Israel Medical Association Journal

Background: The neutrophil to lymphocyte ratio (NLR) has demonstrated prognostic value in various malignant conditions, including gastric adenocarcinoma. However, chemotherapy may affect NLR.

Objectives: To evaluate the prognostic value of NLR as an accessory decision-making tool in terms of operating patients after neoadjuvant chemotherapy in patients with resectable gastric cancer.

Methods: We collected oncologic, perioperative, and survival data of patients with gastric adenocarcinoma who underwent curative intent gastrectomy and D2 lymphadenectomy between 2009 and 2016. The NLR was calculated from preoperative laboratory tests and classified as high (> 4) and low (≤ 4). The t-test, chi-square, Kaplan-Meier analysis, and Cox multivariate regression models were used to assess associations of clinical, histologic, and hematological variables with survival.

Results: For 124 patients the median follow-up was 23 months (range 1–88). High NLR was associated with greater rate of local complication (r=0.268, P < 0.01). The rate of major complications (Clavien-Dindo ≥ 3) was higher in the high NLR group (28% vs. 9%, P = 0.022). Among the 53 patients who received neoadjuvant chemotherapy, those with low NLR had significantly improved disease-free survival (DFS) (49.7 vs. 27.7 months, P = 0.025). Low NLR was not significantly associated with overall survival (mean survival, 51.2 vs. 42.3 months, P = 0.19). Multivariate regression identified NLR group (P = 0.013), male gender (P = 0.04), and body mass index (P = 0.026) as independently associated with DFS.

Conclusions: Among gastric cancer patients planned for curative intent surgery who underwent neoadjuvant chemotherapy, NLR may have prognostic value, particularly regarding DFS and postoperative complications.

Background: Population screening for the BRCA mutations in Ashkenazi Jewish women was recently implemented in Israel and is expected to lead to a 10-fold increase in the diagnosis of asymptomatic carriers. Performing the screening follow-up within multidisciplinary dedicated clinics for carriers is recommended for early detection and risk reduction.

Objectives: To determine the availability, capacity, and practices of dedicated screening clinic for BRCA carriers in Israel.

Methods: A telephone-based survey of all public hospitals in Israel was conducted October 2020 to August 2021 to determine whether they had a dedicated clinic. Dedicated clinics were defined as multidisciplinary screening clinics offering at least breast and gynecological screening and risk reducing services on site. The clinic director or nurse navigator answered a questionnaire about screening practices followed by a semi-structured interview.

Results: Of the ten dedicated BRCA clinics found in Israel, nine participated. Approximately 4500 BRCA carriers are currently being followed. No specialized clinics are available in the southern district or in the northernmost half of the northern district of Israel, leading to a disparity between periphery and center. Screening recommendations, although asserted as adhering to international guidelines, vary among clinics including age at initiating of clinical exam, use of adjunct imaging modalities, and follow-up during lactation and after risk reducing surgery.

Conclusions: There is a suboptimal distribution of dedicated clinics for BRCA carriers in Israel. Nationally centralized attempt to create guidelines that will unify screening practices is warranted, especially considering the expected increase in demand.

Background: Pilonidal sinus is a chronic, inflammatory condition. Controversy exists regarding the best surgical  management for pilonidal sinus, including the extent of excision and type of closure of the surgical wound.

Objectives: To assess the short- and long-term outcomes and success rate of the trephine procedure for the treatment of pilonidal sinus.

Method: A retrospective observational cohort study was conducted at a single center. Patients who underwent trephine procedure between 2011 and 2015 were included. Data collection included medical records review and a telephone interview to establish long-term follow-up.

