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Abstract Background Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. Methods Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan–Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. Results A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01–14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39–10.89). Conclusions We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.

Objective: The current study aimed to investigate the basic principles and clinical applications, including the selection of proper candidates, follow-up strategies, and radiation protection issues relating to peptide receptor radionuclide therapy (PRRT). Data Sources and Study Selection: We searched various scientific databases using specific keywords. Results: Due to the overexpression of somatostatin receptors in neuroendocrine tumors (NETs), PRRT is currently considered an important therapeutic modality for the management of NETs. Conclusion: PRRT incorporates the systemic administration of a tumor-targeting radiolabeled peptide to patients with tumors, allowing for more precise delivery of radiation doses to tumor sites while sparing normal tissues.

Abstract Background Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population. Methods Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHR mut , including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy. Results Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0–43.7), the median overall survival (OS) was not significantly different among patients with gHR mut , non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHR mut . Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7–33.7) versus 9.6 months (95% CI 5.9–17.6), P = 0.001. However, the median OS of patients without gHR mut was 14.5 months (95% CI 13.2–16.9) and 12.6 months (95% CI 10.8–14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis. Conclusions Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHR mut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.

Abstract Background Tumor cells may aberrantly express metabolic enzymes to adapt to their environment for survival and growth. Targeting cancer‐specific metabolic enzymes is a potential therapeutic strategy. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and links the tricarboxylic acid cycle and glycolysis/gluconeogenesis. Mitochondrial PEPCK (PEPCK‐M), encoded by PCK2, is an isozyme of PEPCK and is distributed in mitochondria. Overexpression of PCK2 has been identified in many human cancers and demonstrated to be important for the survival program initiated upon metabolic stress in cancer cells. We evaluated the expression status of PEPCK‐M and investigated the function of PEPCK‐M in breast cancer. Methods We checked the expression status of PEPCK‐M in breast cancer samples by immunohistochemical staining. We knocked down or overexpressed PCK2 in breast cancer cell lines to investigate the function of PEPCK‐M in breast cancer. Results PEPCK‐M was highly expressed in estrogen receptor‐positive (ER+) breast cancers. Decreased cell proliferation and G0/G1 arrest were induced in ER+ breast cancer cell lines by knockdown of PCK2. PEPCK‐M promoted the activation of mTORC1 downstream signaling molecules and the E2F1 pathways in ER+ breast cancer. In addition, glucose uptake, intracellular glutamine levels, and mTORC1 pathways activation by glucose and glutamine in ER+ breast cancer were attenuated by PCK2 knockdown. Conclusion PEPCK‐M promotes proliferation and cell cycle progression in ER+ breast cancer via upregulation of the mTORC1 and E2F1 pathways. PCK2 also regulates nutrient status‐dependent mTORC1 pathway activation in ER+ breast cancer. Further studies are warranted to understand whether PEPCK‐M is a potential therapeutic target for ER+ breast cancer.

Abstract Tyrosine kinase inhibitors (TKIs) improve the prognosis of patients with gastrointestinal stromal tumors (GISTs). We conducted a retrospective cohort study using cancer registries linked with health utilization data in Japan and Taiwan to assess TKI usage in older and non-older patients. Patients diagnosed with GIST (2012–2014) were categorized into the following: adjuvant and advanced/metastatic settings. The duration and patterns of imatinib therapy were compared between the older (aged ≥ 75 years) and non-older (

