Israel Medical Association Journal

Background: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that is important for the development, maintenance, and repair of the peripheral nervous system. The BDNF gene commonly carries a single nucleotide polymorphism (Val66Met-SNP), which affects the cellular distribution and activity-dependent secretion of BDNF in neuronal cells.

Objectives: To check the association between BDNF Val66Met-SNP as a predisposition that enhances the development of chemotherapy-induced peripheral neuropathy in an Israeli cohort of patients with breast cancer who were treated with paclitaxel.

Methods: Peripheral neuropathy symptoms were assessed and graded at baseline, before beginning treatment, and during the treatment protocol in 35 patients, using the reduced version of the Total Neuropathy Score (TNSr). Allelic discrimination of BDNF polymorphism was determined in the patients' peripheral blood by established polymerase chain reaction and Sanger sequencing.

Results: We found Val/Val in 20 patients (57.14%), Val/Met in 15 patients (42.86%), and Met/Met in none of the patients (0%). Baseline TNSr scores were higher in Met-BDNF patients compared to Val-BDNF patients. The maximal TNSr scores that developed during the follow-up in Met-BDNF patients were higher than in Val-BDNF patients. However, exclusion of patients with pre-existing peripheral neuropathy from the analysis resulted in equivalent maximal TNSr scores in Met-BDNF and Val-BDNF patients.

Conclusions: These observations suggest that BDNF Val66met-SNP has no detectable effect on the peripheral neuropathy that is induced by paclitaxel. The significance of BDNF Val66Met-SNP in pre-existing peripheral neuropathy-related conditions, such as diabetes, should be further investigated.

Background: Trabectedin is a marine-derived chemotherapy, which has received U.S. Food and Drug Administration approval for use in anthracycline-resistant advanced soft tissue sarcoma (STS), especially liposarcoma and leiomyosarcoma (L-sarcomas).

Objectives: To describe our 10 year real-life experience with trabectedin regarding safety and efficacy in a cohort of 86 patients.

Methods: In our study cohort, 46.51% were diagnosed with liposarcoma and 43.02% with leiomyosarcoma. A total of 703 cycles of trabectedin were given, with a median of five cycles per patient (range 1–59). Median overall survival was 13.5 months for the whole cohort, 11 months for liposarcoma patients (range 1–63), and 15 months for leiomyosarcoma patients (range 1–35).

Results: There was no statistically significant difference in progression free survival when stratified according to previous treatment lines given. Trabectedin exhibited a favorable safety profile, with only 22% requiring dose reductions. Grade 3 and higher toxicity was noted in 25% of the patients, mostly due to myelosuppression. There were no treatment-related deaths.

Conclusions: Trabectedin is a safe and effective drug for treating advanced STS. Our results reflect real-life data with patients receiving the drug as a third and even fourth line of treatment, or with a suboptimal performance status, yet achieving impressive clinical benefit rates and survival.

Background: Adjuvant radiotherapy for breast cancer reduces local recurrence and improves survival. In patients with left sided breast cancer, anterior heart position or medial tumor location may cause inadequate breast coverage due to heart shielding. Respiration gating using the Real-time Position Management (RPM) system enables pushing the heart away from the tangential fields during inspiration, thus optimizing the treatment plan.

Objectives: To compare breathing inspiration gating (IG) techniques with free breathing (FB), focusing on breast coverage.

Methods: The study comprised 49 consecutive patients with left sided breast cancer who underwent lumpectomy and adjuvant radiation. RPM was chosen due to insufficient breast coverage caused by an anterior heart position or medial lumpectomy cavity. FB and IG computed tomography simulations were generated for each patient. Breast (PTVbreast) and lumpectomy cavity (CTVlump) were defined as the target areas. Optimized treatment plans were created for each scan. A dosimetric comparison was made for breast coverage and heart and lungs doses.

