The Potential Role of Adjuvant Chemoradiotherapy in Patients with Microscopically Positive (R1) Surgical Margins after Resection of Cholangiocarcinoma.

(1) Background: Biliary tract cancers (BTCs) are a heterogeneous group of neoplasms with dismal prognosis and the role of adjuvant chemoradiotherapy in high-risk resected patients is unclear. (2) Methods: We retrospectively analyzed the outcomes of BTC patients who received curative intent surgery with microscopically positive resection margins (R1) and adjuvant chemoradioradiotherapy (CCRT) or chemotherapy (CHT) from January 2001 to December 201. (3) Results: Out of 65 patients who underwent R1 resection, 26 received adjuvant CHT and 39 adjuvant CCRT. The median recurrence-free survival (RFS) in the CHT and CHRT groups was 13.2 and 26.8 months, respectively (p = 0.41). Median overall survival (OS) was higher in the CHRT group (41.9 months) as compared to the CHT group (32.2 months), but the difference was not statistically significant (HR 0.88; p = 0.7). A promising trend in favor of CHRT was observed in N0 patients. Finally, no statistically significant differences were observed between patients undergoing adjuvant CHRT after R1 resection and patients treated with chemotherapy alone after R0 surgery. (4) Conclusions: Our study did not show a significant survival benefit with adjuvant CHRT over CHT alone in BTC patients with positive resection margins, while a promising trend was observed.

The CXCR1/CXCR2 Inhibitor Reparixin Alters the Development of Myelofibrosis in the Gata1 low Mice.

A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-ß, the megakaryocytes from the bone marrow of the Gata1 low mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched Gata1 low mice demonstrated reductions in bone marrow and splenic fibrosis. Of note, the levels of fibrosis detected using two independent methods (Gomori and reticulin staining) were inversely correlated with plasma levels of Reparixin. Immunostaining of marrow sections indicated that the bone marrow from the Reparixin-treated group expressed lower levels of TGF-ß1 than those expressed by the bone marrow from vehicle-treated mice while the levels of mCXCL1, and expression of CXCR1 and CXCR2, were similar to that of vehicle-treated mice. Moreover, immunofluorescence analyses performed on bone marrow sections from Gata1 low mice indicated that treatment with Reparixin induced expression of GATA1 while reducing expression of collagen III in megakaryocytes. These data suggest that in Gata1low mice, Reparixin reduces fibrosis by reducing TGF-ß1 and collagen III expression while increasing GATA1 in megakaryocytes. Our results provide a preclinical rationale for further evaluation of this drug alone and in combination with current JAK inhibitor therapy for the treatment of patients with myelofibrosis.

Encephalic Leukocytoclastic Vasculitis during Treatment with Sunitinib for Renal Cell Carcinoma: A Case Report.

Renal cell carcinoma is a malignant tumor that arises in the kidney parenchyma. For many years, sunitinib has represented the mainstay of medical treatment for metastatic renal cell carcinoma. Herein, we present the case of a 66-year-old woman with metastatic clear cell renal carcinoma undergoing treatment with sunitinib for two years that developed encephalic leukocytoclastic vasculitis, probably due to a paraneoplastic syndrome.

Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: a meta-analysis.

Only a minority of studies addressing the association between immune-related adverse events (IrAE) and outcome considered the immortal time bias, with conflicting results. PubMed, Embase, Web of Science and Scopus were searched through 2 January 2020. Studies reporting the impact of IrAE on outcome in patients treated with antiprogrammed death receptor 1 or PD-L1 were included. Twenty nine articles were included. IrAEs were associated with improved outcomes with high heterogeneity. With a landmark approach, the association between IrAE and outcome remains significant but the effect size was smaller (hazard ratio 0.61 vs 0.41 for overall survival; p = 0.015; hazard ratio 0.66 vs 0.47 for progression-free survival, p = 0.029; odds ratio 2.59 vs 6.77 for overall response rate; p < 0.001), no significant heterogeneity. Our analysis suggests a confounding effect of immortal time bias and a real effect of IrAE on outcome.

CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors.

