Influence of CASP9 c.-1339A>G and CASP3 c.-1191A>G variants in outcome of patients with head and neck squamous cell carcinoma.

BACKGROUND: Abnormalities in the intrinsic apoptosis pathway, associated with single nucleotide variants (SNVs) in caspase (CASP) genes, alter head and neck squamous cell carcinoma (HNSCC) proliferation and progression. This prospective study aimed to evaluate whether CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs influence the outcome of patients with HNSCC. Two hundred sixty-two HNSCC patients were enrolled in the study. METHODS: DNA and RNA of peripheral blood samples were analyzed using real-time polymerase chain reaction (PCR) for genotyping and quantitative PCR method for gene expression, respectively. Differences in CASP3 expressions were analyzed using the Mann-Whitney test. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier curves, log-rank test, and Cox analyses. RESULTS: CASP3 c.-1191AG or GG genotype was associated with higher CASP3 expression when compared with AA genotype (0.50 arbitrary units (AUs) ± 0.29 standard deviation (SD) vs 0.28 AUs ± 0.12 SD; P = .02). Patients with CASP9 c.-1339GG genotype had 1.54 more chance of presenting disease progression or relapse than patients with CASP9 c.-1339AA or AG genotype. Patients with CASP9 c.-1339GG and CASP3 c.-1191GG combined genotype had 2.64 more chance of presenting progression or relapse of the disease and 2.84 more chance of evolving to death than those with the remaining combined genotypes. CONCLUSIONS: Our findings provide, for the first time, preliminary evidence that inherited abnormalities in the intrinsic apoptosis pathway, related to CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs, act as predictors of HNSCC patients' survival.

Association between genetic polymorphisms in DNA mismatch repair-related genes with risk and prognosis of head and neck squamous cell carcinoma.

We examined the influence of MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p = 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p = 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p = 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p = 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p = 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P = 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.

Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk nonmetastatic prostate cancer: A systematic review and metaanalysis.

OBJECTIVES: To investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. MATERIALS AND METHODS: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. RESULTS: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. CONCLUSIONS: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted.

Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis.

BACKGROUND: Previous studies hypothesized that androgen deprivation therapy (ADT) may reduce severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infectivity. However, it is unknown whether there is an association between ADT and a higher survival in prostate cancer patients with COVID-19. METHODS: We performed a retrospective analysis of prostate cancer (PC) patients hospitalized to treat COVID-19 in Brazil's public health system. We compared patients with the active use of ADT versus those with non-active ADT, past use. We constructed propensity score models of patients in active versus non-active use of ADT. All variables were used to derive propensity score estimation in both models. In the first model we performed a pair-matched propensity score model between those under active and non-active use of ADT. To the second model we initially performed a multivariate backward elimination process to select variables to a final inverse-weight adjusted with double robust estimation model. RESULTS: We analyzed 199 PC patients with COVID-19 that received ADT. In total, 52.3% (95/199) of our patients were less than 75 years old, 78.4% (156/199) were on active ADT, and most were using a GnRH analog (80.1%; 125/156). Most of patients were in palliative treatment (89.9%; 179/199). Also, 63.3% of our cohort died from COVID-19. Forty-eight patients under active ADT were pair matched against 48 controls (non-active ADT). All patients (199) were analyzed in the double robust model. ADT active use were not protective factor in both inverse-weight based propensity score (OR 0.70, 95% CI 0.38-1.31, P = 0.263), and pair-matched propensity score (OR 0.67, 95% CI 0.27-1.63, P = 0.374) models. We noticed a significant imbalance in the propensity score of patients in active and those in non-active ADT, with important reductions in the differences after the adjustments. CONCLUSIONS: The active use of ADT was not associated with a reduced risk of death in patients with COVID-19.

Outcomes of COVID-19 Patients under Cytotoxic Cancer Chemotherapy in Brazil.