Abstract Background Phosphatase and tensin homolog (PTEN) is a tumor suppressor. Low PTEN expression has been observed in pancreatic neuroendocrine tumors (pNETs) and is associated with increased liver metastasis and poor survival. Vascular endothelial growth factor receptor 3 (VEGFR3) is a receptor tyrosine kinase and is usually activated by binding with vascular endothelial growth factor C (VEGFC). VEGFR3 has been demonstrated with lymphangiogenesis and cancer invasiveness. PTEN is also a phosphatase to dephosphorylate both lipid and protein substrates and VEGFR3 is hypothesized to be a substrate of PTEN. Dual-specificity phosphatase 19 (DUSP19) is an atypical DUSP and can interact with VEGFR3. In this study, we investigated the function of PTEN on regulation of pNET invasiveness and its association with VEGFR3 and DUSP19. Methods PTEN was knocked down or overexpressed in pNET cells to evaluate its effect on invasiveness and its association with VEGFR3 phosphorylation. In vitro phosphatase assay was performed to identify the regulatory molecule on the regulation of VEGFR3 phosphorylation. In addition, immunoprecipitation, and immunofluorescence staining were performed to evaluate the molecule with direct interaction on VEGFR3 phosphorylation. The animal study was performed to validate the results of the in vitro study. Results The invasion and migration capabilities of pNETs were enhanced by PTEN knockdown accompanied with increased VEGFR3 phosphorylation, ERK phosphorylation, and increased expression of epithelial–mesenchymal transition molecules in the cells. The enhanced invasion and migration abilities of pNET cells with PTEN knockdown were suppressed by addition of the VEGFR3 inhibitor MAZ51, but not by the VEGFR3-Fc chimeric protein to neutralize VEGFC. VEGFR3 phosphorylation is responsible for pNET cell invasiveness and is VEGFC-independent. However, an in vitro phosphatase assay failed to show VEGFR3 as a substrate of PTEN. In contrast, DUSP19 was transcriptionally upregulated by PTEN and was shown to dephosphorylate VEGFR3 via direct interaction with VEGFR3 by an in vitro phosphatase assay, immunoprecipitation, and immunofluorescence staining. Increased tumor invasion into peripheral tissues was validated in xenograft mouse model. Tumor invasion was suppressed by treatment with VEGFR3 or MEK inhibitors. Conclusions PTEN regulates pNET invasiveness via DUSP19-mediated VEGFR3 dephosphorylation. VEGFR3 and DUSP19 are potential therapeutic targets for pNET treatment.

Abstract Chemotherapy is generally considered as the main treatment for metastatic gastric adenocarcinoma. The role of gastrectomy for metastatic gastric cancer without obvious symptoms is controversial. The objective of this study is to investigate survival outcomes of treatment modalities using a real-world data setting. A retrospective cohort study was designed using the Taiwan Cancer Registry database. We identified the treatment modalities and used Kaplan–Meier estimates and Cox regressions to compare patient survival outcomes. From 2008 to 2015, 5599 gastric adenocarcinoma patients were diagnosed with metastatic disease (M1). The median overall survival (OS) of patients with surgery plus chemotherapy had the longest survival of 14.2 months. The median OS of the patients who received chemotherapy alone or surgery alone was 7.0 and 3.9, respectively. Age at diagnosis, year of diagnosis, tumor grade, and treatment modalities are prognostic factors for survival. The hazard ratios for patients who received surgery plus chemotherapy, surgery alone, and supportive care were 0.47 (95% CI 0.44–0.51), 1.22 (95% CI 1.1–1.36), and 3.23 (95% CI 3.01–3.46), respectively, by multivariable Cox regression analysis when using chemotherapy alone as a referent. Chemotherapy plus surgery may have a survival benefit for some selected gastric adenocarcinoma patients with metastatic disease.

Objective: Anaplastic thyroid cancer (ATC) is a rare thyroid cancer subtype with a devastating prognosis. Novel treatment strategies are under investigation to improve the survival of patients with ATC. Methods: We present a case of recurrent ATC treated with a combination of radiation therapy (RT) and pembrolizumab, a programmed death-1 inhibitor, with a durable complete response. Results: A 63-year-old woman underwent total thyroidectomy and left neck lymph node dissection and was diagnosed with papillary carcinoma in December, 2017. She received radioiodine in April, 2018. However, a left neck mass was noted in April, 2018 with biopsy demonstrating ATC with 95% positivity for programmed death-ligand 1 immunostaining. Positron emission tomography showed fluorodeoxyglucose uptake in the left thyroid bed and multiple lymph nodes in the left retropharyngeal, left neck, and right upper paratracheal areas. Hypofractionated RT for the recurrent areas was initiated in August,2018, and concomitant pembrolizumab was given 2 days after RT. A total of 10 cycles of pembrolizumab (2 mg/kg) were given every 3 weeks. The computed tomography scan after completion of RT and 3 cycles of pembrolizumab showed shrinkage of the neck lymph nodes. The serial follow-up computed tomography scans showed further shrinkage of the lymph nodes, and there was no recurrence of ATC as of October, 2020. Conclusion: We describe an ATC case successfully treated with a combination of RT and pembrolizumab with a durable response of 26 months and acceptable toxicities. This result warrants further investigation of this combination regimen in the treatment of ATC.