Results: A total of 169 patients underwent the trephine technique for the repair of pilonidal sinus. Follow-up included 113 patients, median age 20 years. Initial postoperative period, 35.6% recalled no pain and 58.6% reported a mild to moderate pain. Postoperative complications included local infection (7.5%) and mild bleeding (15.1%). On early postoperative follow-up, 47.1% recalled no impairment in quality of life, and 25%, 21.2 %, and 6.7% had mild, moderate and sever disturbance respectively. The median time to return to work or school was 10 days. At a median follow-up of 29 months (IQR 19–40), recurrence rate was 45.1% (51/113), and 38 (33.9%) of the patients underwent another surgical procedure. Overweight, smoking, and family history were associated with higher recurrence rate.

Conclusion: The trephines technique has a significant long-term recurrence rate. Short-term advantages include low morbidity, enhanced recovery, and minimal to mild postoperative impairment to quality of life. The trephine procedure may be justified as a first treatment of pilonidal disease

Background: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials.

Objectives: To report the first Israeli experience with HSCT for progressive SSc and review the current literature.

Methods: Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages.

Results: Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded.

Conclusions: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

Background: Recent studies have analyzed risk factors associated with complications after gastric cancer surgery using the Clavien-Dindo classification (CD). However, they have been based on Asian population cohorts (Chinese, Japanese, Korean).

Objectives: To prospectively analyze all post-gastrectomy complications according to severity using CD classification and identify postoperative risk factors and complications.

Methods: We analyzed all gastrectomies for gastric cancer performed 2009–2014. Recorded parameters included demographic data, existing co-morbidities, neo-adjuvant treatment, intra-operative findings, postoperative course, and histologic findings. Postoperative complications were graded using CD classification.

Results: The study comprised 112 patients who underwent gastrectomy. Mean age was 64.8 ± 12.8 years; 53 patients (47%) underwent gastrectomy, 37 (34%) total gastrectomy, and 22 (19%) total extended gastrectomy. All patients had D2 lymphadenectomy. The average number of retrieved lymph nodes was 35 ± 17. Severe complication rate (≥ IIIa) was 14% and mortality rate was 1.8%. In a univariate analysis, age > 65 years; ASA 3 or higher; chronic renal failure; multi-organ resection; and tumor, node, and metastases (TNM) stage ≥ IIIc were found to be significantly associated with CD complication grade > III (P = 0.01, P = 0.05, P = 0.04, P = 0.04, and P = 0.01, respectively). Multivariate regression analysis revealed advanced stage (≥ IIIc) and age > 65 years to be significant independent risk factors (P < 0.05).

Conclusions: Age > 65 and advanced stage (≥ IIIc) were the primary risk factors for complications of grade > III according to the CD classification following gastrectomy for gastric cancer.

Background: Selection of appropriate reference charts for fetal biometry is mandatory to ensure an accurate diagnosis. Most hospitals and clinics in Israel use growth curves from the United States. Charts developed in different populations do not perform well in the Israeli population.

Objectives: To construct new reference charts for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), using a large sample of fetuses examined at 14–42 weeks gestational age in a medical center and a community ultrasound unit located in two different regions of Israel. 

Methods: Data from the medical center and the community clinic were pooled. The mean and standard error of each measure for each week was calculated. Based on these, reference charts were calculated using quantiles of the normal distribution. The performance of the reference charts was assessed by comparing the new values to empirical quantiles.

Results: Biometric measurements were obtained for 79,328 fetuses. Growth charts were established based on these measurements. The overall performance of the curves was very good, with only a few exceptions among the higher quantiles in the third trimester in the medical center subsample.

Conclusions: We present new local reference charts for fetal biometry, derived from a large and minimally selected Israeli population. We suggest using these new charts in routine daily obstetric practice.

 

Objectives: To retrospectively determine the clinical response to ¹³¹I-MIBG therapy at low doses in patients with refractory neuroblastoma.

Methods: We performed a retrospective chart review of 10 patients with neuroblastoma treated with ¹³¹I-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of ¹³¹I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course.

Results: Twenty-one courses of ¹³¹I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5–6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of ¹³¹I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed.

Conclusions: Low dose ¹³¹I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with ¹³¹I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose ¹³¹I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.