BACKGROUND: Cancer patients present a distinct vulnerability to COVID-19. It is unclear if chemotherapy could accentuate the overall risk in these patients. METHODS: We performed a retrospective analysis linking COVID-19 data and oncological information systems to compare lethality in patients undergoing cytotoxic chemotherapy before COVID-19. We considered patients who received chemotherapy in the last 30 days as in "active treatment", and patients who did not receive drugs in this period as "non-active treatment" for propensity-score pair matching. We also tested the influence of baseline variables in our results in a multivariate model. RESULTS: 66.1% (162/246) of patients in matched active chemotherapy died vs. 70.2% (172/246) in the matched non-active chemotherapy group. The risk of death was positively associated with palliative intent of treatment and hematologic neoplasms. Being in active chemotherapy was not associated with increased mortality compared to non-active treatment. We also noted in exploratory propensity-score matchings that the use of alkylating agents (odds ratio [OR] 0.38, 95% confidence interval [CI], 0.21-0.70) and topoisomerase II inhibitors (OR 0.28, 95% CI 0.14-0.56) were protective factors. CONCLUSIONS: This study does not demonstrate an increase in mortality for cancer patients under active cytotoxic chemotherapy with COVID-19.

Effectiveness of Platinum-Based Chemotherapy in Patients With Metastatic Prostate Cancer: Systematic Review and Meta-analysis.

BACKGROUND: Taxanes are the only cytotoxic drugs that have demonstrated a survival benefit for patients with castration-resistant prostate cancer (CRPC), but there is some evidence that platinum compounds may also benefit such patients. METHODS: We performed a systematic search on electronic databases. We sought prospective clinical studies testing platinum compounds for CRPC. Platinum compounds could be delivered alone or in combination with other drugs. Both randomized and nonrandomized studies were included for qualitative synthesis, only randomized studies were included for meta-analyses. Clinical overall response rate (cORR), prostate-specific antigen overall response rate (sORR), progression-free survival (PFS), overall survival (OS), and toxicity were the outcomes of interest. RESULTS: We identified 53 studies delivering platinum agents for patients with CRPC. cORR varied from 0 to 82%, while sORR varied from 2% to 100%. Response rates were higher in patients who received combination treatments rather than platinum compounds alone. Pooled data from randomized trials demonstrated a statistically significant increase in both cORR (odds ratio = 5.3; 95% confidence interval, 1.89-14.92) and sORR (odds ratio = 2.07; 95% confidence interval, 1.33-3.22) when adding platinum compounds to chemotherapy. PFS varied from 2.1 to 12 months and OS 4.2 to 28 months with platinum-containing chemotherapy. Nausea and myelosuppression were the most common adverse effects. Toxicity was manageable in most studies. CONCLUSION: Platinum compounds are a safe and active treatment for CRPC. Response rates are higher when cytotoxic chemotherapy containing platinum agents are compared to nonplatinum chemotherapy. Data on OS and PFS are inconclusive. More research is needed to evaluate whether platinum-based chemotherapy results in a survival benefit for patients with CRPC, as well as to establish predictive biomarkers.

Photobiomodulation Therapy in Cancer Patients with Mucositis: A Clinical Evaluation.

Objective: To evaluate the use of photobiomodulation therapy (PBM-T) in patients undergoing chemotherapy and/or radiotherapy and affected by oral mucositis (OM). Background: Few clinical studies have evaluated PBM-T, particularly in combination with photodynamic therapy (PDT), for the treatment of OM. Methods: Thirty-one patients were divided by convenience into two groups. One received PBM-T (n = 17) alone, consisting of low-intensity laser (LIL) irradiation (wavelength 660 nm, continuous mode, spot energy 4 J, energy density 142 J/cm2, irradiation time 40 s per spot), once weekly for 4 weeks. The other (n = 14) received a combination of PBM-T and PDT, with curcumin as photosensitizer. Patients were instructed to rinse their mouth with 20 mL of curcumin solution for 5 min. The oral cavity was irradiated with a blue light-emitting diode (power 1200 mV, wavelength 468 nm) for 5 min. LIL was applied as in the PBM-T group. After treatment, OM severity was reassessed. The results were analyzed by the Wilcoxon and Mann-Whitney tests. Results: Both PBM-T alone and PBM-T+PDT yielded significant reductions in OM grade (p < 0.01). PDT+PBM-T resulted in a significantly shorter healing time compared with PBM-T alone (p = 0.0321). Conclusions: Within the parameters of this study, PBM-T+PDT was an effective method to accelerate the OM healing process.