Abstract Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals genetically susceptible to the carcinogenic effect of alcohol might have higher pancreatic cancer risk after drinking alcohol. The current study investigated the association between alcohol use and pancreatic cancer with 419 pancreatic cancer cases and 963 controls recruited by a hospital-based case–control study in Taiwan. Gene-environment interaction between alcohol use and polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on pancreatic risk was evaluated. Our results showed no significant association between alcohol drinking and an increased pancreatic cancer risk, even at high levels of alcohol consumption. Even among those genetically susceptible to the carcinogenic effect of alcohol (carriers of ADH1B*2/*2(fast activity) combined with ALDH2*1/*2(slow activity) or ALDH2*2/*2(almost non-functional)), no significant association between alcohol use and pancreatic cancer was observed. Overall, our results suggested that alcohol drinking is not a significant contributor to the occurrence of pancreatic cancer in Taiwan.

Abstract Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase‐deficient. Pegylated arginine deiminase (ADI‐PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI‐PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor‐risk AML patients. We conducted a phase I, dose‐escalation study combining ADI‐PEG20 and low‐dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI‐PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI‐PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty‐three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose‐limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI‐PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5‐not reached) months. In seven treatment‐naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI‐PEG20 and LDC combination was well‐tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI‐PEG20 Plus Low‐Dose Cytarabine in Older Patients With AML, NCT02875093).

Abstract The incidence of neuroendocrine tumors (NETs) has been increasing in recent decades. Previously, we reported the incidence and survival of NETs in Taiwan by analyzing the 1996–2008 data from the Taiwan Cancer Registry. Here we performed an updated analysis on the incidence and survival of NETs in Taiwan from 1996 to 2015. The incidence of NETs was 0.244 per 100,000 in 1996 and increased to 3.162 per 100,000 in 2015. The most common site of NETs was rectum (29.65%), followed by lung/bronchus (17.22%), and pancreas (10.71%). The 5- and 10-year overall survival rates of all NETs were 54.6% and 45.3%, respectively. Female and younger NETs patients had a better survival. The survival of all NETs diagnosed between 2010 and 2015 was better than those diagnosed between 2004 and 2009. Among the common sites of NETs, an improved survival of pancreatic NETs diagnosed between 2010 and 2015 compared to those diagnosed between 2004 and 2009 was observed. Overall, the incidence of NETs in Taiwan has continued to increase. The survival of pancreatic NET has shown a recent improvement. The development of novel therapeutic agents has the potential to improve the prognosis of NETs of other sites in the near future.

Abstract Background Ectopic insulin-like growth factor binding protein 3 (IGFBP3) expression has been shown to enhance cell migration and lymph node metastasis of oral squamous cell carcinoma (OSCC) cells. However, OSCC patients with high IGFBP3 expression had improved survival compared with those with low expression. Therefore, we speculated that IGFBP3 expression may play a role in response to conventional OSCC therapies, such as radiotherapy. Methods We used in vitro and in vivo analyses to explore IGFBP3-mediated radiosensitivity. Reactive oxygen species (ROS) detection by flow cytometry was used to confirm IGFBP3-mediated ionizing radiation (IR)-induced apoptosis. Geneset enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were used to analyze the relationship between IGFBP3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Assays involving an NF-κB inhibitor, ROS scavenger or interleukin 6 (IL-6) were used to evaluate the NF-κB/IL-6/ROS signaling in IGFBP3-mediated radiosensitivity. Results Ectopic IGFBP3 expression enhanced IR-induced cell-killing in vitro. In vivo, IGFBP3 reduced tumor growth and increased apoptotic signals of tumor tissues in immunocompromised mice treated with IR. Combined with IR, ectopic IGFBP3 expression induced mitochondria-dependent apoptosis, which was apparent through mitochondrial destruction and increased ROS production. Ectopic IGFBP3 expression enhanced NK-κB activation and downstream cytokine expression. After IR exposure, IGFBP3-induced NF-κB activation was inhibited by the ROS scavenger N-acetyl-L-cysteine (NAC). IGFBP3-mediated ROS production was reduced by the NF-κB inhibitor BMS-345541, while exogenous IL-6 rescued the NF-κB-inhibited, IGFBP3-mediated ROS production. Conclusions Our data demonstrate that IGFBP3, a potential biomarker for radiosensitivity, promotes IR-mediated OSCC cell death by increasing ROS production through NF-κB activation and cytokine production.

