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Fulltext Prolonged survival of metastatic hepatocellular carcinoma: a case report

Zainal N, Hasbullah HH

J Gastrointest Oncol, 2018 Apr;9(2):E6-E8.
PMID: 29755781 DOI: 10.21037/jgo.2018.01.04

Management of hepatocellular carcinoma (HCC) generally follows EASL-EORTC clinical practise guideline. We report a case of a 50-year-old man who had multinodular HCC with lung metastases, whose management had deviated from the standard guideline but still survive 5 years after initial diagnosis.
Fulltext Gene Therapy Targeting p53 and KRAS for Colorectal Cancer Treatment: A Myth or the Way Forward?

Hasbullah HH, Musa M

Int J Mol Sci, 2021 Nov 03;22(21).
PMID: 34769370 DOI: 10.3390/ijms222111941

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and is responsible as one of the main causes of mortality in both men and women. Despite massive efforts to raise public awareness on early screening and significant advancements in the treatment for CRC, the majority of cases are still being diagnosed at the advanced stage. This contributes to low survivability due to this cancer. CRC patients present various genetic changes and epigenetic modifications. The most common genetic alterations associated with CRC are p53 and KRAS mutations. Gene therapy targeting defect genes such as TP53 (tumor suppressor gene encodes for p53) and KRAS (oncogene) in CRC potentially serves as an alternative treatment avenue for the disease in addition to the standard therapy. For the last decade, significant developments have been seen in gene therapy for translational purposes in treating various cancers. This includes the development of vectors as delivery vehicles. Despite the optimism revolving around targeted gene therapy for cancer treatment, it also has various limitations, such as a lack of availability of related technology, high cost of the involved procedures, and ethical issues. This article will provide a review on the potentials and challenges of gene therapy targeting p53 and KRAS for the treatment of CRC.
Fulltext Metastatic Prostate Cancer Synchronous with Male Breast Papillary Ductal Carcinoma in situ: Management Dilemma and Literature Review

Hasbullah HH, MdYusof FW, Ahmad AH, Alzallal O, T Sharif SET

Case Rep Oncol, 2021 06 08;14(2):784-791.
PMID: 34177531 DOI: 10.1159/000515784

Prostate cancer is common in men, but tumour of the male breast is rare. For these two tumours to be presented synchronously in a male patient is even rarer. The focus of this paper is the case of a 72-year-old man diagnosed with papillary ductal carcinoma in situ after he presented with a unilateral breast mass associated with nipple discharge. Imaging staging for his breast tumour and subsequent prostate biopsy found an incidental synchronous asymptomatic prostate adenocarcinoma as well as bone metastases. He denies risk factors for malignancies and refuses genetic testing. The first part of our discussion will highlight the uncommon occurrence of male breast ductal carcinoma in situ and its management controversies. The subsequent part of our discussion will focus on the association between male breast cancer and prostate cancer, and implication of this on the future treatment of these patients. More importantly, our case will illustrate the challenges in managing dual primaries that present concurrently.
Fulltext KRAS Mutational Profiles among Colorectal Cancer Patients in the East Coast of Peninsular Malaysia

Hasbullah HH, Sulong S, Che Jalil NA, Abdul Aziz AA, Musa N, Musa M

Diagnostics (Basel), 2023 Feb 21;13(5).
PMID: 36899966 DOI: 10.3390/diagnostics13050822

