Vitamin D3 and COVID-19 Outcomes: An Umbrella Review of Systematic Reviews and Meta-Analyses.

BACKGROUND: The immune system (innate and adaptive) is influenced by vitamin D3, which affects gene expression and inflammatory pathways. An umbrella review was conducted to evaluate the power and accuracy of data connecting vitamin D3 to the outcomes of COVID-19 infection and to appraise the proof provided by published meta-analyses. METHODS: MEDLINE, Embase, and the Cochrane Library were searched from database inception to 31 May 2022. Meta-analyses of prospective or retrospective observational studies and randomized trials were included. Evidence of association was graded according to the established criteria: strong, highly suggestive, suggestive, weak, or not significant. RESULTS: From 74 publications, 27 meta-analyses described five associations between vitamin D3 levels and supplementation and COVID-19 outcomes. Low levels of vitamin D3 were significantly associated with severity (highly suggestive evidence; OR = 1.97 [95% CI, 1.55-2.51], p < 0.01; I2 = 77%, p < 0.01) and mortality risk due to COVID-19 disease (OR = 1.83 [95% CI, 1.55-2.16], p < 0.01; I2 = 50%, p < 0.01). Vitamin D3 supplementation, after a diagnosis of COVID-19 infection, was associated with significantly reduced infection severity (e.g., ICU admission) and mortality. CONCLUSIONS: This umbrella review of the available evidence suggests that insufficient vitamin D3 may increase COVID-19 infection risk, severity, and mortality, in addition to showing a highly suggestive association between vitamin D3 supplementation and reduced severity and mortality among infected patients.

COVID-19 and Lung Cancer Survival: An Updated Systematic Review and Meta-Analysis.

Introduction: The outbreak of COVID-19 poses an unprecedented challenge to global public health. Patients with cancer are at a higher risk during the SARS-CoV-2 pandemic. Patients with lung cancer and COVID-19 were compared to those without cancer and those with other malignancies for the main outcome of this study. The aim of this study was to evaluate the differences in susceptibility, disease severity, and mortality between lung cancer patients and the general population. Methods: Using PRISMA reporting guidelines, we conducted a systematic review and meta-analysis of the published literature. The Cochrane Library database, PubMed, EMBASE, and PubMed Central were comprehensively searched for published papers until 31 May 2022. A pooled risk ratio (OR) with 95% CI was presented as the result of this meta-analysis. Results: We included 29 studies involved 21,257 patients with lung cancer and SARS-CoV-2 infection. Analysis data showed that mortality in patients with lung cancer was significantly higher than that in patients without cancer (HR = 2.00 [95%CI 1.52, 2.63], p < 0.01) or with other malignancies (HR = 1.91 [95%CI 1.53, 2.39], p < 0.01). In addition, we also observed a higher risk of severe infection in terms of life-threatening or required ICU admission/mechanical ventilation for lung cancer patients (HR = 1.47 [95%CI 1.06, 2.03], p = 0.02) than for patients with no cancer or other malignancies. Regarding lung cancer as a risk factor for acquiring SARS-CoV-2 infection, we could not reach statistical significance (hazard ratio [HR] =2.73 [95%CI 0.84, 8.94], p = 0.1). Conclusion: Lung cancer represents an important comorbidity and modifies COVID-19 prognosis in terms of disease severity and mortality. More patients experience severe or even fatal events. Considering their inherent fragility, patients with lung cancer, and generally all oncological populations, should be treated more carefully during the COVID-19 pandemic.

Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies.

Vitamin D modulates the systemic inflammatory response through interaction with immune system. As such, it has a possible protective role against the risk of respiratory tract infections and other diseases. It may be useful in particular, during COVID-19 pandemic. PubMed, the Cochrane Library, and EMBASE were searched from inception until January 31, 2021, for observational or clinical studies reporting the prognosis (and therapeutic effect) of COVID-19 infection in patients with deficient vitamin D levels. The infection rate, severity, and death from COVID-19 infection were pooled to provide an odds ratio with a 95 % confidence interval (OR 95 % CI). An OR > 1 was associated with the worst outcome in deficient compared with nondeficient patients. We assessed the association between vitamin D and risk, severity, and mortality for COVID-19 infection, through a review of 43 observational studies. Among subjects with deficient vitamin D values, risk of COVID-19 infection was higher compared to those with replete values (OR = 1.26; 95 % CI, 1.19-1.34; P < .01). Vitamin D deficiency was also associated with worse severity and higher mortality than in nondeficient patients (OR = 2.6; 95 % CI, 1.84-3.67; P < .01 and OR = 1.22; 95 % CI, 1.04-1.43; P < .01, respectively). Reduced vitamin D values resulted in a higher infection risk, mortality and severity COVID-19 infection. Supplementation may be considered as preventive and therapeutic measure.

