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.

Osteopontin Upregulation, Induced by the Continuous Mechanical Load in Adipose Tissue-Derived Mesenchymal Stem Cells, is Strongly Restricted in INF-γ/TNF-α/IL-22 Microenvironment.

The osteogenic potential of mesenchymal stem cells (MSc) in axial spondyloarthritis (AxSpA) depends on the interplay of inflammation and multiple hormonal and local mechanical factors. In this study, MCs, derived from the adipose tissue of a healthy donor, were cultured under or without continuous mechanical load in the osteogenic differentiation medium with or without the addition of testosterone, cocktail of INF-γ/TNF-α/IL-22, or both. Real-time PCR for osteogenic transcription factors demonstrated that in the absence of INF-γ/TNF-α/IL-22, mechanical load causes significant upregulation of SPP1 (osteopontin), while the presence of the inflammatory cytokines almost completely abolishes this effect. In addition, exposure to INF-γ/TNF-α/IL-22 slightly upregulated BMP2, but suppressed the expression of ALPL, Col1A1, and SPP1, reinforcing the hypothesis that the inflammatory environment allows MSc to commit toward the IL-22-driven osteogenic differentiation but can restrict the later stages of osteogenesis. In summary, osteopontin can play a role in the pathogenesis of AxSpA, linking between mechanical load and pathological bone formation.

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.

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.

Cabergoline treatment for recurrent Cushing's disease during pregnancy.

OBJECTIVE: Cushing's disease during pregnancy is associated with an increased risk for maternal and fetal complications. In recurrent Cushing`s disease following transsphenoidal surgery, and when re-operation is not feasible, medical treatment is usually considered. Cabergoline was found to be effective in reducing hypercortisolism in Cushing's disease. Evolving data concerning the safety of cabergoline use during pregnancy show no significant increase in the rate of complications during pregnancy or the postnatal period. METHODS: We report a 29-year-old woman, gravida 0, para 0, with recurrent Cushing`s disease, three years after transsphenoidal resection of pituitary ACTH-secreting macroadenoma. Repeated MRI revealed an empty sella with a small gadolinium-enhancing lesion, suspected to be an adenoma remnant on the medial wall of the right cavernous sinus. As the patient was not willing to undergo repeat surgical intervention, treatment with cabergoline was initiated, with a gradual dose titration up to 3.5 mg/week. Clinical improvement ensued, and 4 months later, she conceived spontaneously. After discussing treatment options with the patient, cabergoline treatment at a dose of 2 mg/week was continued throughout pregnancy. RESULTS: The patient showed complete clinical remission during pregnancy. Consecutive tests of 24-h urinary free cortisol concentration were not found to be elevated. Pregnancy and delivery were uneventful except for mild hypothyroidism observed during the second trimester. At full term the patient delivered a healthy female infant, by an elective cesarean section. CONCLUSION: This case report demonstrates that cabergoline may be an effective and safe therapeutic option for the treatment of Cushing's disease during pregnancy.

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.

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.

Metastatic type 1 gastric carcinoid: a real threat or just a myth?

AIM: To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1). METHODS: Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients' data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria. RESULTS: We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period. CONCLUSION: Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels.

Adrenalectomy for adrenocortical adenoma causing Cushing's syndrome in pregnancy: a case report and review of literature.

We present a case of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome diagnosed in a patient in the third trimester of her pregnancy, with an adrenal mass observed on imaging studies. Laparoscopic adrenalectomy was performed successfully at 32 weeks. To the best of our knowledge, this is the latest gestational age at which laparoscopic adrenalectomy has been reported. We present the various considerations for determining the surgical approach and the optimal timing for surgery. Adrenalectomy during pregnancy for the treatment of Cushing's syndrome caused by adrenocortical adenoma has been reported in 23 patients in the English-language medical literature to date and seems safe and beneficial. According to the data, surgical treatment has led to a reduction in perinatal mortality and maternal morbidity rates, but has not affected the occurrence of preterm birth and intrauterine growth restriction. The best outcome can be achieved by a multidisciplinary approach, with a team comprising a maternal-fetal medicine specialist, an endocrinologist and a surgeon. The timing of surgery and the surgical approach need to be determined according to the surgeon's expertise, the severity of the condition, the patient's preferences, and gestational age. Laparoscopy may prove to be the preferred surgical approach. The small number of cases precludes providing evidence-based recommendations.