AIMS: To assess prognostic value of pre-therapy carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) blood levels in non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICIs) and their early change as predictor of benefit. MATERIALS AND METHODS: This is a retrospective cohort study including patients with stage IIIB-IV NSCLC who received anti PD-1/PD-L1 in first or advanced lines of therapy in two institutions. A control cohort of patients treated only with chemotherapy has been enrolled as well. RESULTS: A total of 133 patients treated with nivolumab or atezolizumab were included in the test set, 74 treated with pembrolizumab first line in the validation set and 89 in the chemotherapy only cohort. CYFRA 21-1 >8 ng/mL was correlated with overall survival (OS) in the test set, validation set and in univariate and multivariate analysis (pooled cohort hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.24-2.93, p 0.003). Early 20% reduction after the third cycle was correlated with OS for CEA (HR 0.12; 95% CI 0.04-0.33; p < 0.001), and for CYFRA 21-1 (HR 0.19; 95% CI 0.07-0.55; p 0.002). CONCLUSIONS: CYFRA 21-1 pre-therapy assessment provides clinicians with relevant prognostic information about patients treated with ICI. CEA and CYFRA 21-1 repeated measures could be useful as an early marker of benefit.

ECOG performance status ≥2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors-A systematic review and meta-analysis of real world data.

OBJECTIVES: ICIs have been approved and are routinely administered regardless of performance status (PS), despite randomized clinical trials of ICIs alone or combined with chemotherapy or target therapy enrolled patients with ECOG PS 0 or 1, while patients with ECOG PS 2 or more were excluded. MATERIALS AND METHODS: We carried out a meta-analysis of available clinical studies exploring the prognostic impact of PS ≥ 2 on Overall Survival (OS), Progression Free Survival (PFS) or Overall Response Rate (ORR) in patients with non small cell lung cancer (NSCLC) treated with immunotherapy (any line). RESULTS: We reviewed 19 studies, comprising 3600 NSCLC patients, 757 of whom with ECOG PS > 1 (average 21.0%, range 6.0-48.6%). In the overall population PS ≥ 2 resulted in worse OS, PFS and ORR (OS pooled hazard ratio of 2.72; 95% CI: 2.03-3.63; I2 72.70%, p < 0.001; PFS pooled hazard ratio of 2.39; 95% CI 1.81-3.15, p < 0.0001; I2 73.03%; ORR pooled odds ratio 0.25; 95% CI 0.11-0.56, p 0.001; I2 0.00%). CONCLUSION: ECOG PS ≥ 2 retains an important prognostic validity in patients treated with ICI similar, in terms of effect size, to that reported for chemotherapy in NSCLC. The high level of heterogeneity for OS and PFS analysis (but not for ORR), not completely explained by the different proportion of ECOG 3-4 patients (ranging from 0% to 50% of the PS ≥ 2 population), could be the result of both patient heterogeneity within the PS 2 population and the subjectivity of ECOG PS assessment. Whether poorer PS is also a predictor of lower immunotherapy efficacy remains still to be demonstrated.

A Case of Response to Immunotherapy in a Patient With MSI Metastatic Colorectal Cancer and Autoimmune Disease Receiving Steroid Therapy.

Colorectal cancer is one of the most commonly diagnosed tumors worldwide and a leading cause of cancer-related death. Although the majority of gastrointestinal cancers are generally considered poorly immunogenic, recent data from clinical trials have demonstrated that the subgroup of patients with DNA mismatch repair system is highly responsive to immune checkpoint inhibitor-based therapy. We present the case of a 74-year-old man with pulmonary autoimmune intersitiopathy and microsatellite instability metastatic colorectal cancer who responded to nivolumab despite the concomitant steroid therapy. Furthermore, his autoimmune disease did not worsen during immunotherapy.

Third- and later-line treatment in advanced or metastatic gastric cancer: a systematic review and meta-analysis.