Effects of hypertension on cancer survival: A meta-analysis.

BACKGROUND: Hypertension is usually associated with increased cardiovascular mortality. Uncertainty exists about the possible role of hypertension as a poor prognostic factor for cancer-specific mortality (CSM). To assess the association between pre-existing hypertension and the risk of mortality and relapse after a diagnosis of cancer, we performed a systematic review and meta-analysis of published studies. METHODS: PubMed, Scopus, Web of Science, the Cochrane Library and EMBASE were searched from inception until May 2020, without language restrictions, for observational studies reporting the prognosis of patients with hypertension and cancer. The primary outcome of the study refers to CSM in hypertensive vs nonhypertensive patients, and secondary endpoints were overall mortality (OM) and progression- or relapse-free survival. The effect size was reported as hazard ratios (HRs) with 95% CIs. RESULTS: Mortality and relapse associated with hypertension in patients with various cancers were evaluated among 1 603 437 participants (n = 66 studies). Overall, diagnosis of cancer and hypertension was associated with an increased independent risk of OM (HR = 1.2 [95% CI, 1.13-1.27], P < .01) and CSM (HR = 1.12 [95% CI, 1.04-1.21], P < .01) but not of relapse (HR = 1.08 [95% CI, 0.98-1.19], P = .14). CONCLUSIONS: Among cancer patients, those with pre-existing hypertension have a poorer outcome, probably due to multifactorial reasons. Adequate control of lifestyle, more intensive follow-ups, monitoring for hypertension- and anticancer-related cardiovascular complications, and establishing multidisciplinary cardio-oncology units can be useful measures for reducing mortality and improving care in this setting.

Association of Steroids use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24-1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02-1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41-4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22-1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS.

Lower limb myalgias in a man who used to "climb the stairs": an atypical abdominal aortic aneurysm.

Atypical presentation of emergency abdominal aortic aneurysm comprises a wide spectrum of symptoms. Lower limbs' involvement is infrequent, usually monolateral and with clear vascular features. We report the case of a 58-year-old patient who complained exclusively about symmetric lower limb myalgias without vascular features, after having repeatedly climbed the stairs of the school he worked in. The surprising final diagnosis was of rupturing abdominal aortic aneurysm; the patient was sent to emergency surgery and survived.

Telmisartan: just an antihypertensive agent? A literature review.

INTRODUCTION: The modulation of the renin angiotensin aldosterone system (RAAS) is an important pathway in managing high blood pressure, and its overexpression plays a key role in target end-organ damage. Telmisartan is an angiotensin II receptor blocker (ARB) with unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a significant and 24-h sustained reduction of blood pressure. Telmisartan has well-known antihypertensive properties, but there is also strong clinical evidence that it reduces left ventricular hypertrophy, arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection. AREAS COVERED: This paper reviews telmisartan's pharmacological properties in terms of efficacy for hypertension control and, importantly, focuses on its new therapeutic indications and their clinical implications. EXPERT OPINION: ONTARGET (ongoing telmisartan alone and in combination with ramipril global endpoint trial) demonstrated, that telmisartan confers cardiovascular protective effects similar to those of ramipril, but with a better tolerability. Moreover, recent investigations focused on the capability of telmisartan to modulate the peroxisome proliferator-activated receptor-gamma (PPAR-γ), an established target in the treatment of insulin resistance, diabetes and metabolic syndrome, whose activation is also correlated to anti-inflammatory and, finally, anti-atherosclerotic properties. Telmisartan shows peculiar features that go beyond blood pressure control. It presents promising and unique protective properties against target end-organ damage, potentially able to open a scenario of new therapeutic approaches to cardiovascular disease.

The addition of rituximab to anthracycline-based chemotherapy significantly improves outcome in 'Western' patients with intravascular large B-cell lymphoma.

Some case reports and a Japanese series suggest benefit from the use of rituximab in patients with intravascular large B-cell lymphoma (IVL). Rituximab efficacy was evaluated in Western patients with IVL, comparing outcome of 10 patients treated with rituximab + chemotherapy (R-CT) and of 20 patients treated with chemotherapy alone (CT). There were no significant differences in patients' characteristics between the two subgroups. The addition of rituximab was associated with improved complete remission rate (90% vs. 50%; P = 0.04), event-free survival (3-year: 89% vs. 35%; P = 0.003) and overall survival (3-year: 89% vs. 38%; P = 0.01). In conclusion, rituximab may substantially change the dismal prognosis of IVL.

