Response Rate of the Third and Fourth Doses of the BNT162b2 Vaccine Administered to Cancer Patients Undergoing Active Anti-Neoplastic Treatments.

The BNT162b2 vaccine is globally used for preventing morbidity and mortality related to COVID-19. Cancer patients have had priority for receiving the vaccine due to their diminished immunity. This study reports the response rate of administering the third and fourth vaccine doses to cancer patients receiving active anti-neoplastic treatment. A total of 142 patients received two doses of the mRNA-based BNT162b2 COVID-19 vaccine, while 76 and 25 patients received three and four doses, respectively. The efficacy of the humoral response following two vaccine doses was diminished in cancer patients, especially in the group of patients receiving chemotherapy. In a multivariate analysis, patients who received three and four BNT162b2 vaccine doses were more likely to have antibody titers in the upper tertile compared to patients who received two doses of the vaccine (odds ratio (OR) 7.62 (95% CI 1.38-42.12), p = 0.02 and 17.15 (95% CI 5.01-58.7), p < 0.01, respectively). Unlike the response after two doses, the third and fourth BNT162b2 vaccine booster doses had an increased efficacy of 95-100% in cancer patients while undergoing active treatment. This result could be explained by different mechanisms including the development of memory B cells.

Bnai-Zion Medical Center Healthcare Workers' Levels of Professional Burnout during the COVID-19 Pandemic.

Objectives: Unprecedented challenges in hospital care were imposed in response to the COVID-19 pandemic due to the highly contagious disease. Healthcare services adjusted for working with additional personal protection equipment and hygiene measures while attending to a large number of critically ill patients. In this study, we aimed to determine burnout rates and preferred interventions among healthcare staff, including nurses and physicians, at Bnai-Zion Medical Center during the COVID-19 pandemic. Methods: The Copenhagen Burnout Inventory questionnaire was administered to 185 cross-sectional volunteer participants from the nursing and medical staff between June and August 2020, when Israel experienced its second surge of COVID-19. Results: We found a statistically significant correlation between work-related and personal burnout. COVID-19 ward staff had greater burnout levels than the rest of our institution's personnel. Most highly burned-out healthcare workers were interested in intervention therapy. Conclusions: Dealing with burnout is imperative to improve the well-being of our hospital staff and ensure the best possible performance. Nursing management should consider first-line responders' stressful conditions to be alleviated through support programs.

Factors Predicting Type I Gastric Neuroendocrine Neoplasia Recurrence: A Single-Center Study.

Type I gastric neuroendocrine neoplasms (gNENs) are associated with atrophic gastritis and have a high recurrence rate, which means frequent endoscopies are required. The objective of this study was to identify factors predicting the local recurrence of type I gNENs. The clinical course and the pathological and biochemical data of patients with type I gNENs treated at Bnai Zion Medical Center between 2006 and 2022 were analyzed retrospectively. Twenty-seven type I gNENs were evaluated. The follow-up period was 41 months (range: 11-288 months). Recurrence of the tumor occurred in 13/27 (48%) patients after 35 months (median (M), interquartile range (IQR): 21-67.5). Serum gastrin levels were significantly higher in patients with recurrent disease versus patients with non-recurrent disease (788 vs. 394 ng/L; p = 0.047), while the Ki-67 index was significantly lower in patients with recurrent disease versus patients with non-recurrent disease (1% vs. 3.5%; p = 0.035). Tumor size, mitotic count, and serum chromogranin A levels did not correlate with recurrence. The present study emphasizes the role of gastrin in the pathogenesis of gNEN recurrence and highlights the debate regarding the ability of the Ki-67 index to predict the clinical course of this disease.

Sensitivity of Different ACTH and Cortisol Concentration Values in Corticotropin-Releasing Hormone Based Tests in Cushing's Disease.