Aim: We performed a systematic review and meta-analysis to investigate the efficacy and safety of third-line (TLT) and salvage treatment (ST) in advanced or metastatic gastric cancer. Materials & methods: Eligible studies included randomized clinical trials assessing TLT and ST versus placebo or best supportive care. Outcomes of interest included: overall survival, objective response rate and disease control rate in TLT; progression-free survival in ST; grade 3-4 adverse events in ST. Results: The use of TLT and ST was superior to placebo or best supportive care in terms of prolonging overall survival and progression-free survival. Hematological toxicities were more frequent in ST. Conclusion: TLT and ST are considerable and tolerable treatment options for patients with advanced or metastatic gastric cancer. Given the substantial heterogeneities affecting the efficacy analyses, these results have to be interpreted cautiously.

Proteolytic activity of bovine lactoferrin.

Bovine lactoferrin catalyzes the hydrolysis of synthetic substrates (i.e., Z-aminoacyl-7-amido-4-methylcoumarin). Values of Km and kcat for the bovine lactoferrin catalyzed hydrolysis of Z-Phe-Arg-7-amido-4-methylcoumarin are 50 microM and 0.03 s(-1), respectively, the optimum pH value is 7.5 at 25 degrees C. The bovine lactoferrin substrate specificity is similar to that of trypsin, while the hydrolysis rate is several orders of magnitude lower than that of trypsin. The bovine lactoferrin catalytic activity is irreversibly inhibited by the serine-protease inhibitors PMSF and Pefabloc. Moreover, both iron-saturation of the protein and LPS addition strongly inhibit the bovine lactoferrin activity. Interestingly, bovine lactoferrin undergoes partial auto-proteolytic cleavage at positions Arg415-Lys416 and Lys440-Lys441. pKa shift calculations indicate that several Ser residues of bovine lactoferrin display the high nucleophilicity required to potentially catalyze substrate cleavage. However, a definitive identification of the active site awaits further studies.

Anti-invasive activity of bovine lactoferrin towards group A streptococci.

Group A streptococci (GAS) are able to invade cultured epithelial and endothelial cells without evidence of intracellular replication. GAS, like other facultative intracellular bacterial pathogens, evolved such ability to enter and to survive within host cells avoiding the host defences, and bacterial intracellular survival could explain the recurrence of infections. We report here that 1 mg bovine lactoferrin (bLf)/mL significantly hindered the in vitro invasion of cultured epithelial cells by GAS isolated from patients suffering from pharyngitis and completely inhibited the invasiveness of GAS pretreated with subinhibiting concentrations of erythromycin or ampicillin. One milligram of bLf per millilitre was also able to increase the number of epithelial cells undergoing apoptosis following GAS invasion, although the number of intracellular GAS in the presence of bLf decreased by about 10-fold. The ability of bLf to decrease GAS invasion was confirmed by an in vivo trial carried out on 12 children suffering from pharyngitis and already scheduled for tonsillectomy. In tonsil specimens from children treated for 15 days before tonsillectomy with both oral erythromycin (500 mg t.i.d. (three times daily)) and bLf gargles (100 mg t.i.d.), a lower number of intracellular GAS was found in comparison with that retrieved in tonsil specimens from children treated with erythromycin alone (500 mg t.i.d.).

Antiviral activity of ovotransferrin discloses an evolutionary strategy for the defensive activities of lactoferrin.

Ovotransferrin (formerly conalbumin) is an iron-binding protein present in birds. It belongs to the transferrin family and shows about 50% sequence homology with mammalian serum transferrin and lactoferrin. This protein has been demonstrated to be capable of delivering iron to cells and of inhibiting bacterial multiplication. However, no antiviral activity has been reported for ovotransferrin, although the antiviral activity of human and bovine lactoferrins against several viruses, including human herpes simplex viruses, has been well established. In this report, the antiviral activity of ovotransferrin towards chicken embryo fibroblast infection by Marek's disease virus (MDV), an avian herpesvirus, was clearly demonstrated. Ovotransferrin was more effective than human and bovine lactoferrins in inhibiting MDV infection and no correlation between antiviral efficacy and iron saturation was found. The observations reported here are of interest from an evolutionary point of view since it is likely that the defensive properties of transferrins appeared early in evolution. In birds, the defensive properties of ovotransferrin remained joined to iron transport functions; in mammals, iron transport functions became peculiar to serum transferrin, and the defensive properties towards infections were optimised in lactoferrin.