Purpose: SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival.Experimental design: We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression.Results: SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q.Conclusions: We conclude that clonal loss of SMAD4 expression in adenomas, carcinomas, and liver metastases increases with disease progression. SMAD4 loss, and to a lesser extent weak expression, is strongly associated with poor survival regardless of stage.

Purpose An inherited mutation in KRAS (LCS6-variant, rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal Antibody therapy (moAbs) response in metastatic colorectal cancer patients (mCRC) patients. Experimental Design LCS6-variant and KRAS/BRAF mutational status was determined in 512 mCRC patients treated with salvage anti-EGFR moAbs therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-variant allele to therapy exposure. Results 21.2% (109/512) of mCRC patients had the LCS6-variant (TG/GG), which was found twice as frequently in the BRAF mutated versus the wt group (p = 0.03). LCS6-variant patients had significantly longer PFS with anti-EGFR moAbs monotherapy treatment in the whole cohort (16.85 vs 7.85 weeks, p = 0.019) and in the double wt (KRAS and BRAF) patient population (18 vs 10.4 weeks, p = 0.039). Combination therapy (moAbs plus chemotherapy) led to improved PFS and OS for non-variant patients, and brought their outcome to levels comparable to LCS6-variant patients receiving anti-EGFR moAbs monotherapy. Combination therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR moAbs monotherapy and chemotherapy. Conclusions LCS6-variant mCRC patients have an excellent response to anti-EGFR moAbs monotherapy, without any benefit of additional chemotherapy. These findings further confirm the importance of this mutation as a biomarker of anti-EGFR moAbs response in mCRC patients, and warrant further prospective confirmation.

Background:We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC).Methods:Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0–1 were included in the trial.Results:Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70% 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1–13.4) and the overall median survival time was 30.3 months (95% CI: 18.8–41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient.Conclusion:The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

Background: The advanced lung cancer inflammation index [ALI: body mass index  serum albumin/neutrophil-tolymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). Patients and methods: This retrospective study included 672 stage IV NSCLC patients treated with programmed deathligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. Results: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) ¼ 0.402, P < 0.0001, n ¼ 460], but not chemo-immunotherapy (HR ¼ 0.624, P ¼ 0.111, n ¼ 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P ¼ 0.008) and time-on-treatment (HR ¼ 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR ¼ 0.694, P ¼ 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor

Mutations and the high incidence of 9p LOH detected in our SCC samples imply that inactivation of CDKN2A genes, via allelic loss and/or mutation (probably UV-induced) may play a significant role in nonmelanoma skin cancer development, particularly in the more aggressive SCC type.

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The zygomycetes are a class of fungi that can cause a variety of infections in humans. Rhinocerebral mucormycosis is a rare disease and usually affects diabetic or immunosuppressed patients. The disease progresses rapidly and is usually fatal despite aggressive surgical and medical therapy. We report the management of two cases of rhino-sinusal and orbital mucormycosis in diabetic patients on treatment with corticosteroids, and mild renal impairment, successfully treated with a combination of aggressive surgical debridement and liposomal amphotericin B.