Opioid Use in Cancer Pain Management in Indonesia: a Call For Attention.

Severe pain is a major problem for cancer patients, and pain management often requires the use of opioids. Indonesia is one of the countries where the use of opioids for cancer patients is extremely low, and this calls for attention, as many cancer patients in the country undergo unnecessary suffering as the consequence of this opioid underuse. The inability to assess pain correctly, failure to determine the correct dose, fear of addiction, overly tight regulation, all contribute to the failure to implement rational use of opioids for cancer patients. Breakthrough pain, a problem which requires special attention not only because it is commonly found but also requires proper knowledge to handle them. These hurdles are discussed in the present review, in order to bring a better understanding about the correct use of opioids in severe cancer pain. Some examples where opiods are used inappropriately in cancer pain management are also discussed.

Angiogenesis, inflammation, platelets count, and metastatic status as a predictor for thrombosis risk in nasopharyngeal carcinoma patients.

AIM: to assess the use of of angiogenesis, inflammation, platelets count, and metastatic status as predictors for thrombosis risk represented by soluble P-selectin level in nasopharyngeal carcinoma (NPC) patients. METHODS: a cross sectional study was conducted on NPC patients at the Hematology and Oncology Clinic of Cipto Mangunkusumo Hospital, Jakarta, during Mei to October 2012. Data regarding angiogenesis (CD105 and VEGFR-2), inflammation (IL-6), platelets count, and metastatic status were assessed at enrollment, as well as soluble P-selectin levels in all eligible patients. Bivariate analysis continued with multiple linear regression analysis were done to identify independent predictors for soluble P-selectin levels. RESULTS: sixty NPC patients were enrolled in the study. There was correlation between platelet counts (r=0.389; p=0.002), IL-6 (r=0.595; p<0.001) and number of metastatic sites (r=0.542; p<0.001) with soluble P-selectin level, and a linear regression analysis showed that these three variables can predict soluble P-selectin levels with adjusted R-square 65%. There was no correlation between VEGFR-2 and CD105 levels with soluble P-selectin levels. CONCLUSION: platelet counts, IL-6 level, and number of sites of metastasis can be used as predictors of soluble P-selectin level as parameter of thrombosis risk in NPC patients.

Hemostatic status of pre and post intracoronary injection of peripheral blood stem cells in patients with recent myocardial infarction.

AIM: to investigate hemostatic parameter changes, such as platelet aggregation, blood and plasma viscosity, prothrombin time, APTT, CRP and fibrinogen, before and after administration of stem cell therapy. METHODS: a total of 24 patients were enrolled. Peripheral blood stem cells (PBSCs) were harvested and injected into the infarct-related artery after 5 consecutive days of G-CSF administration. Recombinant human erythropoietin was administered at the time of intracoronary PBSCs injection. RESULTS: we were able to evaluate 11 from 24 of patients regarding hemostatic status pre-post stem cell injection. There were no significant difference between baseline vs 3 months in spontaneous aggregation (p=0.350), PT (p=0.793), aPTT (p=0.255) and TT (p=0.254). There were also no significant difference between baseline vs 3 months in plasma viscosity (p=0.442) and blood viscosity (p=0.843). Nevertheless the patient who had their blood and plasma viscosity above or below normal laboratory range return to normal level after the treatment. Both PT and APTT also show normalization value. Both Fibrinogen and CRP level show significant decrease between baseline and 3 months after treatment (p=0.009) and (p=0.04) respectively. CONCLUSION: combined G-CSF and EPO based-intracoronary infusion of PBSCs may open new perspective in the treatment of hypercoagulable state post AMI.

Semiquantitative assessment of phosphatase and tensin homolog value with immunohistochemistry in colorectal cancer.

INTRODUCTION: Colorectal cancer has emerged as a concerning health problem, ranking the third most common form of cancer in both men and women. The phosphatase and tensin homologue (PTEN) protein is widely known for its role as an inhibitor of the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, playing a major role inhibiting tumor development. Previous studies investigated the role of this protein in the PI3K pathway and how it affected colorectal cancer. However, a standardized cut-off value for PTEN expression has not been established. METHODS: Immunohistochemistry was used in examining PTEN. The staining grade ranging from 0 to 3 was then multiplied by the number of 100 cancer cells counted, with total score between 0 and 300. In this study, receiver operating characteristic (ROC) curve was employed to determine the expression cut-off value for PTEN in colorectal cancer. RESULTS: This study showed statistically significant results (P < 0.001) in either tumor or non-tumor tissues by using the ROC curve with a cut-off value of 199.0. This study also revealed significant correlation between nodal status with PTEN (P = 0.008) and stage with PTEN (P = 0.019) with sensitivity 0.753 and specificity 0.728. CONCLUSION: Semiquantitative assessment with cell counting multiplied by color intensity is a good method in determining PTEN expression. The use of immunohistochemical staining intensity and cell scoring with ROC cut-off is effective to elaborate the effects of PTEN in colorectal cancer (PTEN value > 199.0 was classified as strong and ≤ 199.0 as weak).

