From Transplant to Tablets : A paradigm shift in Oncology

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Chemoresistance to paclitaxel in human ovarian xenografts: The role of apoptosis-regulating proteins

Paclitaxel has established an evolving role in the management of ovarian cancer. However, the emergence of resistance to paclitaxel is likely to become an increasing problem, and thus a reason for failure of therapy of ovarian cancer. Understanding of the molecular pathways involved in the development of resistance to paclitaxel may provide suitable targets for novel therapies to help to circumvent resistance to paclitaxel. Three main mechanisms have been shown to be involved in paclitaxel resistance: (a) altered paclitaxel uptake, (b) altered paclitaxel-microtubules interaction, (c) alterations in apoptosis regulating proteins that control the induction of cell death. The realization that most chemotherapeutic agents- including paclitaxel- induce cell death by a genetically programmed process termed apoptosis together with the demonstration that alteration of apoptosis regulating proteins such as bcl-2 family of proteins or p53 may induce chemoresistance to paclitaxel has led to intense research in this area. Almost all these studies were in vitro with an obvious lack of in vivo studies. Hence, these apoptosis regulating proteins were the focus of the present in vivo study as they may either represent oncogenes responsible for acquired resistance, or alternatively potential targets for molecular intervention to circumvent resistance to paclitaxel. The first part of the study compared the alterations in apoptosis regulating proteins between CH1 paclitaxel sensitive xenografts (CH1/TS) and acquired paclitaxel resistant xenografts (CH1/TR). These xenografts were established from a CH1 paclitaxel sensitive cell line treated with paclitaxel which then acquired resistance in vitro. Following the confirmation of the sensitivity pattern of both tumours to paclitaxel in vivo, it was demonstrated that there was no paclitaxel uptake defect in CH1/TR tumours that may contribute to paclitaxel resistance. Flow cytometric and apoptosis studies provided an insight into the mechanism of action of paclitaxel. They confirmed the response pattern with paclitaxel inducing mitotic arrest, G2/M phase arrest, and apoptosis in CH1/TS tumours. In contrast, these parameters were unaltered in the CH1/TR tumours, consistent with its resistant phenotype. There were clear differences in the induction of apoptosis regulating proteins between the paclitaxel sensitive and resistant tumours. Following the treatment of CH1/TS tumours with paclitaxel, there was a significant early induction of p53, and p21 with evidence of inactivation (phosphorylation) of survival promoting (anti-apoptotic) protein bcl-2, and down regulation of anti-apoptotic protein bc1-xl. These changes were not significantly altered in CH1/TR tumours. Subsequently, these xenografts were treated with cisplatin to compare and contrast its effect to that of paclitaxel. The first difference demonstrated was that both CH1/TS and CH1/TR tumours displayed complete and partial response, respectively, to cisplatin. In contrast to paclitaxel, the main cell cycle alterations to cisplatin were accumulation of cells in S phase, and late G2 arrest. These cell cycle alterations were shown to be associated with induction of apoptosis. More importantly, it was observed that cisplatin was able to induce p53 and down regulate bc1-xl in CH1/TR tumours suggesting that these pathway are intact. This suggested that CH1/TR tumours acquired resistance to paclitaxel was not due to inherent defect in the expression of apoptosis regulating proteins, but instead due to an upstream defect possibly at the level of paclitaxel-microtubule interaction. This is consistent with previous in vitro studies that have shown that successful polymerization of microtubules is required for induction of cell death, induction of p53 and p21 and phosphorylation of bcl-2. Taking all these observations into consideration, it could postulated that resistance to paclitaxel in CH1/TR tumours that was reflected in the lack of significant alteration in apoptosis regulating protein was due to unsuccessful microtubule-paclitaxel interaction which is supported by the lack of G2/M arrest and induction of apoptosis. The paclitaxel-microtubule interaction will be the focus of a subsequent study. The second part of this study demonstrated in vivo that the overexpression of a single apoptosis regulating protein resulted in the modulation of response to chemotherapy. Xenografts of CHI paclitaxel sensitive cells overexpressing the anti-apoptotic protein bc1-xl were established and treated with paclitaxel and cisplatin. The overexpression of bc1-xl protein resulted in development of chemoresistance to paclitaxel and cisplatin. This observation was particularly important because it demonstrated that these proteins do control a common pathway controlling cell death, and further underline their importance as possible targets for molecular therapy

Changing Trends of Breast Cancer Survival in Sultanate of Oman

Breast cancer is the leading cause of cancer-associated mortality in women, with elevated incidence in developing countries. This retrospective study included all 122 patients diagnosed with breast cancer from January 2003 to December 2008 in the Sultanate of Oman. Age at presentation was 47.41 years (SD±12.88), with one-third of patients younger than 40 years. The majority of patients presented with stage III (41.2%) and IV (18.2%) breast cancer. T size (P = .023), skin involvement (P = .003), and stage at presentation (P = .004) were significantly associated with overall survival. Skin involvement at presentation (P = .003), T size (P = .09), lymph node status (P = .013), and stage (P = .003) were strong predictors of relapse-free survival. Patients had a 5-year survival of 78%, compared to 64% of breast cancer patients diagnosed between 1996 and 2002 identified in our previously published study. Thus, despite Omani breast cancer patients continuing to present with advanced breast cancer, survival rates have significantly improved

What are our Options in the Fight against Breast Cancer?