Results: PTVbreast V95% and mean dose (Dmean) were higher with IG vs. FB (82.36% vs. 78.88%, P = 0.002; 95.73% vs. 93.63%, P < 0.001, respectively). CTVlump V95% and Dmean were higher with IG (98.87% vs. 88.92%, P = 0.001; 99.14% vs. 96.73%, P = 0.003, respectively). The cardiac dose was lower with IG. The IG left lung Dmean was higher. No statistical difference was found for left lung V20.

Conclusions: In patients with suboptimal treatment plans due to anterior heart position or medial lumpectomy cavity, RPM IG enabled better breast/tumor bed coverage and reduced cardiac doses.

Background: The salutary effects of statin therapy in patients with cardiovascular disease (CVD) are well established. Although generally considered safe, statin therapy has been reported to contribute to induction of diabetes mellitus (DM).

Objectives: To assess the risk-benefit of statin therapy, prescribed for the prevention of CVD, in the development of DM.

Methods: In a population-based real-life study, the incidence of DM and CVD were assessed retrospectively among 265,414 subjects aged 40–70 years, 17.9% of whom were treated with statins. Outcomes were evaluated according to retrospectively determined baseline 10 year cardiovascular (CV) mortality risks as defined by the European Systematic COronary Risk Evaluation, statin dose-intensity regimen, and level of drug adherence.

Results: From 2010 to 2014, 5157 (1.9%) new cases of CVD and 11,637 (4.4%) of DM were observed. Low-intensity statin therapy with over 50% adherence was associated with increased DM incidence in patients at low or intermediate baseline CV risk, but not in patients at high CV risk. In patients at low CV risk, no CV protective benefit was obtained. The number needed to harm (NNH; incident DM) for low-intensity dose regimens with above 50% adherence was 40. In patients at intermediate and high CV risk, the number needed to treat was 125 and 29; NNH was 50 and 200, respectively.

Conclusions: Prescribing low-dose statins for primary prevention of CVD is beneficial in patients at high risk and may be detrimental in patients at low CV risk. In patients with intermediate CV risk, our data support current recommendations of individualizing treatment decisions.

Background: Cardiac damage caused by oncological therapy may manifest early or many years after the exposure.

Objectives: To determine the differences between sub-acute and late-onset cardiotoxicity in left ventricular ejection fraction (LVEF) recovery as well as long-term prognosis.

Methods: We studied 91 patients diagnosed with impaired systolic function and previous exposure to oncological therapy. The study population was divided according to sub-acute (from 2 weeks to ≤ 1 year) and late-onset (> 1 year) presentation cardiotoxicity. Recovery of LVEF of at least 50% was defined as the primary end point and total mortality was the secondary end point.

Results: Fifty-three (58%) patients were classified as sub-acute, while 38 (42%) were defined as late-onset cardiotoxicity. Baseline clinical characteristics were similar in the two groups. The mean LVEF at presentation was significantly lower among patients in the late-onset vs. sub-acute group (28% vs. 37%, respectively, P < 0.001). Independent predictors of LVEF recovery were trastuzumab therapy and a higher baseline LVEF. Although long-term mortality rates were similar in the groups with sub-acute and late-onset cardiotoxicity, improvement of LVEF was independently associated with reduced mortality.

Conclusions: Our findings suggest that early detection and treatment of oncological cardiotoxicity play an important role in LVEF recovery and long-term prognosis.

Background: Family physicians and internal medicine specialists play an essential role in treating cancer patients. Modern technological advances in radiotherapy are not widely appreciated by primary care physicians. Bone metastases are a frequent complication of cancer. Palliative radiation therapy, as a component of modern advances in radiation treatments, should not subject normal bodily structures to excessive doses of irradiation. The sacrum is a common destination site for bone metastases, yet its concave shape along with its proximity to the rectum, intestines, and femoral heads creates treatment-planning challenges.

Objectives: To investigated whether the volumetric modulated arc therapy (VMAT) technique is preferable to more conventional radiation strategies.

