:

Our preliminary results show that brain MR imaging complemented by a black bone sequence is a promising nonionizing alternative to head CT for the assessment of skull fractures in children. However, accuracy in the detection of linear fractures in young children and fractures of aerated bone remains limited.

Habituation of laser-evoked potentials by migraine phase: a blinded longitudinal study

Migraineurs seem to have cyclic variations in cortical excitability in several neurophysiological modalities. Laser-evoked potentials (LEP) are of particular interest in migraine because LEP specifically targe...

The premarket assessment of the cost-effectiveness of a predictive technology “Straticyte™” for the early detection of oral cancer: a decision analytic model

Approximately half of oral cancers are detected in advanced stages. The current gold standard is histopathological assessment of biopsied tissue, which is subjective and dependent on expertise. Straticyte™, a nov...

Panorama Dermatologische Praxis

Determination of single-kidney glomerular filtration rate (GFR) with CT urography versus renal dynamic imaging Gates method

Abstract

Objectives

To present a single-kidney CT-GFR measurement and compare it with the renal dynamic imaging Gates-GFR.

Materials and methods

Thirty-six patients with hydronephrosis referred for CT urography and 99mTc-DTPA renal dynamic imaging were prospectively included. Informed consent was obtained from all patients. The CT urography protocol included non-contrast, nephrographic, and excretory phase imaging. The total CT-GFR was calculated by dividing the CT number increments of the total urinary system between the nephrographic and excretory phase by the products of iodine concentration in the aorta and the elapsed time, then multiplied by (1- Haematocrit). The total CT-GFR was then split into single-kidney CT-GFR by a left and right kidney proportionality factor. The results were compared with single-kidney Gates-GFR by using paired t-test, correlation analysis, and Bland-Altman plots.

Results

Paired difference between single-kidney CT-GFR (45.02 ± 13.91) and single-kidney Gates-GFR (51.21 ± 14.76) was 6.19 ± 5.63 ml/min, p<0.001, demonstrating 12.1% systematic underestimation with ±11.03 ml/min (±21.5%) measurement deviation. A good correlation was revealed between both measurements (r=0.87, p<0.001).

Conclusion

The proposed single-kidney CT-GFR correlates and agrees well with the reference standard despite a systematic underestimation, therefore it could be a one-stop-shop for evaluating urinary tract morphology and split renal function.

Key points

• A new CT method can assess split renal function

• Only using images from CT urography and the value of haematocrit

• A one-stop-shop CT technique without additional radiation dose

Time-dependent analysis of incidence, risk factors and clinical significance of pneumothorax after percutaneous lung biopsy

Abstract

Objectives

To evaluate the time-dependent incidence, risk factors and clinical significance of percutaneous lung biopsy (PLB)-related pneumothorax.

Methods

From January 2012–November 2015, 3,251 patients underwent 3,354 cone-beam CT-guided PLBs for lung lesions. Cox, logistic and linear regression analyses were performed to identify time-dependent risk factors of PLB-related pneumothorax, risk factors of drainage catheter insertion and those of prolonged catheter placement, respectively.

Results

Pneumothorax occurred in 915/3,354 PLBs (27.3 %), with 230/915 (25.1 %) occurring during follow-ups. Risk factors for earlier occurrence of PLB-related pneumothorax include emphysema (HR=1.624), smaller target (HR=0.922), deeper location (HR=1.175) and longer puncture time (HR=1.036), while haemoptysis (HR=0.503) showed a protective effect against earlier development of pneumothorax. Seventy-five cases (8.2 %) underwent chest catheter placement. Mean duration of catheter placement was 3.2±2.0 days. Emphysema (odds ratio [OR]=2.400) and longer puncture time (OR=1.053) were assessed as significant risk factors for catheter insertion, and older age (parameter estimate=1.014) was a predictive factor for prolonged catheter placement.

Conclusion

PLB-related pneumothorax occurred in 27.3 %, of which 25.1 % developed during follow-ups. Smaller target size, emphysema, deeply-located lesions were significant risk factors of PLB-related pneumothorax. Emphysema and older age were related to drainage catheter insertion and prolonged catheter placement, respectively.

Key Points

• One-fourth of percutaneous lung biopsy (PLB)-related pneumothorax occurs during follow-up.

• Smaller, deeply-located target and emphysema lead to early occurrence of pneumothorax.

• Emphysema is related to drainage catheter insertion for PLB-related pneumothorax.

• Older age may lead to prolonged catheter placement for PLB-related pneumothorax.

• Tailored management can be possible with time-dependent information of PLB-related pneumothorax.

Self-controlled super-selective arterial spin labelling

Abstract

Objectives

Arterial spin labelling (ASL) is a method of non-contrast-enhanced perfusion imaging that is generally based on the acquisition of two images which must be subtracted in order to obtain perfusion-weighted images. This is also the case for some flow territory mapping approaches that require the acquisition of two images for each artery of interest, thereby prolonging scan time and yielding largely redundant information. The aim of this study is to accelerate flow territory mapping using ASL by eliminating the acquisition of a control condition.

Methods

Using super-selective ASL, only one artery of interest is tagged, while the contralateral arteries are in a state similar to the control condition. By using an arithmetic combination of the label images of all territories, selective images of flow territories can be obtained without the need to acquire an additional control condition. This approach for obtaining artery-selective perfusion-weighted images without acquiring a control condition is presented in this study and is referred to as "self-controlled super-selective ASL".

Results

Quantitative perfusion measurements were similar to conventional super-selective and non-selective perfusion imaging across all subjects.

Conclusion

Super-selective arterial spin labelling can be performed without acquiring a control image.

Key Points

• An accelerated method of flow territory mapping is presented.

• Super-selective arterial spin labelling is performed without a control condition.

• A new approach for calculating individual flow territories is presented.

• The presented technique is compared to established approaches.

• The outcome is similar to that using conventional techniques.

A prospective study evaluating the utility of a 2-mm biopsy margin for complete removal of histologically atypical (dysplastic) nevi

Publication date: Available online 2 October 2017
Source:Journal of the American Academy of Dermatology
Author(s): Vitaly Terushkin, Elise Ng, Jennifer A. Stein, Susan Katz, David E. Cohen, Shane Meehan, David Polsky
BackgroundComplete removal of individual dysplastic nevi (DN) is often accomplished by a second surgical procedure after the initial biopsy. The choice to perform the second procedure is strongly influenced by histopathologic margin status of the initial biopsy specimen.ObjectiveTo evaluate the clinical and histopathologic outcomes of in toto biopsy of DN using a predetermined margin of normal skin.MethodsWe conducted a prospective study of a saucerization method using a defined 2-mm margin in patients undergoing biopsy of a pigmented skin lesion.ResultsWe performed 151 biopsies in 138 patients. Overall, 137 of 151 lesions subjected to biopsy (90.7%) were melanocytic: 86 DN (57.0%), 40 nevi without atypia (26.5%), and 11 melanomas (7.3%). Of 78 DN, 68 (87.2%) were removed with clear histopathologic margins (8 DN were excluded because of inadequate processing). There was no clinical evidence of recurrence at any of the biopsy sites that were simply observed (i.e., not re-excised) over a median of 16.9 months.LimitationsThere were few biopsies performed on the face.ConclusionsThe complete histopathologic removal of nearly 9 of 10 DN using a peripheral margin of 2 mm of normal skin and a depth at the dermis and subcutaneous fat junction has the potential to decrease second procedures at DN biopsy sites, thereby decreasing patient morbidity and saving health care dollars.

Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182,alsfakia@gmail.com