PURPOSE: In Cushing's disease (CD) patients, the aim of the present study is to confirm sensitivity of several ACTH and cortisol concentration values in different time points, during corticotropin-releasing hormone (CRH) stimulation test and during CRH stimulation following dexamethasone suppression (DEX-CRH) test. METHODS: We retrospectively analyzed cortisol and ACTH concentration increment during CRH and DEX-CRH tests in 23 patients with confirmed CD. Cortisol and ACTH concentrations were determined immediately before, 15 min and 30 min after CRH stimulation. We evaluated the sensitivity of different cutoff values including those reported in previous studies, in the diagnosis of CD. RESULTS: During DEX-CRH test, 15 min serum cortisol concentration of 1.4 µg/dl (38 nmol/L) had a sensitivity of 90.9%, and serum cortisol concentration ≥1.27 µg/dl (35 nmol/L) had a sensitivity of 100%. For plasma ACTH, sensitivity of 100% was obtained using ACTH ≥3.5pmol/L (16 pg/ml) at 30 min. During CRH test, 35% increase from baseline in ACTH concentration had a sensitivity of 72.7%. Twenty percent increase in cortisol 30 minutes after stimulation yielded a sensitivity of 85.7%. The best sensitivity of ACTH and cortisol increment was obtained 15 min after stimulation, using 19% and 9% increase, respectively (sensitivity of 100% and 92.8%, respectively). CONCLUSION: During CRH and DEX-CRH tests, the study findings agree with the good sensitivity of ACTH and cortisol cutoff values suggested in previous studies; yet, other cutoff values may give a higher diagnostic sensitivity.

The Correlation between Proliferative Immunohistochemical Markers and Papillary Thyroid Carcinoma Aggressiveness.

Background and Objectives: Papillary thyroid carcinoma (PTC) is one of the most common malignancies of the endocrine system. In order to improve the ability to predict tumor behavior, several studies have been conducted to search for surrogate prognostic immunohistochemical tumor markers. Objective: To evaluate the correlation between the intensity of different immunohistochemical marker staining in PTC and the risk for extrathyroidal extension and metastases. Materials and Methods: The study comprised patients who underwent hemi- or total thyroidectomy. Thyroid tissues were immunohistochemically stained for different tumor proliferative markers: Minichromosome maintenance proteins 2 (MCM2), Ki-67 labeling index, E-Cadherin, Neuropilin-1 and Metallothionein. The correlation between the intensity of each marker staining and the final diagnosis (benign neoplasm and PTC) and the correlation between the intensity of each staining and tumor extrathyroidal extension and metastases were evaluated. Results: The study included 66 patients. Staining for Metallothionein, E-Cadherin and MCM2 significantly differed between benign neoplasm (n = 22) and thyroid-confined PTC (n = 21) (p = 0.002, 0.004 and 0.005, respectively), between benign neoplasm and PTC with extrathyroidal extension (n = 11) (p = 0.001, 0.006 and 0.01, respectively), and between benign neoplasm and PTC with metastases (n = 12) (p = 0.01, <0.001 and 0.037, respectively). No staining correlated with extrathyroidal extension. The intensity of E-Cadherin staining was significantly lower in PTC with metastases than thyroid confined PTC and PTC with extrathyroidal extension (p = 0.028 and 0.021, respectively). Conclusions: Immunohistochemical staining for Metallothionein, E-Cadherin and MCM2 significantly distinguished between benign thyroid tumor and PTC. E-Cadherin staining significantly and inversely correlated with the presence of metastases.

The correlation between testosterone, inflammation and cytokine status in type-2 diabetes men.

Type 2 diabetes mellitus (T2DM) is believed to cause hypogonadism through increasing pro-inflammatory cytokines. Tumour necrosis factor-α (TNF-α) is a primary cytokine associated with T2DM. The study explored the association between total testosterone (TT) level and cytokines status in 53 adult males, 27 T2DM (T2DM group) and 26 non-T2DM (control group). Blood samples evaluated fasting plasma glucose, HbA1c, insulin, HOMA-IR, FSH, LH, TT, prolactin, estradiol, cortisol, cortisol-binding globulin, C-reactive protein and eight cytokines (Interferon-gamma, IL-10, IL-13, IL-17A, IL-4, IL-23, IL-6, TNF-α). Data are presented as a median with interquartile interval. TT concentration was lower in the T2DM group [10.9 nmol/L (7.1-12.2) vs. 12.3 nmol/L (10.7-14.9) in control, p = 0.008]. CRP and cortisol in T2DM patients were higher than in control (p = 0.031 and 0.041 respectively). TT was negatively correlated with HOMA-IR, body mass index (BMI) and FSH (p = 0.028, 0.019 and 0.006 respectively). Multiple linear regression models showed that lower TT values were predictable by a linear combination of the independent variables: TNF-α, BMI and T2DM (p = 0.047, 0.023 and 0.019 respectively). High CRP and cortisol levels in T2DM patients suggest an inflammatory state. TT levels associated with TNF-α suggest a role of this cytokine in the aetiology of hypogonadism in T2DM patients.

