Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience.

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.

The relationship between cardiac injury, inflammation and coagulation in predicting COVID-19 outcome.

High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk. In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related; but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the mortality in the whole population, particularly in subjects with higher hsTnT. D-dimer possessed a strong relationship with hsTnT and mortality. Anticoagulation treatment showed greater benefits with regard to mortality. These findings suggest a major role of SARS-CoV-2 coagulopathy in hsTnT elevation and its related mortality in COVID-19. A better understanding of the mechanisms related to COVID-19 might pave the way to therapy tailoring in these high-risk individuals.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Role of Low-Molecular-Weight Heparin in Hospitalized Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia: A Prospective Observational Study.

BACKGROUND: This study was conducted to evaluate the impact of low-molecular-weight heparin (LMWH) on the outcome of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: This is a prospective observational study including consecutive patients with laboratory-confirmed SARS-CoV-2 pneumonia admitted to the University Hospital of Pisa (March 4-April 30, 2020). Demographic, clinical, and outcome data were collected. The primary endpoint was 30-day mortality. The secondary endpoint was a composite of death or severe acute respiratory distress syndrome (ARDS). Low-molecular-weight heparin, hydroxychloroquine, doxycycline, macrolides, antiretrovirals, remdesivir, baricitinib, tocilizumab, and steroids were evaluated as treatment exposures of interest. First, a Cox regression analysis, in which treatments were introduced as time-dependent variables, was performed to evaluate the association of exposures and outcomes. Then, a time-dependent propensity score (PS) was calculated and a PS matching was performed for each treatment variable. RESULTS: Among 315 patients with SARS-CoV-2 pneumonia, 70 (22.2%) died during hospital stay. The composite endpoint was achieved by 114 (36.2%) patients. Overall, 244 (77.5%) patients received LMWH, 238 (75.5%) received hydroxychloroquine, 201 (63.8%) received proteases inhibitors, 150 (47.6%) received doxycycline, 141 (44.8%) received steroids, 42 (13.3%) received macrolides, 40 (12.7%) received baricitinib, 13 (4.1%) received tocilizumab, and 13 (4.1%) received remdesivir. At multivariate analysis, LMWH was associated with a reduced risk of 30-day mortality (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21-0.6; P < .001) and composite endpoint (HR, 0.61; 95% CI, 0.39-0.95; P = .029). The PS-matched cohort of 55 couples confirmed the same results for both primary and secondary endpoint. CONCLUSIONS: This study suggests that LMWH might reduce the risk of in-hospital mortality and severe ARDS in coronavirus disease 2019. Randomized controlled trials are warranted to confirm these preliminary findings.

Obesity prolongs the hospital stay in patients affected by COVID-19, and may impact on SARS-COV-2 shedding.

INTRODUCTION: On the last three months the new SARS-COV-2 coronavirus has created a pandemic, rapidly spreading all around the world. The aim of the study is to investigate whether obesity impacts on COVID-19 morbidity. METHODS: One hundred consecutive patients with COVID-19 pneumonia admitted in our Medical Unit were evaluated. Anthropometric parameters and past medical history were registered. Nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. RESULTS: Patients with (OB, 29) and without obesity (N-OB, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in OB group. At admission, inflammatory markers were higher in OB than N-OB group. OB group showed a worse pulmonary clinical picture, with lower PaO2 (57 ± 15 vs. 68 ± 14 mmHg, p = 0.042), and SaO2 (88 ± 6 vs. 92 ± 5%, p = 0.049) at admission consequently requiring higher volumes of oxygen (Fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). OB group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). Partial least square regression analysis showed that BMI, age and CRP at admission were related to longer length of hospital stay, and time for negative swab. On the contrary, in this cohort, obesity did not predict higher mortality. CONCLUSIONS: Subjects with obesity affected by COVID-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer SARS-COV-2 shedding.

Pancreatoduodenectomy for groove pancreatitis Report of two cases.

Groove pancreatitis is a rare condition with patients having clinical characteristics similar to those of chronic pancreatitis. Differentiating on clinical and radiological basis between groove pancreatitis and paraduodenal head cancer can be extremely challenging. Due to diagnostic uncertainty and to poor response to medical treatment surgery may offer these patients the best chance of cure. As the main localization of the inflammatory process is at the groove between the duodenum and the head of the pancreas, pancreato-duodenectomy is proposed as the most reliable surgical procedure. We report about two patients presenting with clinical and radiological features suggesting a groove pancreatitis in which control of symptoms was achieved by pancreatoduodenectomy. KEY WORDS: Groove pancreatitis, Paraduodenal pancreatic cancer.

Interleukin-1ß, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis.

The aim of this study was to evaluate serum levels of interleukin-1ß (IL-1ß), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN-γ) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC + HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1ß, IFN-γ, and CXCL10 were assayed in 30 patients with MC + HCV without AT, in 30 patients with MC + HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1ß and CXCL10 levels than controls (P < 0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P < 0.01). Serum IFN-γ levels were not significantly higher in MC + HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1ß in patients with MC + HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC + HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1ß and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakirna) in MC remains to be evaluated.

[Obesity and gastroesophageal reflux disease]. / Obesità e malattia da reflusso gastroesofageo.