Abstract S-1, an oral pyrimidine fluoride-derived agent, is effective against various cancers. Sorafenib, an oral multikinase inhibitor, was found to prolong the survival of various cancers and enhance the cytotoxicity of chemotherapeutic agents. We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors. Eligible patients received escalating doses (30, 35, and 40 mg/m2 bid) of S-1 Day 1 (D1)–D14 and continuous sorafenib 400 mg bid from cycle 1 D8 every 21 days in a standard 3 + 3 study design. Primary endpoint was MTD. Thirteen patients were enrolled between May 2010 and Feb 2012. DLT developed in two (one grade 3 erythema and one prolonged grade 2 hand-foot-skin reaction) of the 6 patients at 35 mg/m2 dose level. One pancreatic neuroendocrine tumor (pNET) patient achieved a durable partial response (27.9 months). Four colon cancer patients had stable disease and 3 of them had progression-free survival greater than 6 months. This study determined the recommended (MTD) S-1 dose of 30 mg/m2 bid for this regimen. This result warrants further phase II studies for advanced pNET and colon cancer to evaluate the efficacy of this combination.

Background: Sorafenib has been shown to prolong the progression free survival (PFS) of advanced radioiodine (RAI) refractory differentiated thyroid cancer (DTC) and has been approved by the FDA as the result of the phase III DECISION trial. Sorafenib has been reimbursed for the treatment of RAI refractory DTC in Taiwan since Jan 2017. High percentage of adverse events (AE) was noted in DECISION trial. We conducted a study to show the real-world experience of sorafenib in Taiwan. Methods: We retrospectively collected the clinical data, including dose, AE, and PFS of sorafenib, of the DTC patients who received sorafenib treatment in National Cheng Kung University Hospital and China Medical University Hospital by chart review from 2012 to 2018. Results: Thirty-six advanced DTC patients with progression were included in this study. The starting dose of sorafenib in most patients was 200 mg twice daily and the mean daily maintenance dose was 433 mg. Five patients had partial response (13.9%) and 28 patients had stable disease (77.8%). The median PFS was 17.3 months (95% confidence interval: 11.9–33.6 months). Daily maintenance dose ≥ 600 mg was associated with better PFS (median PFS, not reached). The most common toxicity of sorafenib was hand foot skin reaction (69%), followed by diarrhea (42%), and skin rash (33%). Most of the toxicities were grade I/II. Conclusion: Higher maintenance dose of sorafenib is associated with longer PFS while starting from half dose is feasible to minimize the incidence of high grade toxicities in the real-world use of sorafenib.

Abstract Background Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population. Methods This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk. Results Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer. Conclusions The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.