FOLFOXIRI Regimen for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Cytotoxic chemotherapy is the mainstay treatment for metastatic colorectal cancer (mCRC). Fluoropyrimidines, oxaliplatin, and irinotecan are the most active drugs; however, their optimal sequencing has not yet been established. Some evidence has shown that upfront treatment with 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI regimen) can improve outcomes for patients with mCRC. MATERIALS AND METHODS: We performed a systematic search in electronic databases. Studies reporting results from prospective, randomized clinical trials comparing FOLFOXIRI to less aggressive regimens for treatment of mCRC were selected for meta-analysis. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity were the outcomes of interest. The pooled hazard ratio (HR) and pooled odds ratio (OR) was calculated for the time-to-event endpoints and dichotomous endpoints, respectively. RESULTS: Four studies were included in the final analysis. The pooled data showed a significant benefit favoring FOLFOXIRI in terms of OS (HR, 0.80; 95% confidence interval [CI], 0.70-0.92), PFS (HR, 0.68; 95% CI, 0.55-0.85), and ORR (OR, 1.9; 95% CI, 1.36-2.67). Toxicity was significantly greater in the FOLFOXIRI arm. Heterogeneity across trials and risk of publication bias were low. CONCLUSION: FOLFOXIRI provides superior outcomes for mCRC compared with standard chemotherapy regimens. The toxicity is greater with FOLFOXIRI but manageable. The role of targeted agents combined with FOLFOXIRI is uncertain, and further research is warranted.

Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer.

BACKGROUND: Cetuximab and panitumumab are monoclonal antibodies targeting the epidermal growth factor receptor. Both drugs are active against RAS wild type metastatic colorectal cancer after chemotherapy failure, with similar efficacy and toxicity profiles. However, their cost and limited survival benefits may compromise incorporation in the Brazilian public healthcare system, the Unified Heath System (Sistema Único de Saúde) (SUS). METHODS: A cost-effectiveness analysis was conducted using a Markov model from the Brazilian Public health perspective and a lifetime horizon in patients with RAS -wt mCRC. Transition probabilities and mortality rates were extracted from randomized studies. Treatment costs were obtained from price tables regulated by the Brazilian Health Ministry. The World Health Organization recommendation of three times GDP per capita was used to define the cost-effectiveness threshold. RESULTS: The use of cetuximab or panitumumab for chemotherapy-refractory mCRC patients resulted in 0.22 additional life-years relative to BSC, with incremental cost-effectiveness ratios (ICERs) of $58,240 and $52,772 per LY, respectively. That exceeds the pre-specified threshold for cost-effectiveness. Acquisition of biological agents was the major driver of increased costs. CONCLUSIONS: Our economic evaluation demonstrates that both cetuximab and panitumumab are not a cost-effective approach in RAS-wt mCRC patients. Discussion about drug price should be prioritized to enable incorporation of these monoclonal antibodies in the SUS.

Association between polymorphisms in genes related to DNA base-excision repair with risk and prognosis of oropharyngeal squamous cell carcinoma.

PURPOSE: We examined the influence of OGG1 c.977C>G (rs1052133), APEX1 c.444T>G (rs1130409), XRCC1 c.-77T>C (rs3213245), c.580C>T (rs1799782), c.839G>A (rs25489) and c.1196G>A (rs25487) single-nucleotide polymorphisms (SNPs), involved in base-excision repair (BER) pathway, on oropharyngeal squamous cell carcinoma (OPSCC) risk and prognosis. METHODS: Aiming to identify the genotypes, DNA from 200 consecutive OPSCC patients and 200 controls was analyzed by PCR-RFLP. The prognostic impact of genotypes of SNPs on progression-free survival (PFS) and overall survival of OPSCC patients was examined using the Kaplan-Meier estimates and Cox regression analyses. RESULTS: XRCC1 c.580CT or TT genotypes (19.5 vs. 11.0 %, P = 0.04) and XRCC1 TTGG haplotype from c.-77T>C, c.580C>T, c.839G>A and c.1196G>A SNPs (17.5 vs. 10.0 %, P = 0.04) were more common in patients with OPSCC than in controls. Carriers of combined genotypes of c.580C>T and TTGG haplotype of XRCC1 gene were under 3.35- and 3.22-fold increased risk of OPSCC than others. For survival analysis, we selected only patients with tumor at stage IV. The median follow-up time was 24.5 months. At 24 months of follow-up, PFS was shorter in patients with OGG1 c.977CC genotype when compared with others genotypes (35.5 vs. 52.1 %, log-rank test, P = 0.03). After multivariate Cox analysis, patients with OGG1 c.977CC genotype had more chance to present tumor progression when compared with others (HR 1.68, P = 0.02). CONCLUSIONS: Our data present, for the first time, evidence that inherited OGG1 c.977C>G; XRCC1 c.-77T>C, c.580C>T, c.839G>A and c.1196G>A abnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes.