Methods: The study comprised 22 patients with sacral metastases who were consecutively treated between 2013 and 2014. Two plans were generated for the comparison: three-dimensional (3D) and VMAT.

Results: The planning target volume (PTV) coverage of the sacrum was identical in VMAT and 3D planning. The median values for the rectal dose for 3D and VMAT were 11.34 ± 5.14 Gy and 7.7 ± 2.76 Gy, respectively. Distal sacral involvement (S4 and S5) was observed in only 2 of 22 cases, while the upper pole of the rectum ended at the level above S3 in just 3 cases.

Conclusions: Radiation therapy continues to be an integral component of the palliative armamentarium against painful metastases. Radiation oncologist, in conjunction with referral physicians, can tailor treatment plans to reflect the needs of a given patient.

Background: Accurate diagnosis of community acquired pneumonia (CAP) is crucial to its proper management and to combating antibiotic resistance. Levels of C-reactive protein (CRP) have been shown to distinguish pneumonia from other pathological conditions and can be used to control the severity of infection during admission.

Objective: To investigate an association between consecutive measurements of CRP and the severity of CAP in hospitalized patients.

Methods: A total of 500 patients with CAP were admitted to the hospital. Traditional markers of inflammation including CRP, leukocyte count, body temperature, were measured on the first, second, and fifth days of hospitalization. Correlations between these measures and the length of the hospital stay were calculated.

Results: Mean levels of CRP, body temperature, and leukocyte count were significantly lower on the second day after hospital admission and even lower on the fifth day. A positive correlation of medium strength was found between the level of CRP on the second day of hospitalization and the length of hospital stay (P < 0.001, r_s = 0.447), and a negative correlation was noted between the decrease in CRP level from the first to second day and the length of hospital stay.

Conclusions: CRP levels correlated with body temperature and leukocyte count, traditional markers of inflammation. A greater decrease in CRP level between the first and second day of hospitalization was associated with shorter hospital stay and rapid improvement. These findings support the use of CRP as a marker for the severity and complication of CAP.

Background: Type 2 diabetes mellitus is a multifactorial disease in which genetic susceptibility and environmental factors induce pancreatic β-cell dysfunction and insulin resistance. Additional factors such as hyperglycemia and hyperlipidemia have roles in β-cell dysfunction and disease progression. The phenomenon of lipid-induced pancreatic β-dysfunction, designated as lipotoxicity, has been observed in several in vitro and in vivo experiments; however, there is still no solid evidence for the occurrence of this event in humans. The toxic effect of high lipid levels on β-cell function consists of impaired insulin gene expression, apoptosis, and reduced glucose-stimulated insulin secretion.

Objectives: To demonstrate the importance of treating hypertriglyceridemia in reducing glucose intolerance and the need for insulin therapy in hospitalized diabetic patients.

Methods: We evaluated five clinical case reports and conducted a detailed literature review via the PubMed search engine.

Results: Reduction in elevated blood triglyceride and glucose levels in hospitalized diabetic patients resulted in a rapid decline in glucose levels and in the need for insulin therapy.

Conclusions: A decrease in high triglyceride levels in “lipotoxic” diabetic patients may improve insulin intolerance and glucose homeostasis and reduce the need for insulin therapy.

Background: Gender-related differences (GRD) exist in the outcome of patients with cardiac resynchronization therapy (CRT).

Objectives: To assess GRD in patients who underwent CRT.

Methods: A retrospective cohort of 178 patients who were implanted with a CRT in a tertiary center 2005–2009 was analyzed. Primary outcome was 1 year mortality. Secondary endpoints were readmission and complication rates.