Expression of NF-kB and COX2 in colorectal cancer among native Indonesians: the role of inflammation in colorectal carcinogenesis.

AIM: to evaluate the expression of NF-kB and COX2 in native Indonesians with sporadic colorectal cancer (CRC). METHODS: we conducted a matched-pair case-control study by acquiring both CRC and tumor-adjacent normal tissues from the same subjects. CRC patients who underwent surgery at Cipto Mangunkusumo Hospital, Jakarta, or Hasan Sadikin Hospital, Bandung, were enrolled in the study. The specimens were immunohistologically stained with antibody directed against p65 (RelA) to assess NF-kB expression and against human COX2 protein to assess COX2 expression. RESULTS: sixty-seven specimens consisting of both CRC and tumor-adjacent normal tissues were analyzed. COX2 expression was positive in 39 CRC tissues (58.2%), but in only 19 tumor-adjacent normal tissues (28.4%; p=0.0002). NF-kB expression was positive in 47 CRC tissues (70.1%), but in only 27 tumor-adjacent normal tissues (40.3%; p<0.0001). CONCLUSION: inflammation plays a role in the carcinogenesis of sporadic CRC in native Indonesians. This support potential use of nonsteroidal anti-inflammatory drugs as chemopreventive agents for CRC.

TNFα induces Caspase-3 activity in hematopoietic progenitor cells CD34+, CD33+, and CD41 + of myelodysplastic syndromes.

BACKGROUND: Cytopenia is the primary feature of Myelodysplastic Syndrome, even in the presence of hypercellular bone marrow. TNFα is recognized as both a proinflammatory, and proapoptotic cytokine with a well established role in promoting apoptosis in MDS. Therefore, TNFα has the potential to be a valuable biomarker for predicting the progression of cytopenia in MDS. This study aims to establish the role of TNFα exposure in triggering apoptosis through caspase-3 activity in CD34+, CD33+, and CD41 + cells in MDS. METHODS: This study is an in vitro comparative experimental research. Bone marrow mononuclear cells were isolated as the source of hematopoietic progenitor cells. Subsequently, CD34+, CD33+, and CD41 + cells were exposed to rhTNFα, and the caspase-3 activity was measured using flowcytometry. RESULTS: In MDS CD33 + and CD41 + caspase-3 activity of rhTNFα exposed cells was significantly higher than without exposed cells. The opposite result was found in CD34 + cells, where the caspase-3 activity without rhTNFα exposed cells was significantly higher than rhTNFα exposed cells. CONCLUSION: rhTNFα exposure led to an elevation in caspase-3 activity in MDS progenitor cells, especially in those that had differentiated into myeloid cell CD33 + and megakaryocyte cell CD41+, as opposed to the early progenitor cells CD34+.

Treatment Outcome of Endoscopic Ultrasound Radiofrequency Ablation for Incidentaloma Pancreatic Neuroendocrine Tumor in Young Female Patient: A 2-year Follow-Up.

Pancreatic neuroendocrine tumors (PNETs) or islet cell tumors are neuroendocrine neoplasms that arise from cells of the endocrine and nervous system within the pancreas. Patients with PNET sometimes do not show any symptoms, known as nonfunctioning (NF) sporadic PNET. It is still debatable regarding the best approach in the NF for small PNET. Currently, the surgical approach is considered the best; however, it is a highly invasive procedure, and it has a potentially high risk of complications as it requires a skilled and experienced operator. Herewith, we reported a 48-year-old female with incidentaloma of nonfunctioning PNET (NF-PNET) whose tumor has been successfully treated with endoscopic ultrasound guided radiofrequency ablation (EUSRA). There was no adverse event observed during and after the EUS procedure, and even 1 week after the procedure. One year later, abdominal magnetic resonance imaging (MRI) examination was carried out and size of the tumor was significantly getting smaller where it could hardly be seen anymore. After 2 years of follow-up, the latest abdominal MRI study showed no solid part of the tumor could be seen anymore. In conclusion, EUSRA can be an alternative option for incidentaloma of NF-PNET management.

Cytogenetics in solid tumors: lessons from the Philadelphia Chromosome.