Chlamydophila psittaci is viable and infectious in the conjunctiva and peripheral blood of patients with ocular adnexal lymphoma: results of a single-center prospective case-control study.

Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydophila psittaci (Cp) infection. Viability and infectivity of Cp, demonstrated by growth in culture, has not been yet investigated in these patients. We conducted a single-center prospective case-control study to assess the prevalence, viability and infectivity of Cp in 20 OAML patients and 42 blood donors registered in a 6-month period. The presence of Cp in conjunctival swabs and peripheral blood mononuclear cells (PBMC) of patients and donors was assessed by TETR-PCR and in vitro cultures. From an epidemiological point of view, OAML patients often resided in rural areas, and reported a history of chronic conjunctivitis and prolonged contact with household animals (85% vs. 38% of donors; p = 0.00001). Cp was detected in lymphoma tissue in 15 (75%) patients. Cp DNA was detected in conjunctival swabs and/or PBMC from 10 (50%) patients and in PBMC from 1 (2%) donor (p = 0.01). Viability and infectivity of Cp, demonstrated by growth in culture, were confirmed in conjunctival swabs and/or PBMC from 5 (25%) patients, but not in donors (p = 0.002). This prospective study demonstrates, for the first time, that Cp present in the conjunctiva and PBMC of OAML patients is capable to grow and be isolated in cell cultures. Cp infection is common in OAML patients and exceptional in blood donors. Epidemiological data of OAML patients (prolonged contact with household animals and chronic conjunctivitis) are consistent with Cp exposure risk.

Therapeutic management of ocular adnexal MALT lymphoma.

Non-Hodgkin lymphomas constitute 50% of all orbital malignancies. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histology category in this anatomic region. Ocular adnexal lymphoma of MALT-type is an indolent and rarely lethal malignancy that can often be managed with observation alone. Occasionally, lymphomatous lesions determine the symptoms that condition a patient's quality of life, and so require an immediate antineoplastic treatment. Several strategies are available, but reliable indications supported by prospective trials do not exist. Some therapeutic strategies are associated with substantial side effects and require a well-balanced therapeutic decision, which should take into account several variables related to the patient, the lymphoma, and the treatment itself. In this review, the authors analyze related literature and propose therapeutic guidelines for the management of ocular adnexal lymphoma of MALT-type.

Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions.

BACKGROUND AND OBJECTIVES: This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. DESIGN AND METHODS: The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. RESULTS: Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients (p=0.00001) and in seven (19%) patients from other Asian countries (p=0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. INTERPRETATION AND CONCLUSIONS: The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial.

BACKGROUND: An association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infection has been proposed, and recent reports suggest that doxycycline treatment causes tumor regression in patients with Cp-related OAL. The effectiveness of doxycycline treatment in Cp-negative OAL has not been tested. METHODS: In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were two-sided. RESULTS: Eleven patients were Cp DNA-positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in six patients, and a partial response (> or = 50% reduction of all measurable lesions) was observed in seven patients (overall response rate [complete and partial responses] = 48%). Lymphoma regression was observed in both Cp DNA-positive patients (seven of 11 experienced regression) and Cp DNA-negative patients (six of 16 experienced regression) (64% versus 38%; P = .25, Fisher's exact test). The three patients with regional lymphadenopathies and three of the five patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline-treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. CONCLUSIONS: Doxycycline is a fast, safe, and active therapy for Cp DNA-positive OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR-negative OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria.

Association between Helicobacter pylori infection and MALT-type lymphoma of the ocular adnexa: clinical and therapeutic implications.