Background: Cardiac patients express elevated levels of B-type natriuretic peptide and the amino terminal segment of its prohormone (NT-proBNP). However, there are non-cardiac causes of NT-proBNP level elevation.

Objectives: To determine the upper limit of NT-proBNP for pediatric patients with acute non-cardiac disease.

Methods: We compared NT-proBNP concentrations in healthy children and children with acute non-cardiac, mostly febrile, and acute cardiac disease. We used the Student t-test and Mann-Whitney test for group comparisons, and Pearson's and Spearman's correlation coefficients to test relationships between variables. 

Results: In 138 patients with acute non-cardiac diseases (mean age 3.7 years, 53% male), median NT-proBNP concentration was 162 pg/ml, upper limit (95% percentile) 1049 pg/ml. The level did not vary significantly by disease category; was negatively correlated with weight, weight percentile, age and hemoglobin level; and positively correlated with creatinine level. Multivariant analysis showed weight to be the only factor influencing NT-proBNP level. Levels were higher in children with acute non-cardiac diseases versus healthy children (median 88 pg/ml, P < 0.001, n= 59), and lower than levels in patients with acute cardiac disease (median 29,986 pg/ml, P < 0.001, n=29). Receiver operating characteristic analysis showed good NT-proBNP performance for differentiation between children with acute cardiac versus non-cardiac disease (area under the curve 0.958), at a cutoff of 415 pg/ml.

Conclusions: NT-proBNP levels are higher in children with acute non-cardiac diseases than in healthy children, but lower than in children with acute cardiac disease. NT-proBNP negatively correlated with weight and weight percentile.
 

Background: Persistent creatine kinase elevation is occasionally encountered in subjects without any clinical manifestation of a neuromuscular disorder or any condition known to be associated with increased serum CK[1] levels. It is still unresolved whether extensive investigations and specifically a muscle biopsy should be performed in clinically normal individuals with elevated CK levels.

Objective: To study the muscle pathology of patients with asymptomatic or minimally symptomatic hyperCKemia.

Methods: The clinical and laboratory data of patients with persistent hyperCKemia and normal neurologic examination were reviewed and their muscle biopsies evaluated.

Results: The study group included 40 patients aged 7–67 years; the male to female ratio was 3:1. Nineteen patients were completely asymptomatic, 20 had mild non-specific myalgia, and 1 had muscle cramps. Electromyography was performed in 27 patients and showed myopathic changes in 7 (26%). Abnormal muscle biopsy findings (e.g., increased variation in fiber size, increased number of central nuclei and occasional degenerating fibers) were detected in 22 of the 40 patients (55%). No fat or glycogen accumulation was detected. Immunohistochemistry demonstrated abnormal dystrophin staining in 3 patients (8%), resembling the pathologic changes of Becker muscular dystrophy. No abnormal findings were detected on immunohistochemical staining for merosin, dysferlin, caveolin 3, or alpha and gamma sarcoglycans. The EMG[2] findings did not correlate with the pathologic findings.

Conclusions: Abnormal muscle biopsies were found in 55% of patients with asymptomatic or minimally symptomatic hyperCKemia. Specific diagnosis of muscular dystrophy, however, was possible in only 8% of the patients.

Background: Multifetal pregnancy reduction has been implemented for improving the outcome of multifetal pregnancies. Recent studies reported no difference in pregnancy outcome between reduced twins and non-reduced twins, but the neonatal course and subsequent outcome in reduced twin pregnancies were not well documented.

Objective: To compare the neonatal course and outcome, as well as the gestational and labor characteristics, in twins from reduced multifetal pregnancies and in non-reduced twins.