Results: No statistically significant difference was found in 1 year mortality rates (14.6% males vs. 11.8% females, P = 0.7) or in readmission rate (50.7% vs. 41.2%, P = 0.3). The complication rate was only numerically higher in women (14.7% vs. 5.6%, P = 0.09). Men more often had CRT-defibrillator (CRT-D) implants (63.2% vs. 35.3%, P = 0.003) and had a higher rate of ischemic cardiomyopathy (79.2% vs. 38.2%, P < 0.001). There was a trend to higher incidence of ventricular fibrillation/ventricular tachycardia in men before CRT implantation (29.9% vs. 14.7%, P = 0.07%). A higher proportion of men upgraded from implantable cardioverter defibrillator (ICD) to CRT-D, 20.8% vs. 8.8%, P = 0.047. On multivariate model, chronic renal failure was an independent predictor of 1 year mortality (hazard ratio [HR] 3.6; 95% confidence interval [95%CI] 1.4–9.5), CRT-D had a protective effect compared to CRT-pacemaker (HR 0.3, 95%CI 0.12–0.81).

Conclusions: No GRD was found in 1 year mortality or readmission rates in patients treated with CRT. There was a trend toward a higher complication rate in females. Men were implanted more often with CRT-D and more frequently underwent upgrading of ICD to CRT-D.

Background: Erysipelas, an acute infection of the dermal and subcutaneous tissue, is normally treated with antibiotics. Previous data indicated that treatment with prednisone in combination with antibiotics results in significant acceleration of the healing phase.

Objectives: To investigate the effectiveness of corticosteroids combined with antibiotics for the treatment of erysipelas.

Methods: A retrospective study was conducted on hospitalized patients diagnosed with erysipelas between 2004 and 2011 at the Department of Dermatology at Sheba Medical Center, Israel. Data included epidemiology, medical background, and course of the disease as documented at admission and during hospitalization. 

Results: Data were collected on 173 patients (66% males) who were divided into two groups: a control group treated with antibiotics only (97 patients) and a study group treated with antibiotics and prednisone (76 patients). The study group presented with a more severe form of erysipelas (bullous) and those patients were hospitalized for a longer period (8.5 vs. 7 days). Nevertheless, the study group exhibited a 71% clinical improvement shortly after being treated with prednisone, without significant side effects. Short-term follow-up revealed more edema in the study group; however, long-term follow-up revealed a higher incidence of erythema and recurrence of erysipelas in the control group. The return to full function was faster in the study group than in the control group. 

Conclusions: Combining prednisone with antibiotics for the treatment of erysipelas should be considered, especially in severe cases. In addition, a prospective double-blind study should be conducted to verify these conclusions.

Background: Biological agents for anti-tumor necrosis factor-α therapy have revolutionized treatments for autoimmune diseases; however, approximately 20% of rheumatology and 40% of gastroenterology patients do not respond to the therapy, or they show reduced drug efficacy because of anti-drug antibody (ADA) formation.

Objectives: To evaluate laboratory tools for individual monitoring of infliximab therapy and the relationship between ADA and infliximab serum levels, ADA and clinical response, and ADA and autoantibodies.

Methods: Our study comprised patients treated with infliximab and affected by selected rheumatology and gastroenterology diseases. Sera were analyzed for infliximab, total-anti-drug antibodies (Total-ADA), and free-anti-drug antibodies (Free-ADA) serum levels and for the detection of specific autoantibodies.

Results: We analyzed 73 patients. Total-ADA were detected in 26 rheumatology and 21 gastroenterology patients. Serum infliximab levels were significantly lower in Total-ADA positive patients (P = 0.01 for rheumatology group, P = 0.02 for gastroenterology group). A lack of response was observed in 7 rheumatology and 15 gastroenterology samples. Total-ADA serum levels were statistically significantly higher in patients with treatment failure in both groups (P = 0.01 and P = 0.001, respectively). There was no significant association between the presence of Total-ADA and other autoantibodies. Free-ADA were detected in only 27 rheumatology patients. Results showed a significant correlation with clinical outcome (P = 0.006).

Conclusions: The correlation with clinical response suggests that the presence of ADA could interfere with efficacy of therapy. The tests for monitoring therapy may be an important tool to assist clinicians in early detection and prevention of therapy failure.