がんの科学と治療

Background: Different synonymous codons are decoded at distinct rates during translation elongation due to the difference in tRNA availability, term tRNA adaptation index (tAI). Codons with higher tAI values are translated faster. Synonymous mutations do not change the amino acid (AA) but do sometimes change the tAI. That means synonymous mutations are able to alter the translation efficiency of host genes. In the cancer field, synonymous mutations are often automatically ignored. However, the increased translation of oncogenes or the decreased translation of tumor suppressor genes (TSG) might also lead to oncogenesis even when the protein sequences are unchanged. These changes in translation level could be induced by synonymous mutations.

Results and Discussion: We downloaded the single nucleotide polymorphisms (SNPs) in human populations. The ancestral state is parsed according to genomic alignments between human, macaque and mouse. We found that in the normal human populations, derived synonymous mutations that increase tAI are strongly suppressed in oncogenes but slightly favored in TSG. In oncogenes, mutation sites with higher conservation levels are more likely to decrease the tAI.

Conclusion: Our results indicate that the synonymous mutations in the human genome are not strictly neutral. The potentially increased translation of oncogenes and the decreased translation of TSG caused by synonymous mutations are suppressed in normal human populations. This is an indirect evidence that the synonymous-induced translational changes might be related to oncogenesis and should not be ignored in the cancer studies.

Background: FOLFIRINOX is emerging as the standard of care for fit patients with metastatic pancreatic cancer (MPC). However, use FOLFIRINOX associated with high toxicity rates reported in earlier studies; some physicians are reluctant to use it. We reviewed our experience with FOLFIRINOX in pancreatic adenocarcinoma, focusing on dose adjustments, toxicity, and efficacy. This study aims to evaluate FOLFIRINOX in the treatment of locally advance or metastatic pancreatic adenocarcinoma adult patients at King Fahd Medical City, Riyadh from January 2012 to December 2017.

Methods: We were review data for all locally advanced, or metastatic pancreatic adenocarcinoma adult patients with LAPC or MPC treated with FOLFIRINOX in King Fahd Medical City between January 2012 to December 2017. Efficacy, toxicity, and tolerability were evaluated

Results: Twenty-five patient with locally advance pancreatic cancer and twenty-four patients with metastatic pancreatic cancer were treated with FOLFIRINOX. The overall median survival time 9.27 month, the overall median progression-free survival was 7.44 month. Patient with LAPC had median PFS and OS of 9.7 and 12.7 months, respectively, and patient with MPC median PFS 5.3 month and OS 6.7 months. Forty-seven patients (96%) received FOLFIRINOX in the first line with median PFS 7.4 month and OS 9.27 month. In the whole cohort (LAPC and MPC), ten patients (20%) had partial response to chemotherapy. Further, 18 patients (36%) have stable disease. Twenty-One patients (42%) had no response as they progressed on FOLFORIRNOX. The most frequent grade ¾ toxicity was neutropenia (42%) renal toxicity (4%) and liver toxicity (6%), required emergency admission (51%) of patients.

Conclusion: The efficacy of FOLFIRINOX for pancreatic cancer was less than reported in the clinical trial while toxicity was similar to that report, selected patient and careful monitored toxicity can help the patient.

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer therapy and have significantly improved the clinical outcome of multiple tumor types. ICIs-induced myocarditis is a rare, but potential fatal side effect that requires prompt treatment. The histopathological features of ICIs-induced myocarditis are not well characterized due to limited number of cardiac biopsy or autopsy performed.

Case presentation: Here we reported an autopsy finding from a 70-year-old white male with severe myocarditis induced by pembrolizumab administered during the treatment for high grade urothelial carcinoma. He initially presented with left eye ptosis, diplopia, fatigue, and shortness of breath for four days, followed by quickly developed brachycardia and complete heart block. He was treated with high-dose glucocorticoids, but his condition continued to deteriorate. He experienced two cardiopulmonary arrests and died on the fifth day of admission. Sections from heart show extensive myocarditis with dense mixed inflammatory infiltration and patchy myocyte necrosis. Focal endothelitis associated with scattered micro-hemorrhages are also identified.