Chromogranin A (CgA) is a non-specific biomarker excreted by neuroendocrine tumor (NET) cells. Elevation of circulating CgA level can be detected in gastroenteropancreatic (GEP)-NET patients and has been shown to correlate with tumor burden. The prognostic and predictive roles of CgA level and the change of CgA level are controversial. In this study, we retrospectively analyzed 102 grade 1/2 GEP-NET patients with available baseline or serial follow-up CgA levels from the National Cheng Kung University Hospital to evaluate the association between circulating CgA level and the tumor extent, overall survival (OS), and tumor response prediction. The baseline characteristics, baseline CgA level, and change of CgA level during follow-up and their association was analyzed. Sixty cases had baseline CgA levels available prior to any treatment and ninety-four cases had serial follow-up CgA levels available during treatment or surveillance. Baseline CgA levels were associated with stage and sex. Higher baseline CgA levels were associated with worse OS after adjusting for sex, stage, grade, primary site, and functionality (hazard ratio=13.52, 95% confidence interval (CI), 1.06-172.47, P=0.045). The cross-sectional analysis for the change of CgA level during follow-up showed that a ≥ 40% increase of CgA meant a higher probability of developing tumor progression or recurrence than those with a < 40% increase of CgA level (odds ratio=5.04, 95% CI, 1.31-19.4, P=0.019) after adjusting for sex, age, grade, stage, and functionality. Our study results suggest that CgA may be a predictive marker for tumor burden, OS, and tumor progression in GEP-NET patients.

Abstract Studies have indicated a significant rise in the incidence of pancreatic adenocarcinoma. However, the epidemiology of other rare histologic subtypes of pancreatic cancer is not well understood. This study analyzed the incidence and survival of pancreatic cancer in Taiwan by histologic subtype, sex, age group, and year of diagnosis. The incidence trends of pancreatic cancer in Taiwan from 2002 to 2013 were calculated using data from the Taiwan Cancer Registry. The survival of pancreatic cancer patients was assessed using the life‐table method and Cox proportional hazards analysis. The incidence of pancreatic cancer increased from 4.62 per 100,000 in 2002 to 6.04 per 100,000 in 2013 in Taiwan. The most common histologic subtype of pancreatic cancer was adenocarcinoma followed by carcinoma and neuroendocrine tumors (NETs). Adenocarcinoma and NETs showed a rapid increase in incidence, while the incidences of other subtypes did not change significantly. Patients with adenocarcinoma showed a poor survival with a 5‐year survival of 5.2%. Patients with endocrinomas, NETs, and lymphoma displayed a better survival than those with adenocarcinoma, with a 5‐year survival ranging from 41.8% to 59.1%. The survival of adenocarcinoma, lymphoma, and NETs improved after the introduction of novel therapies. Understanding the risk factors and identifying the biomarkers for the early diagnosis of pancreatic cancer are important to prevent the development and improve the survival of pancreatic cancer.

Despite the advancement in medical knowledge that has improved the survival rate of many cancers, the survival rate of pancreatic cancer has remained dismal with a five-year survival rate of only 9%. The poor survival of pancreatic cancer emphasizes the urgent need to identify the causes or the risk factors of pancreatic cancer in order to establish effective preventive strategies. This review summarizes the current evidence regarding the environmental (non-genetic, including lifestyle, and clinical factors) risk factors of pancreatic cancer. Based on the current evidence, the established risk factors of pancreatic cancer are cigarette smoking, chronic diabetes, and obesity. Other strong risk factors include low consumption of fruits and vegetables, excess consumption of alcohol, poor oral hygiene, and the lack of allergy history. In the future, more studies are needed to identify additional risk factors of pancreatic cancer, especially the modifiable risk factors that could be included in a public health campaign to educate the public in order to reduce the incidence of pancreatic cancer.

The Philadelphia (Ph) chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML). However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1%) with the classic Ph chromosome, 6 (7.2%) with a variant Ph chromosome, and 9 (10.7%) with additional chromosome abnormalities. Fifty-four (64.3%) cases harbored b3a2 transcripts, 29 (34.5%) had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p

Gastrointestinal stromal tumors (GIST) are rare soft tissue sarcomas arising primarily from mesenchymal tissue in the gastrointestinal tract and abdomen. Since there is no effective treatment in the advanced stages, the outcome is poor in such patients. Recently, imatinib mesylate, a selective tyrosine kinase inhibitor, has shown a promising effect in GIST. Hence, we report our experience on the management of advanced GIST with imatinib therapy. A total of 14 patients were enrolled in this study, including 10 males and four females (median age, 51 years). The results showed that the small intestine was the most frequent site of primary lesion, while the liver was the most frequently metastasized organ. Most of the patients experienced tolerable side effects with imatinib therapy, including edema of periorbital area and/or legs and abdominal pain. Only two mortalities were noted during follow-up. The patients clinically benefited from imatinib therapy, with one patient having a complete response, three having a partial response, and seven having stable disease. The results demonstrate promising effects of imatinib in advanced GIST.