Obesity, defined as body mass index >30, and gastroesophageal reflux disease show a prevalence of 30%, and 15-20% respectively, in adults in western countries. Obesity increase prevalence of gastroesophageal reflux disease, through difference physiopathological mechanism, that involve esophageal and gastric motility, sexual hormones, dietary habits and drugs intake, presence of hiatal hernia, elevated intra-abdominal pressure. Several surgical treatment options are avalaible in obese patients, which can be divided into restrictive (acting through reduction of gastric volume), or malabsorptive techniques (acting through functional shortening of digestive tract), or a combination of both. Type of surgical approach influences gastroesophageal reflux disease outcome in obese patients with pre-existing symptoms; Roux-en-Y gastric bypass probably represents the best option for these, eligible for bariatric surgery.

High circulating N-terminal pro-brain natriuretic peptide and tumor necrosis factor-alpha in mixed cryoglobulinemia.

AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor alpha (TNF-alpha) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV). METHODS: Serum NTproBNP and TNF-alpha levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed significantly higher mean NTproBNP and TNF-alpha levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (c2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (c2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as the patients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (c2, P = 0.08). CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-alpha in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction.

Capecitabine and celecoxib as second-line treatment of advanced pancreatic and biliary tract cancers.

OBJECTIVE: An increasing number of patients with advanced pancreatic or biliary tract cancer who progress after a gemcitabine-containing regimen are candidates for further chemotherapy. We therefore evaluated a fully oral regimen of capecitabine and celecoxib (CapCel) as second-line treatment in these patients. METHODS: Thirty-five patients with documented progressive disease after first-line treatment were enrolled. Capecitabine was administered at a dose of 1,000 mg/m(2) b.i.d. for 2 consecutive weeks followed by 1 week of rest; celecoxib was given continuously at 200 mg b.i.d. Progression-free survival at 3 months was the primary study endpoint. RESULTS: The CapCel combination was associated with an overall response rate of 9% and median survival duration of 19 weeks. Sixty percent of patients were free from progression 3 months after the start of treatment. Multivariate analysis identified a positive clinical benefit response and a decline in CA 19.9 serum levels >25% compared with baseline levels as independent predictors of prolonged survival. The treatment protocol was well tolerated with negligible hematological toxicity. The most common grade 3 non-hematological toxicities were hypertransaminasemia, diarrhea and asthenia. CONCLUSIONS: The CapCel combination is a safe treatment option with moderate activity in patients with pancreatic/biliary tract cancer after failure of a previous gemcitabine-containing regimen.

Bi-weekly chemotherapy with cisplatin, epirubicin, folinic acid and 5-fluororacil continuous infusion plus g-csf in advanced gastric cancer: a multicentric phase II study.

BACKGROUND: It has been demonstrated that the 3-weekly PELF regimen is superior to FAM and FAMTX in advanced gastric cancer. The aim of this multicentric phase II study was to evaluate the efficacy and tolerability of a PELF regimen, given every 2 weeks as a first-line therapy in patients with unresectable or metastatic gastric carcinoma. METHODS: Fifty-nine patients were treated with the following schedule: cisplatin (40 mg/m2, day 1), epirubicin (30 mg/m2, day 1), 5-fluorouracil (400 mg/m2 bolus, followed by 600 mg/m2, 22 h continuous infusion, day 1 and 2) and folinic acid (100 mg/m2, 2-h infusion, day 1 and 2). G-CSF (5 microg/kg) was administered on day 6, 8, 10, and 12. Cycles were repeated every 2 weeks for a maximum of twelve courses. RESULTS: Of the 52 evaluable patients, three (5.8%) complete responses, and 15 (28.8%) partial responses were observed, for an overall response rate of 34.6%. The median duration of response was 8 months. Nineteen patients had stable disease and 15 progressed on therapy. At a median follow-up of 12 months, the median time to progression was 8 months and the median survival duration was 13 months, with a 1-year survival rate of 53.5%. Grade 3 or 4 observed toxicities were: neutropenia in 26 patients (44%), thrombocytopenia in four patients (6.7%), and mucositis in seven patients (11.9%). CONCLUSIONS: The bi-weekly PELF regimen seems to be feasible with an acceptable toxicity profile and an activity comparable to the 3-weekly schedule.

Long-term survival in locally advanced oral cavity cancer: an analysis of patients treated with neoadjuvant cisplatin-based chemotherapy followed by surgery.

BACKGROUND: Neoadjuvant chemotherapy has been reported to be extremely active in head and neck cancer but has failed to give a statistically significant improvement in survival. METHODS: From 1981 to 1994, 33 operable patients with locally advanced oral cavity cancer received cisplatin-based chemotherapy before surgery. Postoperative radiotherapy was performed in high-risk patients. RESULTS: The overall clinical and pathologic complete response rates to neoadjuvant chemotherapy were 48% and 30%, respectively. At a median follow-up of 7.0 years (range, 0.3-15.3+ years), the 5-year and 10-year overall survival rates were 54.5% and 39.5%, and the disease-specific median survival was 6.6 years for all patients (8.3 and 2.3 years for stages III and IV, respectively). The univariate analysis showed a positive relationship between survival and male sex (p = .05), pathologic (p = .02), and clinical (p = .03) complete response. The Cox proportional hazard regression model confirmed the independent prognostic value of the clinical response with a 4.67 (95% CI, 1.70-12.86) hazard ratio. A second primary tumor occurred in six patients (18%), with a median of occurrence of 9 years (range, 7-11 years). CONCLUSIONS: This study confirms the prolonged survival expectancy largely exceeding 5 years for selected patients with stage IV and for most with stage III locally advanced oral cavity cancer achieving a clinical and/or pathologic complete response to chemotherapy.