BACKGROUND: The prevalence and the clinical impact of gastric Helicobacter pylori (Hp) infection, as well as its possible correlation with Chlamydia psittaci (Cps) infection and the lymphoma regression rate produced by Hp eradicating antibiotic therapy were investigated in patients with MALT-type lymphoma of the ocular adnexa (OAL). METHODS: During staging, the presence of gastric Hp infection was assessed by gastroscopy and multiple biopsies in 31 OAL patients. Immediately after, Hp-positive patients were treated with eradicating antibiotic therapy, alone or associated with other therapies. RESULTS: Gastric Hp infection was detected in 10 (32%) patients; this feature did not correlate with patients' characteristics and disease. Four Hp-positive patients were treated with Hp-eradicating antibiotics therapy as exclusive strategy (assessable for response), none of them showed lymphoma regression. Conversely, 6 Hp-positive patients were treated with antibiotic therapy concurrently with other therapies, achieving lymphoma regression in all cases. Three Hp-positive patients with Cps-positive lymphoma were treated with doxycycline at relapse, resulting in two CR and one PR, which lasted 24+, 20+, and 18+ months, respectively. One of these patients achieved a CR after doxycycline despite the chronic persistence of Hp infection, whereas Cps-eradication was confirmed in the analysis of PBMC samples. CONCLUSIONS: Gastric Hp infection, even if common among OAL patients, does not influence clinical presentation. Hp-eradicating antibiotic therapy is not active against OAL. Cps-eradicating antibiotic therapy with doxycycline induces lymphoma remission irrespectively of the persistence of Hp infection.

Raltitrexed plus oxaliplatin in the treatment of metastatic colorectal cancer.

AIMS AND BACKGROUND: As raltitrexed and oxaliplatin (L-OHP) are both effective in the treatment of colorectal cancer but have different mechanisms of action, we studied the antitumoral activity and safety of their combined use in patients with advanced colorectal cancer. METHODS: A 15-min intravenous infusion of raltitrexed (2.5 mg/m2) and a 180-min infusion of oxaliplatin (100 mg/m2) were administered on day 1 every three weeks for a maximum of six cycles. RESULTS: The study involved 51 patients (27 males and 24 females) with a median age of 65 years (range, 43-78); 28 were aged > or = 65 years. The primary tumor site was the colon in 35 patients and the rectum in 16. Thirty-four patients had received prior chemotherapy: 20 as adjuvant treatment and 14 as pretreatment. The most frequent metastatic sites were liver (18 cases), lung (10 cases), liver + lung (8 cases) and lymph nodes (3 cases). Twenty-four patients completed the entire treatment plan. The most common toxicities were transaminitis (16 patients, grade 3-4), diarrhea (six patients, grade 3), nausea/vomiting (one patient, grade 4), and asthenia (one patient, grade 3). The treatment was stopped in one patient because of prolonged grade 4 transaminitis. The adverse event profile was similar in the patients aged > 65 years and < 65 years. Complete responses were observed in 2 patients, partial responses in 12, stable disease in 23, and progression in 8. CONCLUSIONS: The results of the study suggest that the raltitrexed plus oxaliplatin regimen is feasible and clinically active in advanced colorectal cancer.

Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients.

OBJECTIVES: As single agents, irinotecan and oxaliplatin are active in colorectal cancer after fluorouracil (FU)-containing regimen failure. Their synergistic activity and non-overlapping toxicity profile are well documented, but more data are needed to explore their exact sequence. The aim of this study was to evaluate the activity and tolerability of irinotecan followed by oxaliplatin in patients with FU-resistant colorectal cancer. METHODS: FU resistance was defined as disease progression during or within 6 months of discontinuing first-line or adjuvant FU/leucovorin chemotherapy. The study treatment consisted of irinotecan 150 mg/m(2) on days 1 and 8 followed by oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. In order to improve the safety profile, we changed the schedule during the study to irinotecan 300 mg/m(2) on day 1 and oxaliplatin 85 mg/m(2) on day 2 every 3 weeks. RESULTS: Of 54 patients treated, the 45 patients with measurable disease were assessed in the efficacy analysis, whereas all patients receiving at least one cycle were evaluated in the safety analysis. Of the patients assessed for efficacy analysis, 19 cases received the first schedule and 26 patients received the second schedule. Twenty-two patients (49%) responded, 10 of the first schedule and 12 of the second schedule group. Stable disease was observed in 35% of all patients. The median response duration was 6.5 months (range 3-10), the median time to progression was 8 months (range 6-10), and the overall survival was 15 months (10-26+). The NCI-CTC grade 3 side effects documented in all of the treated patients were: nausea/vomiting (11%), diarrhea (18%), and neutropenia (7%); grade 4 diarrhea was observed in 2% of patients. CONCLUSION: The combination of irinotecan followed by oxaliplatin combination is well tolerated and highly active in FU-resistant metastatic colorectal cancer patients.

Integrated therapeutic strategies for anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a very rare neoplasm with an aggressive course. The prognosis has not changed in the last decades and the median survival does not exceed six months. Only few patients with incidental limited ATC will be cured. Different therapeutic options have been explored but the results are disappointing. At present, new drugs and new timing for proper treatment are under investigation. In this short review we have summarized these recent developments.