Screening for non-classic congenital adrenal hyperplasia in women: New insights using different immunoassays.

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA. Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH. Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed. Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA. Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP.

Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia: Analysis of 71 Cases.

OBJECTIVE: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by benign bilateral enlarged adrenal masses, causing Cushing's syndrome (CS). The aim of the current article is to define the role of unilateral adrenalectomy (UA) in treating patients with CS related to PBMAH. METHODS: A PubMed database search was conducted to identify articles reporting UA to treat PBMAH. We also report cases of PBMAH from our medical center treated by UA. RESULTS: A total number of 71 cases of PBMAH (62 cases reported in the literature and 9 cases from our center) are presented. Most patients were women (73.2%) and most UA involved the left side (64.3%). In most cases, the resected gland was the larger one. Following UA, 94.4% of cases had remission of hypercortisolism. Recurrence rate of CS was 19.4% and hypoadrenalism occurred in 29.6%. After UA, when the size of the remained adrenal gland was equal or greater than 3.5 cm, CS persisted in 21.4% of cases, and recurrence occurred in 27.3% of cases (after 20±9.2 months). However, when the size of the remained gland was less than 3.5 cm, CS resolved in all cases and recurrence occurred in 21.2% of cases after a long period (65.6±52.1 months). High levels of urinary free cortisol (UFC) were not correlated with post-surgical CS recurrence or persistence. CONCLUSIONS: UA leads to beneficial outcomes in patients with CS related to PBMAH, also in cases with pre-surgical elevated UFC or contralateral large gland.

Metallothionein protein and minichromosome maintenance protein-2 expression in adrenocortical tumors.

AIM: Some resected adrenal-confined adrenocortical carcinomas metastasize and others not. The present study was designed to evaluate the expression of metallothionein protein (MT) and minichromosome maintenance protein-2 (MCM2) in adrenocortical carcinomas and adrenocortical adenomas, and to test the correlation between this and adrenocortical carcinoma aggressiveness. MATERIALS AND METHODS: The study comprised 14 patients operated on for adrenocortical carcinoma, 15 operated on for adrenocortical adenoma and 2 with normal adrenals. Hematoxylin-eosin staining was used for histological evaluation under light microscopy, and sequential sections were used for MCM2 and MT staining. RESULTS: In normal adrenals, positive staining was weak for MT and zero for MCM2. Rates of positive staining for MT and MCM2 were significantly higher in adrenocortical carcinomas than in adrenocortical adenomas (P=0.008 and P<0.001, respectively). In adrenocortical carcinomas, a significant positive correlation was found between MCM2 staining and Weiss revisited score (P=0.022) but not for Weiss score, and a significant positive correlation was found between MCM2 and mitotic rate on histology (P=0.033). MCM2 but not MT staining was also shown to correlate significantly with stage IV carcinoma (P=0.008 and P=0.165, respectively). CONCLUSION: MCM2 and MT are overexpressed in adrenocortical carcinoma, and MCM2 expression correlates significantly with metastatic disease.

[DIABETES AND RAMADAN FASTING - UPDATE 2019].

INTRODUCTION: Fasting during the month of Ramadan and other religious fasting days presents a challenging issue for healthcare practitioners (HCP). Education and instructions for patients with diabetes who intend to fast is mandatory during the pre-Ramadan period. This period represents a golden opportunity to evaluate the general health status of the patients including their risk associated with fasting. Furthermore, it allows HCP to revise and adapt suitable changes for their anti- diabetic therapy before initiating fasting. Therapy with high safety profile agents such as incretin-based therapy is more favorable than therapy with moderate-low safety profile agents such as sulphonylureas(SUs) and insulin to be administrated during the month of Ramadan. Patients already receiving treatment with sodium glucose co-transporter 2 inhibitors (SGLT2i) need thorough medical evaluation during the pre-Ramadan period in order to enable them to fast safely during the month of Ramadan using this class of agents. The aim of this review is to provide HCP in Israel with instructions and recommendations for better management of diabetic patients during Ramadan, while taking into consideration the recently published data and therapies available in Israel.

Performance of low-dose cosyntropin stimulation test in the afternoon.