Although presently known as an environmentally-related disease and appears mostly sporadic, cancer is regarded as a genetic disease based on the presence of gene mutation as a consistent factor. The "Philadelphia Chromosome" found consistently among chronic myeloid leukemia (CML) patients was the first significant finding of a chromosomal abnormality specifically related to a particular disease. Starting from this point, cytogenetics as the study of chromosomes has become a valuable tool in the assessment of cancer - as an aid in diagnosis, thus guiding therapy, and as a prognostic marker. As is the nature of the proliferating marrow, chromosomal abnormalities were found mostly in hematologic malignancies, and the findings more pathognomonic. The situation is different in solid tumors, which when visible to the naked eye already will have complex chromosomal changes and thus pose technical difficulties to the cytogeneticist. However, scientists believe that the shift in chromosomal studies from conventional cytogenetics to molecular cytogenetics will provide further information regarding solid tumors.

Expression of mRNA TNFα and level of protein TNFα after exposure sCD40L in bone marrow mononuclear cells of myelodysplastic syndromes.

BACKGROUND: Cytopenia is the primary phenomenon in myelodysplastic syndrome (MDS) amidst hypercellular bone marrow. The soluble CD40 ligand (sCD40L) is considered as a cytokine that can trigger synthesis of tumor necrosis factor α (TNFα) that promotes apoptosis. The objective of this study is to prove that recombinant human sCD40L (rh-sCD40L) exposure on bone marrow mononuclear cells (BMMC) MDS increases TNFα expression at mRNA level and at protein level. METHODS: BMMC from MDS patients whom diagnosed and classified using the WHO 2008 criteria, were exposed to rh-sCD40L and antiCD40L. The expressions of TNFα mRNAs were quantified by qRT-PCR, level of TNFα were measured using the ELISA method. RESULTS: Exposure of rh-sCD40L significantly increased the expression of TNFα mRNA. The similar exposure also significantly increased the level of TNFα compared to controls. TNFα mRNA expression on BMMC in MDS samples exposed to rh-sCD40L is 3.32 times compared to TNFα mRNA expression without exposure. level of TNFα in supernatant media exposed to rh-sCD40L in MDS samples was higher than that of control samples which were 44.44 and 4.85 pg/mL, P=0.018. CONCLUSIONS: The sCD40L plays a role in increasing the synthesis of TNFα in mRNA level and protein level in BMMC MDS.

Biomolecular markers as determinants of patients selection for adjuvant chemotherapy of sporadic colorectal cancers.

Colorectal cancer (CRC) is a disease classified and based on genetic alteration resulting from interaction of environmental factors, individual cancer susceptibility and accumulated somatic changes of the colorectal epithelium. Advanced knowledge in genetics and epigenetics of colorectal cancer develops a hypothesis that various clinical manifestations of colorectal cancer are caused by different carcinogenesis pathways. Different carcinogenesis pathways and types of colorectal cancer appear to bring effects on different response against chemotherapy and prognosis. Chemotherapy is mainly provided for patients with stage III CRC which are also the largest proportion of CRC patients in Indonesia. However, it is also provided for some patients with high risk stage II CRC. Classically, clinical factors have been generally accepted as prognostic factors including depth of tumor invasion, regional nodal metastasis, vascular invasion, poor differentiation, and serologic tumor marker such as carcinoembryonic antigen (CEA). However, clinical and histopathological factors themselves do not provide accurate prediction for colorectal cancer prognosis and treatment. A biomolecular marker is necessary to provide such prediction. Numerous studies have been conducted to evaluate the molecular biological markers in order to determine either the possibility of successful treatment for colorectal cancer (predictive factor) or life-expectancy (prognostic factor). Results of several studies demonstrate different status of some molecular markers to determine successful treatment between stage II and stage III colorectal cancer. Certainly, such finding should be followed up but it shall be accepted that there will be a shift of paradigm of CRC treatment. Therefore, the success of colorectal cancer, excluding the patient's socioeconomic factors and the surgeon's skill, will depend extremely on molecular parameter and not only the stage.

The Clinical Significance of Colon Polyp Pathology in Nonalcoholic Fatty Liver Disease (NAFLD) and Its Impact on Screening Colonoscopy in Daily Practice.

