Serologic response to COVID-19 infection and/or vaccine in cancer patients on active treatment.

BACKGROUND: It was shown that immunocompromised patients have significantly reduced immunologic responses to COVID-19 vaccines. The immunogenicity of COVID-19 vaccine/infection in patients with solid tumors is reduced. We evaluated the immunologic response to COVID-19 and/or the BNT162b2 mRNA COVID-19 vaccine among cancer patients on active treatments and reviewed previous literature to identify subgroups that may require third vaccination. PATIENTS AND METHODS: Anti-SARS-CoV-2 S1/S2 antibodies were measured in a cohort of 202 cancer patients on active treatment with chemotherapy (96), immunologic (52), biologic (46), and hormonal (12) treatments for early (n = 66, 32.7%) or metastatic disease (n = 136, 67.3%). Of those, 172 had received two vaccine doses, and 30 had COVID-19 infection (20/30 also received one dose of vaccine). Specific anti-S receptor-binding domain antibodies were further measured in patients with equivocal anti-S1/S2 results. RESULTS: Among cancer patients, the SARS-CoV-2 antibody response rate was 89.1% (180/202) after COVID-19 vaccination or infection and 87.2% (150/172) in patients after vaccination without a history of COVID-19, compared with 100% positive serologic tests in a control group of 30 health care workers (P < 0.001). Chemotherapy treatment was independently associated with significantly reduced humoral response to infection or vaccination, with an 81.3% response rate, compared with 96.2% in patients on other treatments (P = 0.001). In vaccinated patients on chemotherapy, the positive response rate was 77.5%. In a multiple regression model, a neutralizing antibody titer (>60 AU/ml) was more likely with immunotherapy (odds ratio 2.44) and less likely with chemotherapy (odds ratio 0.39). CONCLUSIONS: Overall, both COVID-19 vaccine and natural infection are highly immunogenic among cancer patients. Our study, however, identifies those under chemotherapy as significantly less responsive, and with lower antibody levels. These findings justify close virological and serological surveillance along with consideration of these patients for booster (third dose) vaccine prioritization, as new highly spreading SARS-CoV-2 variants emerge.

Alterations of microRNAs throughout the malignant evolution of cutaneous squamous cell carcinoma: the role of miR-497 in epithelial to mesenchymal transition of keratinocytes.

Skin carcinogenesis is known to be a multi-step process with several stages along its malignant evolution. We hypothesized that transformation of normal epidermis to cutaneous squamous cell carcinoma (cSCC) is causally linked to alterations in microRNAs (miRNA) expression. For this end we decided to evaluate their alterations in the pathologic states ending in cSCC. Total RNA was extracted from formalin fixed paraffin embedded biopsies of five stages along the malignant evolution of keratinocytes towards cSCC: Normal epidermis, solar elastosis, actinic keratosis KIN1-2, advanced actinic keratosis KIN3 and well-differentiated cSCC. Next-generation small RNA sequencing was performed. We found that 18 miRNAs are overexpressed and 28 miRNAs are underexpressed in cSCC compared to normal epidermis. miR-424, miR-320, miR-222 and miR-15a showed the highest fold change among the overexpressed miRNAs. And miR-100, miR-101 and miR-497 showed the highest fold change among the underexpressed miRNAs. Heat map of hierarchical clustering analysis of significantly changed miRNAs and principle component analysis disclosed that the most prominent change in miRNAs expression occurred in the switch from 'early' stages; normal epidermis, solar elastosis and early actinic keratosis to the 'late' stages of epidermal carcinogenesis; late actinic keratosis and cSCC. We found several miRNAs with 'stage specific' alterations while others display a clear 'gradual', either progressive increase or decrease in expression along the malignant evolution of keratinocytes. The observed alterations focused in miRNAs involved in the regulation of AKT/mTOR or in those involved in epithelial to mesenchymal transition. We chose to concentrate on the evaluation of the molecular role of miR-497. We found that it induces reversion of epithelial to mesenchymal transition. We proved that SERPINE-1 is its biochemical target. The present study allows us to further study the pathways that are regulated by miRNAs along the malignant evolution of keratinocytes towards cSCC.

Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease.

Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription-PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho-FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.

A modified ambulatory arterial stiffness index is independently associated with all-cause mortality.

