Tzippy Shochat

The syndrome of inappropriate antidiuretic hormone secretion: Distribution and characterization according to etiologies.

PURPOSE To determine the distribution of etiologies for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in hospitalized patients and to characterize patients according to the different etiologies. METHODS A single-center retrospective study including all patients diagnosed with SIADH in a large community hospital and tertiary center between 1.1.2007 and 1.1.2013. Two physicians reviewed every patients medical file for predetermined relevant clinical data. RESULTS The study cohort included 555 patients. The most common etiologies were malignancies and medication-induced SIADH, followed by idiopathic SIADH, pulmonary infections, pain and nausea, and central nervous system (CNS) disorders. Subgroup analysis according to etiology showed that CNS disorders were associated with more severe episodes of SIADH. Patients with idiopathic SIADH were older than patients with a specific diagnosis, had a lower urine osmolality, and required less treatment with hypertonic saline. Long-term survival was determined primarily by SIADH etiology rather than hyponatremia severity, with hazard ratios for death of up to 7.31 (95% CI 4.93-10.82, p<0.001) for patients with malignancy-associated SIADH as compared to patients with idiopathic SIADH. Hyponatremia grade at short-term follow-up was also predictive for long-term survival (HR 1.42 per grade, 95% CI 1.21-1.66, p<0.001). CONCLUSIONS Patients with SIADH have different characteristics and a different prognosis according to SIADH etiology. Serum sodium concentration at short-term follow-up is predictive of long-term survival. These findings might have diagnostic and treatment-related implications.

Relationship Between Body Mass Index and Intraocular Pressure in Men and Women: A Population-based Study.

Purpose:To assess the possibility of a relationship between body mass index (BMI) and intraocular pressure (IOP) in both men and women. Materials and Methods:A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 18,575 subjects, within an age range 20 to 80 years. Results:The mean (±SD) age of the study sample was 46 (±10) years, 68% were men. A positive linear correlation was found between BMI and IOP for both men and women (r=0.166, P<0.0001 in men and r=0.202, P<0.0001 in women). Mean (95% confidence interval) IOP in subjects with BMI<25 kg/m2 was 12.8 mm Hg (range, 12.7 to 12.9 mm Hg) and increased significantly to 13.4 (range, 13.3 to 13.5 mm Hg); 13.9 mm Hg (range, 13.8 to14.0 mm Hg), and 14.3 mm Hg (range, 14.1 to 14.5 mm Hg) for BMI subcategories 25 to 29.9, 30 to 35, and >35 kg/m2, respectively (P<0.0001). These differences remained significant after multivariate adjustment for age, hypertension, and diabetes mellitus (P<0.0001). Similar multivariate adjustments showed that the coefficient factors for BMI (95% confidence interval) affecting IOP were 0.087 (range, 0.076 to 0.098) P<0.0001 and 0.070 (range, 0.058 to 0.082) P<0.0001 for men and women respectively, indicating that in men and women, the changes in IOP associated with a 10 kg/m2 increase in BMI were 0.9 and 0.7 mm Hg, respectively. Subjects with abnormal BMI compared with subjects with normal BMI had increased odds ratio of having IOP≥18 mm Hg after adjusting for confounding factors (P<0.001). Conclusions:This study shows that obesity is an independent risk factor for increasing IOP in both men and women. We consider this finding particularly pertinent in the context of the current obesity epidemic.

Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study

Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR‐MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR‐MM outside of a clinical trial setting was conducted by our group. One hundred and thirty‐five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two‐ or three‐drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three‐drug combination and patients presenting without extramedullary disease. The median progression‐free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [CI] 3·8–6·4) and 12·2 months (95% CI 9‐not reached), respectively. Toxicity was manageable, although treatment‐related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.

ALK-Rearranged Non–Small-Cell Lung Cancer Is Associated With a High Rate of Venous Thromboembolism

Background Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non–small‐cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)‐rearranged NSCLC. Patients and Methods We identified all patients with ALK‐rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK‐rearranged NSCLC treated in 2 tertiary centers in Israel. Results Within the PM CC cohort, of 55 patients with ALK‐rearranged NSCLC, at a median follow‐up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow‐up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). Conclusion The rate of VTE in our ALK‐rearranged cohort was 3‐ to 5‐fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts. Micro‐Abstract We examined the rate of venous thromboembolism in a cohort of consecutive patients with ALK‐rearranged non–small‐cell lung cancer (NSCLC) at a single center and found it to be 3‐ to 5‐fold higher than previously reported in the setting of advanced NSCLC. The results were comparable when we included a validation cohort of consecutive patients at 2 other centers, with an overall rate of 36%. Prospective confirmation is warranted.

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors

Introduction: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. Methods: Multi‐institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non‐V600E (group B, n = 18). Programmed death ligand 1 (PD‐L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression‐free survival (PFS) with ICPi, and overall survival were analyzed. Results: High (≥50%), intermediate (1–49%), and no (<1%) PD‐L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status–high. Twenty‐two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6–6.6), and 4.1 months (95% CI: 0.1–19.6) in groups A and B, respectively (log‐rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD‐L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13–NR) and comprised 21.1 months (95% CI: 1.8–NR) for patients who were and were not exposed to ICPi, respectively (log‐rank test = 5.58, p = 0.018). Conclusions: BRAF mutant NSCLC is associated with high level of PD‐L1 expression, low/intermediate TMB and microsatellite‐stable status. ICPi have favorable activity both in BRAF V600E and BRAF non‐V600E mutant NSCLC.