Aim: Nonalcoholic fatty liver disease (NAFLD) has been known as a risk for the presence of colon polyp and CRC development. This study was aimed to find out the clinical significance of colon polyps' pathology among NAFLD patients. Method: A retrospective database study was done in patients who underwent elective colonoscopy within one-year period in a referral private hospital, Jakarta. Subjects were adult patients who also had documented abdominal ultrasound (US). The association between NAFLD and colonic polyp was analyzed using Chi-square test with odds ratio (OR) and its corresponding 95% confidence interval (CI). Results: A total of 138 adult patients were enrolled; 68 (51.1%) were men. Patients' mean age was 56.8 ± 15.3 years old. Colon polyps were found in 49 (35.5%) cases; the most common histopathology was adenoma (42.9%). NAFLD was found in 68 (49.3%) of patients. Colon polyps were found to be more among patients with NAFLD than in those without NAFLD (44.1% vs. 27.1%; OR: 2.119; 95% CI: 1.040-4.318). Colon polyps were found in 30 (44.1%) NAFLD patients, where 18 (26.5%) patients had adenomatous polyp, and from this subset of patients with adenomatous polyp, 6 (8.8%) patients had mild dysplasia, 8 (11.8%) had moderate dysplasia, 1 (1.5%) had severe dysplasia, and 3 (4.4%) had adenocarcinoma. Conclusions: NAFLD is associated with increased risk of any colon polyp, regardless of the histopathological type, compared with patients without NAFLD. This finding implies the necessity to perform screening colonoscopy in patients with NAFLD in the future.

Expression of NF-kappaB and COX-2 in young versus older patients with sporadic colorectal cancer.

AIM: To distinguish the expression of NF-kappaB and COX-2 between young and older group of sporadic colorectal cancer patients. METHODS: This was a comparative study between sporadic CRC patients aged 40 years or younger and patients aged 60 years or more. Expression of NF-kappaB and COX-2 were assessed by immunohistochemical method using rabbit polyclonal antibodies against human p65 NF-kappaB and COX-2 proteins. RESULTS: There were 98 cases of sporadic colorectal cancers between 1999 and 2007 obtained from the Department of Anatomical Pathology, Faculty of Medicine University of Indonesia, Jakarta and Department of Anatomical Pathology, Faculty of Medicine Padjajaran University, Bandung. There were 60 patients aged 60 years or more and 38 patients aged 40 years or less. Most tumors were located in the distal colon. Positive expression of NF-kappaB was found in 72 (73.5%) cases, whereas COX-2 expression was found in 48 (49.0%) cases. No significant difference of NF-kappaB and COX-2 expression between young and older patients. CONCLUSION: The expression of nuclear factor kappaB (NF-kappaB) in Indonesian patients with sporadic colorectal cancer was high. However, cyclooxygenase-2 (COX-2) was only expressed in half of patients. There was no significant difference of NF-kappaB and COX-2 expressions between patients aged 40 years or less and patients aged 60 years or more. Further studies are needed to elaborate the role of inflammation in sporadic colorectal carcinogenesis.

Increased CD8 Tumor Infiltrating Lymphocytes in Colorectal Cancer Microenvironment Supports an Adaptive Immune Resistance Mechanism of PD-L1 Expression.

BACKGROUND: Tumor cells express programmed death ligand-1 (PD-L1) through several biological processes, thereby having different clinical significance depending on the underlying mechanism of expression. Currently, mechanisms leading to PDL1 gene expression in colorectal cancer (CRC) are not fully understood. METHODS: We investigated 98 Indonesia CRC patients to determine PD-L1 protein expressions and their correlations with PD-L1 gene copy number status, tumor infiltrating lymphocytes (TILs), tumor mutational profile, as well as clinicopathologic features. RESULTS: Our investigation demonstrated that 18% of patients positively expressed PD-L1. Further analysis on PD-L1 copy number revealed that all PD-L1+ tumors had normal copy number, indicating that the expression of PD-L1 was not a consequence of genetic amplification of PD-L1. From TILs analysis, there was a significant increase of CD8 in all tumor cells expressing PD-L1 (P=0.0051), indicating that the inducible PD-L1 expression was the prominent mechanism occurred in CRC. Furthermore, the expression of PD-L1 in this CRC population was significantly associated with high frequency of MSI compared to the remainder PD-L1- tumors (P=0.0001), suggesting the natural immunogenicity of tumors via MSI status plays role in attracting immune response. On the other hand, p53 mutations which were frequently observed within Indonesian CRCs (76.5%), they were not associated with PD-L1 expression (p=0.1108), as well as KRAS gene (29.6%; p=0.5772) and BRAF gene mutations (5%; p=0.2171). CONCLUSION: Our study demonstrated that PD-L1 expressions in CRC were predominantly found as a consequence of infiltrating CD8 T lymphocytes that in part arise in the setting of microsatellite instability. Taken together, our findings further support the role of adaptive immune resistance to drive PD-L1 induction in tumor microenvironment and may provide important rationale for strategy implementation of immunotherapy for CRC cases.
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