BACKGROUND: Earlier research on 1 µg low-dose test (LDT) performed using 20.3 cm plastic IV tubing on healthy volunteers, has shown that afternoon testing was associated with a sevenfold increased likelihood of failing the test. Nevertheless, it has been claimed that subnormal cortisol response using plastic tubes might have resulted from cosyntropin adherence to the tube and, thus, loss of the delivered dosage. Following from our previous study, which showed that using a short (2.5 cm) plastic tube does not alter in-vitro-cosyntropin dosage delivery or healthy-volunteers' morning cortisol responses, we predicted that, when using the same short plastic tube, LDT would show comparable morning and afternoon cortisol stimulation. The current study was designed to investigate this prediction by comparing morning and afternoon cortisol responses in healthy volunteers during LDT, using a short plastic tube. METHODS: Thirteen healthy adult volunteers were recruited for the study. Each subject underwent morning and afternoon LDT via 25 mm plastic intravenous line tube. Baseline serum cortisol (SC) in addition to SC and salivary free cortisol (SFC) 30-minute responses were determined. RESULTS: Mean baseline morning SC concentration was higher in the morning than in the afternoon (13.63±3.42 and 9.18±2.78 µg/dL, respectively; P<0.001); however, mean absolute SC-concentration increment between baseline and 30-minute time point was higher in the afternoon than in the morning (11.89±3.50 and 7.71±3.12 µg/dL, respectively; P=0.002). Subsequently, LDT resulted in comparable morning and afternoon 30-minute SC (21.33±3.08 and 21.08±3.43 µg/dL, respectively; P=0.782) and SFC concentration (0.939±0.256 and 1.036±0.372 µg/dL, respectively; P=0.463). CONCLUSIONS: In healthy volunteers, using a 2.5 cm plastic tube, LDT provides comparable morning and afternoon 30-minute stimulated SC and SFC concentration.

The influence of anti-hyperglycemic drug therapy on cardiovascular and heart failure outcomes in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (DM) are at a substantially increased risk of heart failure (HF) and HF mortality. Despite the lack of evidence that tight glycemic control reduces the incidence of cardiovascular (CV) events, a growing body of evidence suggests that the choice of glucose-lowering agents may influence outcomes including HF. Thiazolidinediones are associated with a significant risk of HF. For metformin, sulphonylureas and insulin, little data is available to indicate the impact on HF. The glucagon-like peptide-1 (GLP-1) agonists, liraglutide and semaglutide, have been shown to reduce major CV events, but did not affect rates of hospitalization for HF. Clinical trials have demonstrated diverse effects of Dipeptidyl peptidase-4 (DPP-4) inhibitors on HF; saxagliptin showed an increased risk of HF admissions, alogliptin was associated with higher rates of new HF admissions, while sitagliptin had a neutral effect. The sodium-glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have been recently shown to reduce the incidence of HF and cardiovascular mortality in patients with and without a history of HF. This review will summarize key findings of the impact of glucose-lowering agents on CV safety and HF-associated outcomes, present available data on the underlying mechanisms for the benefits of the SGLT2 inhibitors on HF, and discuss strategies to improve outcomes in patients with DM and high CV risk.

Performance of low-dose cosyntropin stimulation test handled via plastic tube.

PURPOSE: Studies on 1 µg low-dose test showed that among 1 µg cosyntropin samples pushed through long IV plastic tubing, some adrenocorticotropic hormone dosage was not recovered, and in healthy volunteers it provided subnormal cortisol responses. The aim of the current study is to assess whether there is any loss in adrenocorticotropic hormone 1-24 concentration when pushed through a short plastic tube, and to assess serum and salivary cortisol responses in low-dose test among healthy volunteers, using a similar short plastic tube vs. direct intravenous consyntropin injection. METHODS: We evaluated in vitro if adrenocorticotropic hormone was absorbed in a 2.5 cm plastic tube by measuring adrenocorticotropic hormone 1-24 concentration in a 1 µg/ml adrenocorticotropic hormone aliquot solution before and after being flushed through the plastic tube. For the in vivo study, we recruited 20 healthy adult volunteers. Each subject underwent low-dose test via 2.5 cm plastic tube via plastic tube and via direct intravenous injection by a metal syringe via direct intravenous injection, and cortisol responses were determined. RESULTS: Mean adrenocorticotropic hormone 1-24 concentration did not differ significantly when flushed via plastic tube or measured in the aliquot solution (P = 0.25). In vivo, mean 30-min serum cortisol concentrations were 20.47 ± 2.87 and 21.62 ± 3.89 µg/dl in via plastic tube and in via direct intravenous injection tests, respectively, and did not show a significant difference (P = 0.16). CONCLUSIONS: In low-dose test, using a 2.5 cm plastic tube ensures completeness of the intravenous adrenocorticotropic hormone injection dosage and provides equivalent cortisol responses.