Neoadjuvant endocrine therapy for resectable breast cancer: A systematic review and meta-analysis.

INTRODUCTION: The role of neoadjuvant endocrine therapy for resectable breast cancer is not well established, despite encouraging results obtained in the metastatic and adjuvant settings. This systematic review aims to examine existing medical literature on neoadjuvant hormone therapy (HT). METHODS: Data from prospective, randomized trials was included if comparing neoadjuvant HT versus surgery alone without adjuvant treatment, or neoadjuvant HT versus chemotherapy (CT), or HT plus CT versus CT alone, or HT plus CT versus HT alone, or two distinct HT. Odds Ratios (OR) were calculated from pooled data. RESULTS: Five studies compared HT with tamoxifen versus HT with aromatase inhibitors (AI). A meta-analysis of their results demonstrated superiority of AIs in overall response rate (ORR) (OR 1.9; 95% CI 1.17-3.08). Two trials compared HT against CT, and pooled data from them demonstrated a trend favoring CT (OR for ORR 0.75; 95% CI 0.35-1.6). That trend disappeared when only postmenopausal women were considered (OR 1.01; 95% CI 0.62-1.63). One trial compared HT plus CT with no neoadjuvant treatment, and obtained an 83% ORR. One trial compared HT plus CT versus CT alone and found a non-significant increase in ORR for adding HT to CT (OR 1.48; 95% CI 0.58-3.77). No trial compared HT plus CT versus HT alone. CONCLUSIONS: Neoadjuvant HT is a safe and feasible option, but it cannot be considered equivalent to CT. If neoadjuvant HT is performed, AIs are preferable over tamoxifen due to higher response rates.

Gemcitabine-related thrombotic microangiopathy: a single-centre retrospective series.

INTRODUCTION: Thrombotic microangiopathy (TMA) has been reported as a complication of chemotherapy. Many antineoplastic agents have been linked to TMA, gemcitabine being one of the most frequently cited as related to this syndrome. METHODS: A retrospective search for chemotherapy-induced TMA cases among gemcitabine users in a single oncology centre from January 2009 to September 2012 was performed. RESULTS: Three cases of gemcitabine-induced TMA were reported, from a total of 264 patients (incidence: 1·13%) who received the drug. From the three cases reported, two (66%) patients died as a consequence of the syndrome. DISCUSSION: These findings are compatible with previous analyses, which report an incidence of gemcitabine-associated TMA ranging from 0·008 to 2·2% and mortality rates from 15 to 90%. Unlike previously reported, however, cumulative dose was not predictive of risk. CONCLUSION: Gemcitabine-induced TMA is an underdiagnosed condition characterized by high mortality rates. Attention should be called for a higher level of awareness to provide early diagnosis and proper treatment.

Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: A systematic review and meta-analysis

To investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent.

Reducing discomfort while measuring crown-heel length in neonates.

AIM: To assess the degree of discomfort caused by length measurement in neonates, performed with one or both lower limbs extended, on the first and second day after birth, with either one or both lower limbs extended. METHODS: Healthy full-term neonates were systematically sampled during the months of February and March 2004. Crown-heel length was measured, using a 1-mm precision neonatometer, at approximately 8 h and 32 h after birth, with one and both lower limbs extended. The Neonatal Facial Coding System was used to assess discomfort during measurements. Data were analysed by parametric and non-parametric tests as appropriate. RESULTS: Whatever the measurement technique, discomfort scores are significantly higher during the length measurement than at baseline. Whenever length measurements are performed, discomfort scores are significantly higher when extending both lower limbs rather than one lower limb (p < 0.006). The measured length is greater with one lower limb extended; however, the difference decreases over time, being 0.19 cm (95% CI 0.1-0.3; p < 0.001) at approximately 32 h of age. No significant differences in length were found between measurements at approximately 8 or 32 h, regardless of the technique used. The best correlation between length measurements with one or both lower limbs extended was observed at approximately 32 h after birth (r = 0.98). CONCLUSION: Measuring crown-heel length is a distressful procedure for the neonate. Measurements with one lower limb extended result in less discomfort than when both lower limbs are extended, without decreasing the accuracy.