Methods: This is a retrospective case-control study of the neonatal course of twins from reduced multifetal pregnancies. We found 64 mothers with multifetal pregnancy reduction who delivered twins during 1989–1997; 64 gestational age-matched non-reduced twin pregnancies served as controls. The following neonatal variables were examined: major malformations; small birth weight for gestational age; and neonatal morbidities including respiratory distress syndrome, apnea, pneumothorax, bronchopulmonary dysplasia, hyperbilirubinemia, sepsis, necrotizing enterocolitis, retinopathy of prematurity, seizures, intraventricular hemorrhage, periventricular leukomalacia, ventriculomegaly, and hydrocephalus. In addition, we evaluated several neonatal interventions (surfactant replacement, mechanical ventilation, phototherapy, total parenteral nutrition), and some laboratory abnormalities (thrombocytopenia, leukopenia, anemia, and hypoglycemia), duration of hospitalization, and neonatal mortality.

Results: Gestational and labor variables were not significantly different between multifetal pregnancies reduced to twins and non-reduced twin pregnancies. The neonatal morbidity and mortality were not significantly different between twin neonates from multifetal pregnancy reduction and non-reduced control twins.

Conclusions: Multifetal pregnancy reduction to twins appears to bear no adverse effect on the intrauterine course of the remaining fetuses or their neonatal course and outcome when born after 28 weeks of gestation.
 

Background: The prediction that Duchenne muscular dystrophy patients have out-of-frame deletions and Becker muscular dystrophy patients have in-frame deletions of the dystrophin gene holds well in the vast majority of cases. Large in-frame deletions involving the rod domain only have usually been associated with mild (BMD[1]) phenotype.

Objectives: To describe unusual cases with large in-frame deletions of the rod-shaped domain of the dystrophin gene associated with severe (Duchenne) clinical phenotype

Methods: Screening for dystrophin gene deletion was performed on genomic DNA by using multiplex polymerase chain reaction. Needle muscle biopsies from the quadriceps were obtained using a BergstrÖm needle. The biopsies were stained with histologic and histochemical techniques as well as monoclonal antibodies to dystrophin 1, 2 and 3.

Results: In three children with large in-frame deletions of the rod domain (exons 10–44, 13–40 and 3–41), early-onset weakness and a disease course suggested the DMD[2] phenotype.

Conclusions: This observation emphasizes the uncertainty in predicting the Becker phenotype in a young patient based on laboratory evaluation, and that the clinical picture should always be considered.

Background: Articular cartilage is incapable of undergoing self-repair since chondrocytes lose their mitotic ability as early as the first year of life. Defects in articular cartilage, especially in weight-bearing joints, will predictably deteriorate toward osteoarthritis.  No method has been found to prevent this deterioration. Drilling of the subchondral bone can lead to fibrocartilage formation and temporary repair that slowly degrades. Animal experiments indicate that introducing proliferating chondrocytes such as cultured articular chondrocytes can reliably reconstruct joint defects.

Objectives: To describe our clinical experience in culturing and transplanting autologous chondrocytes. 

Methods: Biopsies were obtained from 10 patients, aged 18–45, undergoing a routine arthroscopy in which a cartilage defect was identified with indications for cartilage transplantation. The biopsies were further processed to establish chondrocyte cultures. ACT was performed in 8 of the 10 patients because of persistent symptoms for at least 2 months post-arthroscopy. All patients (6 men and 2 women) had a grade IV cartilage defect in the medial or lateral femoral condyle, and three had a defect in the trochlear region as well. Biopsies were removed from the lateral rim of the superior aspect of the femur, and cells were cultured in a clean room. Following a 2 order of magnitude expansion, cells were implanted under a periosteal flap.

Results: The eight patients implanted with autologous cells were followed for 6 months to 5 years (average 1 year). Complaints of giving-way, effusion and joint locking resolved in all patients, and pain as assessed by the visual analogue score was reduced by an average of 50%. Follow-up magnetic resonance imaging studies in all patients revealed that the defects were filled with tissue having similar signal characteristics to cartilage.

Conclusions: Chondrocyte implantation is a procedure capable of restoring normal articular cartilage in cases with isolated joint defects. Pain can be predictably reduced, while joint locking and effusion are eliminated. The effect on osteoarthritis progression in humans has not yet been elucidated.

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ACT = autologous chondrocyte transplantation