Investigating the role of Chk1 in mouse skin homeostasis and tumourigenesis

Chk1 is a key regulator of DNA damage response and genome stability in eukaryotes. To better understand how checkpoint proficiency affects cancer development particularly tumours induced by chemical carcinogens in murine skin, I investigated the effect of conditional genetic ablation of chk1. I found that complete deletion of chk1 immediately prior to carcinogen exposure strongly suppressed papilloma formation, and the few, small lesions that did form always retained Chk1 expression. Remarkably, chk1 deletion was accompanied by spontaneous cell proliferation followed by DNA damage and cell death within the hair follicle. This also affected and led to proliferation and ultimately depletion of label-retaining stem cells (LRCs) within the bulge region of hair follicles, the principal source for carcinogen-induced tumours. At later times, ablated skin became progressively repopulated by Chk1-expressing cells and normal sensitivity to tumour induction was restored if carcinogen treatment was delayed. In marked contrast, papillomas formed normally in chk1 hemizygous skin but showed an increased propensity to progress to carcinomas. I conclude that Chk1 is essential for the survival of incipient cancer cells but that partial loss of function (haploinsufficiency) fosters tumour progression

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

<p>Background: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.</p> <p>Case presentation: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.</p> <p>Conclusion: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.</p&gt

Molecular testing for advanced non-small cell lung cancer in Malaysia: Consensus statement from the College of Pathologists, Academy of Medicine Malaysia, the Malaysian Thoracic Society, and the Malaysian Oncological Society

In the recent years, increased understanding of the molecular profiles of non-small cell lung cancer (NSCLC) has allowed for targeted treatment of actionable genetic mutations. The management of NSCLC now requires multiple molecular tests to guide the treatment strategy. In the light of this, there is a need to establish a molecular testing consensus statement for advanced NSCLC patients in Malaysia. This Malaysian consensus statement was developed by a panel of experts, chaired by a pathologist and composed of three other pathologists, four respiratory physicians and three oncologists. It reflects currently available scientific data and adaptations of recommendations from international guidelines to the local landscape. Expert recommendations on different aspects of molecular testing agreed upon by the panel are provided as structured discussions. These recommendations address the appropriate patients and samples to be tested, as well as when and how these tests should be performed. The algorithms for molecular testing in metastatic NSCLC, in the first line setting and upon disease progression beyond first line therapy, were developed

Defining optimal cut-off values and research methodology for evaluating systemic inflammatory markers in clinical outcome prediction

No abstract available

Lung cancer in Malaysia

Malaysia is a Southeast Asian country occupying parts of the Malay Peninsula and the island of Borneo. The population of Malaysia (just over 30 million) is multi-ethnic; approximately half the population is ethnically Malay, with large minorities of Chinese, Indians, and indigenous peoples. Approximately 70% of the population is urban (Fig. 1).1 Life expectancy of Malaysians at birth is 74.9 years.2 Health care services in Malaysia are dichotomous between systems of public and private health care. Most patients (w65%) in Malaysia seek health care services in public facilities.3 However, the main drawback of public health care is a shortage of doctors and specialists in public hospitals.3 Public health care in Malaysia is heavily subsidized and offers services at a fraction of the cost of treatment in the private sector. Patients receiving treatment in private facilities, on the other hand, are usually covered by private health care insurance or make out-of-pocket payments.3 There is currently no universal-access national health care scheme in Malaysia.3 The total expenditure on health was 4.24% of the gross domestic product in 2017.

Real-world treatment and outcomes of ALK-positive metastatic non–small cell lung cancer in a southeast Asian country

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non–small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. Methods: This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan–Meier method. Results: There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01). Conclusion: Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit. Keywords: ALK inhibitors, chemotherapy, ALK-positive, NSCL

Outcomes of patients with EGFR-mutant advanced NSCLC in a developing country in Southeast Asia

Background: Although first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment. Methods: This multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included. Results: Of 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation – 54.1%, second generation – 25.6% and third-generation – 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after firstor second-generation EGFR TKI were started on a third-generation EGFR TKI. Conclusion: In the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients. Keywords: tyrosine kinase inhibitors, lung cancer, time on treatment, overall surviva

Asian Thoracic Oncology Research Group Expert Consensus Statement on Optimal Management of Stage III NSCLC

Stage III NSCLC represents a heterogeneous disease for which optimal treatment continues to pose a clinical challenge. Recent changes in the American Joint Commission on Cancer staging to the eighth edition has led to a shift in TNM stage grouping and redefined the subcategories (IIIA-C) in stage III NSCLC for better prognostication. Although concurrent chemoradiotherapy has remained standard-of-care for stage III NSCLC for almost 2 decades, contemporary considerations include the impact of different molecular subsets of NSCLC, and the roles of tyrosine kinase inhibitors post-definitive therapy and of immune checkpoint inhibitors following chemoradiotherapy. With rapid evolution of diagnostic algorithms and expanding treatment options, the need for interdisciplinary input involving multiple specialists (medical oncologists, radiation oncologists, pulmonologists, radiologists, pathologists and thoracic surgeons) has become increasingly important. The unique demographics of Asian NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to health care resources including molecular testing, prompting the need for critical review of existing data and identification of current gaps. In this expert consensus statement by the Asian Thoracic Oncology Research Group, an interdisciplinary group of experts representing Hong Kong, Korea, Japan, Taiwan, Singapore, Thailand, Malaysia, and Mainland China was convened. Standard clinical practices for stage III NSCLC across different Asian countries were discussed from initial diagnosis and staging through to multi-modality approaches including surgery, chemotherapy, radiation, targeted therapies, and immunotherapy. (C) 2019 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.