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Signet ring cell carcinoma of the rectal stump in a known ulcerative colitis patient

Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer worldwide and is the second most common cause of cancer-related deaths. However, the Omani population shares the major burden as the most prevalent carcinoma. The disease is comparatively higher in males than females. Patients with pre-existing risk factors, including inflammatory bowel disease, are at increased risk of developing neoplasia. Among the various histopathological subtypes of adenocarcinoma in the rectum, signet ring cell carcinoma is the rarest and accounts for approximately 1% of the cases. Given the aggressive nature of this tumor, advanced presentation, stage, and poor prognosis, regular endoscopic surveillance is essential. Hereby, we report a rare case of signet ring cell carcinoma arising in the rectal stump in an already diagnosed and operated patient of Ulcerative colitis

Outcomes of Women with Non-Metastatic Triple-Negative Breast Cancer in Oman: A single-centre experience

Objectives: Triple-negative breast cancer (TNBC) is one of the most aggressive and heterogeneous variants of breast cancer. However, little is known regarding the prevalence and outcome of this entity in the Middle East. This study aimed to evaluate the outcomes of TNBC patients at a university hospital in Oman. Methods: This retrospective study took place at the Sultan Qaboos University Hospital, Muscat, Oman, in May 2017. All patients diagnosed with non-metastatic TNBC between December 2000 and December 2015 were included. The patients’ electronic medical records were reviewed to identify their clinical and pathological characteristics as well as survival outcomes. Results: A total of 79 patients were diagnosed with non-metastatic TNBC during the study period. The median age was 46 years, with approximately one-third of patients (31.6%) under 40 years of age. Almost half had an advanced tumour size (49.4%) or node-positive disease (48.1%) at presentation and only 16.6% demonstrated a complete pathological response (pCR) to neoadjuvant chemotherapy. The median survival for all patients was not reached within the study period; however, the median overall survival for stage III patients was 44.6 months. The five-year overall survival for all patients was 64%, increasing to 100% and 72% for patients with stage I and II, respectively, and dropping to 47% for those with stage III disease. Conclusion: The findings of this study indicate that the majority of women with TNBC in Oman present at an advanced stage; moreover, such women have low rates of pCR to neoadjuvant chemotherapy and poor five-year survival.Keywords: Breast Cancer; Triple-Negative Breast Cancer; Neoadjuvant Therapy; Survival; Patient Outcome Assessment; Oman

Customised, Individualised Treatment of Metastatic Non-Small-Cell Lung Carcinoma (NSCLC)

A series of phase II and randomised phase III trials in Asia and Europe have confirmed recently that advanced stage non-small-cell lung carcinoma patients with adenocarcinoma subtypes harbouring specific mutations when subjected to targeted therapy experience equivalent survival outcomes as those treated with chemotherapy and are spared from its side effects. The concept of chemotherapy for all is fading, and therapy optimisation has emerged as a paradigm shift in treatment. This article briefly describes cellular mechanisms involved in lung carcinogenesis which provide a molecular basis for targeted therapy. Advances in molecular biology have improved our understanding of mechanisms involved in primary or secondary drug resistance. Evolving biomarkers of prognostic and predictive importance, and the impact of translational research on outcomes are also covered. A marker is considered prognostic if it predicts the outcome, regardless of the treatment, and predictive if it predicts the outcome of a specific therapy

Improving Outcomes in Advanced Lung Cancer : Maintenance therapy in non-small-cell lung carcinoma

Systemic chemotherapy has remained the traditional treatment for metastatic non-small-cell lung carcinoma (NSCLC), enhancing survival rate at 1 year to 29%. The median survival had plateaued at around 10 months until early 2008, and in an attempt to enhance survival in advanced disease, maintenance chemotherapy trials were initiated which had recently demonstrated prolongation of survival by an additional 2–3 months in patients who had performance status (PS) 0–1 and well-preserved organ functions. Suitable patients with any degree of clinical benefit are treated with 4–6 cycles, and then one of the active agents is continued until best response, or toxicity (continued maintenance), or changed to a cross non-resistant single agent (switch maintenance). The article briefly reviews the evolution of systemic therapy and describes key randomised trials of maintenance therapy instituting chemotherapy and targeted agents in an attempt to improve outcomes in advanced metastatic NSCLC, based on certain clinical features, histology, and genetics

Predictors of Hypersensitivity Reactions to Platinum-Based Chemotherapy in a Tertiary Hospital in Oman: A case-control study

Objectives: Platinum-based compounds (PBC) play an important role in cancer therapy. However, one of the drawbacks of PBC is the occasional occurrence of hypersensitivity reactions (HSR) which can lead to serious consequences. The aim of the study is to estimate the prevalence and evaluate risk factors of HSR to PBC in cancer patients. Methods: A case-control study of patients who received any PBC for the management of non-haematological cancers from 2013 to 2020 at Sultan Qaboos University Hospital, Oman. Data regarding demographic features and diseases and treatment details were collected from the hospital’s electronic patients record. We quantitatively described the data, and Student’s t-test and Wilcoxon Man-Whittney tests were used to detect significant differences. Results: A total of 38 cases and 148 matched controls were studied. The prevalence of HSR to PBC in our cohort was 4.7% (95% confidence interval: 3.33%-6.37%), more with carboplatin compared to cisplatin and oxaliplatin. In our study, female gender (p=0.032), concomitant taxanes (p=0.002) and concurrent radiation (p<0.001) were significant predictors of HSR to PBC. The majority of reactions were of mild to moderate severity and the rechallenge rate after HSR development was 13%. Conclusion: HSR to PBC impact therapy decisions and understanding the risk factors are important to improve treatment outcomes in cancer patients. Keywords: Hypersensitivity; Platinum; Anti-neoplastic; Oncology; Oman