BACKGROUND: KRAS is a key driver gene in colorectal carcinogenesis. Despite this, there are still limited data on the mutational status of KRAS amongst colorectal cancer (CRC) patients in Malaysia. In the present study, we aimed to analyze the KRAS mutational profiles on codons 12 and 13 amongst CRC patients in Hospital Universiti Sains Malaysia, Kelantan, located on the East Coast of Peninsular Malaysia.
METHODS: DNA were extracted from formalin-fixed, paraffin-embedded tissues obtained from 33 CRC patients diagnosed between 2018 and 2019. Amplifications of codons 12 and 13 of KRAS were conducted using conventional polymerase chain reaction (PCR) followed by Sanger sequencing.
RESULTS: Mutations were identified in 36.4% (12/33) of patients, with G12D (50%) being the most frequent single-point mutation observed, followed by G12V (25%), G13D (16.7%), and G12S (8.3%). No correlation was found between mutant KRAS and location of the tumor, staging, and initial carcinoembryonic antigen (CEA) level.
CONCLUSION: Current analyses revealed that a significant proportion of CRC patients in the East Coast of Peninsular Malaysia have KRAS mutations, where this frequency is higher compared to those in the West Coast. The findings of this study would serve as a precursor for further research that explores KRAS mutational status and the profiling of other candidate genes among Malaysian CRC patients.
Fulltext The Elusive Primary: Metastatic Adenocarcinoma of the Breast Presenting Solely as a Hard Sternal Mass

Mohd Omar R, Ismail IA, Md Yasin M, Ahmad Affandi K, Hasbullah HH, Mohamad Ali ND

Am J Case Rep, 2023 Aug 23;24:e940594.
PMID: 37608536 DOI: 10.12659/AJCR.940594

BACKGROUND Carcinoma of unknown primary (CUP) is a diverse category of malignancies diagnosed in patients who have metastatic disease but without an identifiable primary tumor at initial presentation. CASE REPORT We report a case of CUP which was later diagnosed to be metastatic adenocarcinoma of the breast in a 62-year-old woman. The patient initially presented to a primary care clinic with an incidental finding of a small hard mass in the middle of the sternum, with no other clinical findings in the breast or axillary lymph nodes. Chest X-ray, ultrasound, and CT scan of the sternum suggested a benign sternal lesion, and a mammogram was normal. Due to the persistence of the mass, a biopsy was performed. The histopathological findings revealed a metastatic adenocarcinoma, most likely from breast origin, with positive estrogen receptor (ER) and mammaglobin on immunohistochemistry studies. The patient subsequently underwent PET scan, repeat mammogram, and MRI of the breast. Following high uptake in the rectum on PET, a colonoscopy was performed, revealing a suspicious rectal mass. The mass was surgically excised, and the final histopathological examination concluded the mass was a second primary adenocarcinoma of the rectum. Genetic analyses for BRCA1 and BRCA2 were negative. CONCLUSIONS This is a rare case of an isolated bone-like lesion on the sternum due to metastatic adenocarcinoma of the breast in a patient with no prior history of breast cancer and lacking any clinical or radiological evidence of breast or axillary lymph node lesions on presentation. The patient was also subsequently diagnosed with 2 primary carcinomas. Thorough clinical examination, extensive radiological investigations, laboratory investigations, histopathological examination, and a multidisciplinary approach are essential in managing CUP.
Fulltext A novel and non-invasive approach utilising nasal washings for the detection of nasopharyngeal carcinoma

Tan GW, Sivanesan VM, Abdul Rahman FI, Hassan F, Hasbullah HH, Ng CC, et al.

Int J Cancer, 2019 Oct 15;145(8):2260-2266.
PMID: 30698824 DOI: 10.1002/ijc.32173

Nasopharyngeal carcinoma (NPC) is an epithelial cancer of the nasopharynx which is highly associated with Epstein-Barr virus (EBV). Worldwide, most of the top 20 countries with the highest incidence and mortality rates of NPC are low- and middle-income countries. Many studies had demonstrated that EBV could be detected in the tissue, serum and plasma of NPC patients. In this study, we explored the potential of assays based on non-invasive nasal washings (NW) as a diagnostic and prognostic tool for NPC. A total of 128 patients were evaluated for NW EBV DNA loads and a subset of these samples were also tested for 27 EBV and human miRNAs shortlisted from literature. EBV DNA and seven miRNAs showed area under the receiver operating characteristic curve (AUC) values of more than 0.7, suggestive of their potential utility to detect NPC. Logistic regression analyses suggested that combination of two NW assays that test for EBNA-1 and hsa-miR-21 had the best performance in detecting NPC. The trend of NW EBV DNA load matched with clinical outcome of 71.4% (10 out of 14) NPC patients being followed-up. In summary, the non-invasive NW testing panel may be particularly useful for NPC screening in remote areas where healthcare facilities and otolaryngologists are lacking, and may encourage frequent testing of individuals in the high risk groups who are reluctant to have their blood tested. However, further validation in an independent cohort is required to strengthen the utility of this testing panel as a non-invasive detection tool for NPC.
Fulltext Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway

Sham NFR, Hasani NAH, Hasan N, Karim MKA, Fuad SBSA, Hasbullah HH, et al.

Sci Rep, 2023 Feb 22;13(1):3108.
PMID: 36813833 DOI: 10.1038/s41598-023-29925-x

Cancer recurrence is often associated with the acquisition of radioresistance by cancer tissues due to failure in radiotherapy. The underlying mechanism leading to the development of acquired radioresistance in the EMT6 mouse mammary carcinoma cell line and the potential pathway involved was investigated by comparing differential gene expressions between parental and acquired radioresistance cells. EMT6 cell line was exposed to 2 Gy/per cycle of gamma-ray and the survival fraction between EMT6-treated and parental cells was compared. EMT6RR_MJI (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6RR_MJI cells was confirmed with further irradiation at different doses of gamma-ray, and both the survival fraction and migration rates were measured. Higher survival fraction and migration rates were obtained in EMT6RR_MJI cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6RR_MJI and parental cells was compared, and 16 genes identified to possess more than tenfold changes were selected and validated using RT-PCR. Out of these genes, 5 were significantly up-regulated i.e., IL-6, PDL-1, AXL, GAS6 and APCDD1. Based on pathway analysis software, the development of acquired radioresistance in EMT6RR_MJI was hypothesized through JAK/STAT/PI3K pathway. Presently, CTLA-4 and PD-1 were determined to be associated with JAK/STAT/PI3K pathway, where both their expressions were significantly increased in EMT6RR_MJI compared to parental cells in the 1st, 4th and 8th cycle of radiation. As a conclusion, the current findings provided a mechanistic platform for the development of acquired radioresistance in EMT6RR_MJI through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers.
Nasopharyngeal carcinoma in adolescent patients: A Case Series

Sathasivam HP, Chew SYL, Kim WR, Saw CL, Tan LP, Tengku Din TADA, et al.

Clin Otolaryngol, 2022 Feb 16.
PMID: 35170855 DOI: 10.1111/coa.13917

1. Majority of adolescent nasopharyngeal carcinoma (NPC) patients present with advanced locoregional disease. 2. The ethnic distribution of patients with adolescent NPC could be different from that of adult NPC suggesting a possible difference in aetiopathogenesis. 3. The late presentation of adolescent NPC underlies the importance of recognizing the clinical presentation and characteristics of this cancer.
Fulltext Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer

Yoshino T, Argilés G, Oki E, Martinelli E, Taniguchi H, Arnold D, et al.

Ann Oncol, 2021 12;32(12):1496-1510.
PMID: 34411693 DOI: 10.1016/j.annonc.2021.08.1752

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.
Fulltext Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country

Poh ME, How SH, Ho GF, Pang YK, Hasbullah HH, Tho LM, et al.

Cancer Manag Res, 2023;15:31-41.
PMID: 36660237 DOI: 10.2147/CMAR.S393729

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.
Fulltext Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Poh ME, Chai CS, Liam CK, Ho GF, Pang YK, Hasbullah HH, et al.

Transl Lung Cancer Res, 2024 Feb 29;13(2):307-320.
PMID: 38496703 DOI: 10.21037/tlcr-23-691

BACKGROUND: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear.
METHODS: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1st January 2015 to 31st December 2020 were analyzed.
RESULTS: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months.
CONCLUSIONS: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

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