Discussion and conclusion: We reviewed the published case reports or case series from 2015 to 2018 and identified 13 cases of ICIs-induced myocarditis with available histopathologic description. We summarized the finding of these 14 patients including our own case in this paper. Although lymphocytic myocarditis was present in all cases, some histopathologic features are not consistently observed. Better characterization of histopathologic features of ICIs-induced myocarditis will help us understand the mechanism of this fatal toxicity and lead to potentially more specific treatment.

Background: Pelvic exenteration is an extensive operation, which offers the potential of cure to women with centrally recurrent gynaecological malignancy. The aim of this study was to assess the clinical outcome and factors influencing survival in these patients.

Methods: This was an observational cohort study of all patients who underwent pelvic exenteration for centrally recurrent gynaecological malignancy between March 1999 and October 2015. Data were collected from both the pelvic and gynaecologic oncology prospective databases. Determinants of survival were analysed using Kaplan-Meier survival curves.

Results: This study included 41 women who underwent pelvic exenteration for centrally recurrent gynaecological malignancy. The median patient age was 66 (range 27-79) years with a median follow up of 30 (range 0.4- 178) months. The median survival time was 22.3 (range 0-178.4) months. The 5- year survival rate was 32.4% for the entire cohort. A negative resection margin (R₀) was achieved in 85.4% (35/41). This group had a median survival of 36.2 (range 0.4-178.4) months compared to patients who had a positive resection margin (R₁), who had a median survival of 9.8 (range 1.2-15.1) months (p=0.0053). Postoperative radiotherapy was administered in 24.4% (10/41). Postoperative morbidity and mortality rates were 51% and 2.4% respectively. Major complications were noted in 24.4% of patients.

Conclusion: Pelvic exenteration for recurrent gynaecological malignancy was associated with a reasonably good survival rate, especially if complete resection was achieved. Optimising patient selection and peri-operative care, combined with a high-quality multi-disciplinary surgical approach are key factors in achieving good outcomes.

Background: Risk Reducing Mastectomy (RRM) is a rising practice chosen by the woman to reduce an unacceptable high breast cancer risk. Current guidelines are considering such a practice in presence of suggestive family history and/ or BRCA 1/2 genetic pathogenic mutations. However, it has been reported that in clinical practice other factors (surgeon attitude, women psychological traits, cultural/geographical aspects) are playing a role in the decision process for RRM.

Method: We analyzed the characteristics of a consecutive series of women who received RRM in the Comprehensive Cancer Institute of Bari; in particular information on BRCA test, family history, diagnostic imaging, clinical pathological factors were collected.

Results: A consecutive series of 59 women receiving RRM was retrospectively selected. No Mammographic/NMR breast characteristics supporting the need for RRM were present. 8 (14% had a bilateral RRM while 51 (86%) a contralateral RRM (CRRM). The decision to receive a RRM was based on the presence of a BRCA alteration in 31/59 (53%) of cases, but, interestingly, 47% of women women decided for such a surgery even with a genetic test negative for BRCA mutations (17%) or with BRCA genetic test not performed (30%). Bilateral RRM was chosen only by women carrying a germline BRCA mutation. The decision for a CRRM was not based on specific primary tumor characteristics and performed in one time with respect to primary surgery in 26/51 cases while in the remaining subgroup of women in a delayed time. The multivariate analysis confirmed BRCA test stronger but not unique factor influencing the decision for RRM.

Conclusion: We confirm the prevalent role played by BRCA test in the decision of women to have a RRM but other factors seem to be able to suggest this practice also when no clear clinical benefit could be expected. In order to reduce the heterogeneity of approach to such practice, we suggest that: a) A multidisciplinary approach should be guaranteed; b) A clear intra-hospital clinical pathways should be adopted; c) Social education attenuating the perception of risk and expectations for such preventive practice should be activated.