Dexamethasone-suppressed corticotropin-releasing hormone stimulation test in morbid obese adults.

PURPOSE: In order to differentiate between Cushing's syndrome (CS) and Pseudo-Cushing's syndrome, it is customary to use a test that is conducted by cortisol suppression with low-dose dexamethasone, followed by the administration of corticotropin releasing hormone (Dex-CRH test). In children with severe obesity, Dex-CRH test has shown a specificity of 55%. The aim of current study was to evaluate the specificity of Dex-CRH test in morbid obese adults. METHODS: The study included a total of 19 subjects with a body mass index (BMI) equal or higher than 40kg/m(2). In all subjects Dex-CRH test was performed, and 24h urinary free cortisol was collected prior the test and during the second day of dexamethasone administration (2nd-day-UFC). RESULTS: BMI was 45.1±4.6kg/m(2) and 45.7±3.3kg/m(2) in women and men, respectively. 14 subjects underwent bariatric surgery. No subject had surgical or perioperative complications and surgically treated subjects had mean body weight loss of 46.5±16.6kg. All except for 2 subjects had normal Dex-CRH test, as 15-min cortisol falling below 1.4µg/dl. During follow-up, no subject gained additional weight, neither developed signs of CS. 15-min-cortisol concentration of 1.4µg/dl revealed a specificity of 89% and 2nd-day-UFC of 16µg/24h showed a specificity of 100%. CONCLUSIONS: Morbid obesity in adults seems not to comprise a significant confounder in Dex-CRH test, and 15-min-cortisol concentration of 1.4µg/dl had a higher specificity than previously reported in obese children.

[CHALLENGES IN THE DIAGNOSIS OF CUSHING'S SYNDROME IN THE MODERN ERA].

Cushing's syndrome results from prolonged and excessive exposure to medically prescribed corticosteroids, or from excess endogenous cortisol secretion. When endogenous cortisol secretion is suspected, several screening tests are conducted in order to confirm or to rule out the diagnosis. In recent years, as the cut-off point of cortisol concentration on the 1 mg overnight dexamethasone suppression test was lowered, the prevalence of Cushing's syndrome has increased, and more cases of mild syndromes, with negative results on one or more screening tests, have increasingly been reported. In this paper, we will describe the various screening tests used for Cushing's syndrome, and will discuss their degree of sensitivity in the diagnosis of mild cases. We conclude that, in cases of mild syndromes, the sensitivity of some tests appears to be notably lower than has been reported. Until recently, the major challenge has been to distinguish between pseudo-Cushing's states and Cushing's syndrome. Today, however, the challenge has become to avoid misdiagnosis of mild cases, presenting with normal results on some screening tests. The sensitivity of urinary free cortisol seems to be lower than previously reported. Therefore, we recommend not to rely solely on this test in ruling out Cushing's syndrome.

A possible analytical and clinical role of endogenous antibodies causing discrepant adrenocorticotropic hormone measurement in a case of ectopic Cushing's syndrome.

Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing's syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference.

Granular cell tumor of the neurohypophysis: case report and review of the literature.

A 54-year-old woman presented with a stalk mass that was discovered incidentally with mild visual fields defect. The mass was operated surgically by the fronto-temporal approach, and histology met the diagnosis of neurohypophesial granular cell tumor (GCT). After surgery, the patient suffered from an irreversible severe bi-temporal visual deficit and an irreversible hypopituitarism. We review the literature and discuss the clinical nature of GCTs, treatment options and outcome. In an effort to avoid the severe complications that may result from surgical removal of neurohypophesial GCT, we discuss also the possibility of choosing the conservative approach with close follow-up. The tumor's firm consistency, tendency to hemorrhage, involving the pituitary stalk and lack of dissection plane from basal brain structure render surgery difficult, and maximal resection often requires sacrificing the stalk. Moreover, small asymptomatic neurohypophysial GCTs are common findings, most probably benign tumors with slow growing nature. Hence, for a neurohypophesial tumor which is suspected to be a GCT, we offer to consider the alternative approach, with close clinical, visual field and radiological study follow up.