Dependence of the ambulatory arterial stiffness index (AASI) on data scattering interferes with its potential clinical relevance. We assessed the correlates and all-cause mortality associations of a modified AASI (s-AASI). AASI was derived from the 24-h diastolic vs. systolic blood pressure linear regression line, whereas s-AASI was derived by symmetric regression (bisecting the line of diastolic vs systolic and systolic vs. diastolic). Of 2918 patients 55% were women; age was 56 +/- 16 years and body mass index was 27.3 +/- 4.5 kg/m(2). Average 24-h ambulatory blood pressure was 138 +/- 16/78 +/- 10 mm Hg. Applying the modified method for calculating AASI yielded a different measure: the negative correlation between AASI and blood pressure dipping (r = -0.304, P < 0.0001) was abolished (r = +0.223, P < 0.0001), s-AASI was more dependent on age (r = 0.266 vs. r = 0.089 for AASI), and prediction of all-cause mortality was enhanced; hazard ratio (95% confidence intervals) 1.17 (1.00-1.36) per 1 s.d. increase in s-AASI in the fully adjusted model as compared with 1.15 (0.97-1.36) for AASI.

Normal ambulatory blood pressure: a clinical practice-based comparison of two recently published definitions.

The European Society of Hypertension (ESH) has issued guidelines for the detection and treatment of hypertension. According to these guidelines, normal 24-h ambulatory blood pressure (ABP) is defined as lower than 125/80 mmHg. Another publication of ESH recommendations for blood pressure (BP) measurement defines normal awake and asleep blood pressure as lower than 135/85 and 120/70 mmHg, respectively. Our aim was to investigate the compatibility of these two recently proposed ABP cutoffs in clinical practice. We analysed 1495 consecutive ABP measurements. In all, 56% of the subjects were female; age 58 +/- 16 years; body mass index 27 +/- 4 kg/m(2); clinic BP 151+/-22/84 +/- 13 mmHg. Two-thirds were treated for hypertension, and 11% for diabetes. Subjects were classified as having normal 24-h BP if the corresponding value was <125/80 mmHg. Normal awake-sleep BP was diagnosed if awake BP was <135/85 mmHg and sleep BP was <120/70 mmHg. Concordance between the cutoffs was found in 93% of the subjects. Among the 7% discordant subjects, 4.5% were hypertensive applying the 24 h, but not awake-sleep, BP values, whereas only 2.5% were hypertensive according to awake-sleep, but not 24 h, BP values (P < 0.005). In Conclusion, in real-life ABP measurement, a good agreement was found between two recently issued ABP normality definitions. However, some subjects are classified as hypertensive only according to one of these methods, more often by the 24-h cutoff of 125/80. This discordance may be significant in large-scale clinical BP monitoring.

Kidney transplantation unraveling Wolfram syndrome: a case report.

BACKGROUND: In Wolfram syndrome insulin-dependent diabetes is associated with a multisystem neurodegenerative disorder. There are no prior reports of kidney transplantation in patients with Wolfram syndrome. METHODS: Kidney transplantation was undertaken in a child with dysplastic kidneys, sensorineural hearing impairment and bilateral optic atrophy-a combination of features insufficient to define Wolfram syndrome. RESULTS: After the procedure diabetes mellitus, diabetes insipidus and urinary bladder dysfunction emerged, thereby revealing Wolfram syndrome. CONCLUSIONS: We discuss the etiology of our patient's postoperative events, and conclude that kidney transplantation may expose dormant manifestations-or aggravate existing manifestations-of Wolfram syndrome.

Drug-resistant pulmonary tuberculosis in Israel, a society of immigrants: 1985-1994.

SETTING AND OBJECTIVES: Drug-resistant tuberculosis was uncommon in Israel until 1985, when the waves of immigration began. We studied the incidence and clinical course of resistant pulmonary tuberculosis nationwide. DESIGN: Isolates of Mycobacterium tuberculosis between 1985 and 1994 were surveyed. Data on 150 patients with resistance and 110 patients with drug-sensitive disease were reviewed. Ethnic origin, type of resistance, radiological findings and outcome were analysed. RESULTS: In total, 16.7% of the isolates showed resistance to at least one drug; 58% had resistance to multiple drugs. In 67% of the patients the resistance was primary. Most patients were immigrants from the former USSR and from Ethiopia; none were Israeli-born Jews. Mortality with resistance was 10%, and was highest (14%) with multiple drug resistance. Mortality among drug-resistant cases was lowest (3%) among Ethiopian Jews. Cavities and extensive disease were more common with drug resistance. CONCLUSION: Drug resistance has become relatively common in Israel due to immigration from the former USSR and Ethiopia. It is more extensive radiologically and carries a poorer outcome.