Bone mineral density utilization in patients with newly diagnosed multiple myeloma

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual‐energy X‐ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One‐hundred seventy three patients were included. The T‐scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femurs T‐scores (r = 0.56–0.61, p < 0.0001), although different sets of variables were correlated with LS and femurs T‐scores. There was no correlation between BMD measurements and osteolytic disease extent. Patients with vertebral fracture(s) had significant lower T‐scores of the spine in comparison to patients without vertebral fractures. Sixty‐three patients (36.4% of the cohort) had follow‐up DXA exam. In general, there was an increase in the LS T‐scores, while femoral values decreased. However, in patients who achieved complete response (CR) and in those who retained CR during follow‐up, femoral BMD increased as well. Because correlation between BMD and the extent of osteolytic lesions was not seen, our data support the recent exclusion of BMD assessment from the definition of symptomatic myeloma. Still, its use should be considered for evaluation of age‐ or therapy‐related osteoporosis. Copyright

Uninvolved immunoglobulins predicting hematological response in newly diagnosed AL amyloidosis.

Immunoparesis serves as a marker for elevated risk for progression in plasma cell proliferative disorders. However, the impact of immunoparesis in AL amyloidosis has not been addressed. Immunoparesis was defined qualitatively as any decrease below the low reference levels of the uninvolved immunoglobulins and quantitatively, as the relative difference between the uninvolved immunoglobulins and the lower reference values. Forty-one newly diagnosed AL amyloidosis patients were included. Sixty-six percent of patients had a suppression of the uninvolved immunoglobulins. The median relative difference of the uninvolved immunoglobulins was 18% above the low reference levels [range (-71%)-210%]. Ninety percent of the patients were treated with novel agents-based regimens, mostly bortezomib-containing regimens. Nineteen percent of the patients did not attain response to first line treatment. Patients with relative difference of uninvolved immunoglobulins below -25% of the low reference levels were less likely to respond to first line treatment compared to patients with a relative difference of -25% and above [odds ratio for no response vs. partial response and better 30 [(95% CI 4.1-222.2), P=0.0004]. Patients who failed first line treatment were successfully salvaged with lenalidomide-based treatment. Immunoparesis, if assessed quantitatively, may serve as a predictor of response in AL amyloidosis patients treated with bortezomib-containing regimens.

Extracellular-like matrices and leukaemia inhibitory factor for in vitro culture of human primordial follicles

The possibility of maturing human primordial follicles in vitro would assist fertility restoration without the danger of reseeding malignancies. Leukaemia inhibitory factor (LIF) and certain culture matrices may promote human follicular growth. The present study compared human primordial follicular growth on novel culture matrices, namely human recombinant vitronectin (hrVit), small intestine submucosa (SIS), alginate scaffolds and human recombinant virgin collagen bioengineered in tobacco plant lines (CollPlant). The frozen-thawed ovarian samples that were used had been obtained from girls or young women undergoing fertility preservation. In the first part of the study, 20 samples were cultured for 6 days on hrVit or SIS with basic culture medium alone or supplemented with one of two concentrations of LIF (10ngmL-1 and 100ngmL-1), with and without LIF-neutralising antibody. In the second part of the study, 15 samples were cultured for 6 days on alginate scaffolds or CollPlant matrices with basic culture medium. Follicular development was assessed by follicular counts and classification, Ki67 immunohistochemistry and 17β-oestradiol and anti-Müllerian hormone measurements in spent media samples. Primordial follicular growth was not enhanced by LIF. Despite some significant differences among the four matrices, none appeared to have a clear advantage, apart from significantly more Ki67-stained follicles on alginate and CollPlant matrices. Further studies of other culture matrices and medium supplements are needed to obtain an optimal system.

Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: the real-life data

OBJECTIVES Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.

Relationship Between Serum Glucose Levels and Intraocular Pressure, a Population-based Cross-sectional Study

Purpose: The purpose of this study is to assess the relationship between serum glucose levels and intraocular pressure (IOP) both in subjects with impaired fasting glucose (IFG) as well as in subjects with diabetes mellitus (DM). Materials and Methods: Data of a cross-sectional sample of 18,406 subjects who underwent routine annual screening at a tertiary medical center in 2000 to 2013 were analyzed. Results: Mean (SD) age of the subjects was 46 (10) years; 68% were male. Mean (95% confidence interval) IOP measured 13.1 (13.0-13.1) mm Hg in subjects with normal glucose levels, 13.7 (13.6-13.8) mm Hg in subjects with IFG, and 14.3 (14.1-14.4) mm Hg in subjects with diabetes. The difference in IOP between subjects with normal and abnormal (DM or IFG) serum glucose levels were significant, even after adjusting for age, body mass index, and hypertension (P<0.0001). There was a positive linear correlation between serum glucose levels and IOP in both men (r=0.12; P<0.0001) and women (r=0.17; P<0.0001). For every 10 mg/dL increase in fasting serum glucose, IOP increased by 0.09 mm Hg in men and by 0.11 mm Hg in women. Conclusions: This study demonstrated that similar to subjects with DM, subjects with IFG also have IOP levels that are higher than those with normal serum glucose. Moreover, there is a direct correlation between fasting serum glucose levels and changes in IOP. These findings highlight another end-organ effect of uncontrolled glucose levels.