Combined small-cell lung carcinoma (SCLC) is a rare tumor. We report a case of combined SCLC of the lung, including adenocarcinoma and spindle-shaped cell tumor, with an unusual initial presentation. The patient suffered from a right shoulder mass, subsequently undergoing biopsy. A lung nodule was noted later after complete examination. The diagnosis turned out to be combined cell carcinoma with three different components (small-cell carcinoma, adenocarcinoma, and spindle-shaped cell tumor) after examination upon total removal of the lung nodule by lobectomy. In addition to the rarity of the three components in such a tumor, soft tissue metastasis also made it an unusual case.

Invasive fungal infections, a serious problem among cancer patients, are increasing in incidence, and can cause morbidity and mortality. Such infections may hinder additional treatment, especially for patients with leukemia. We report here our experiences in the management of invasive fungal infection in patients with acute leukemia. A total of 18 patients were enrolled in the study: 12 had microabscesses of the liver and/or spleen and/or kidneys; four had sinonasal infections; and two had pulmonary infections. Most of the patients (88.9%) received amphotericin B during treatment for fungal infection. Thirteen patients achieved complete response without evidence of fungal infection in follow-up. In the study, there were 11 mortalities, including five patients who died during therapy and six who later died as a result of relapse or refractoriness of the leukemia. We suggest that many patients may have a good response to antifungal therapy, and that fungal infection does not have to preclude additional chemotherapy after proper management. The state of the underlying disease has a strong impact on outcome.

Because there are no standardized radiologic and histologic criteria, the differential diagnosis of malignant peripheral nerve sheath tumors (MPNSTs) from other spindle cell neoplasms poses great challenges for pathologists. Because early diagnosis of MPNSTs arising from benign peripheral nerve sheath tumors (BPNSTs) means a better prognosis, many immunohistochemical and molecular studies have recently emerged. Nevertheless, no gold standard diagnostic criterion is to be found in the literature. For example, S-100 protein is widely used in the diagnosis of MPNST. Other promising ancillary markers are p53 and Ki-67; however, the staining patterns and possible mechanisms of these markers are seldom mentioned in the literature. These evoke our interest. Only six cases diagnosed as MPNST were retrieved from the archives of the Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital between 1988 and September 2005. Clinical files were available for three of them, and we found nuances in the immunohistochemistry from these previous reports. Here, we present these rare sarcomas and review the literature.

Primary mediastinal germ-cell tumors (GCTs) without gonadal involvement are rare and can be divided into benign mature teratoma and malignant seminoma or nonseminoma. We describe our experience of malignant mediastinal GCTs and compare the presentations and outcome with those of benign teratomas. Four malignant GCTs (1 seminoma, 1 choriocarcinoma, and 2 yolk-sac tumors) have been treated in our hospital. All patients were men with obvious symptoms before diagnosis. The patient with seminoma was treated with surgery and radiation, while those with nonseminoma tumors were treated with chemotherapy and/or surgery. Two patients died, one with extended pulmonary metastasis and the other with relapsed disease and high levels of tumor markers. Compared with the nine cases of benign teratomas, the four malignant GCTs showed overwhelming male dominance, advanced symptoms at presentation, and poor outcome. These cases highlight the important role of disease staging and tumor-marker levels in malignant GCTs, and suggest that new treatment strategies for malignant GCTs await further investigation.

Pure red cell aplasia (PRCA) is a complication of ABO-incompatible allogeneic stem cell transplantation. The mechanism is not well known, although the isoagglutinin titer before transplantation or cyclosporine use is considered to be the cause. Patients with this complication require more blood transfusions than those without it. There is no standard treatment. We report two cases of PRCA after allogeneic peripheral blood stem cell transplantation that were successfully treated with plasma exchange and low-dose steroid.

BACKGROUND: The epidemiology of neuroendocrine tumors (NETs) is not well illustrated, particularly for Asian countries. METHODS: The age-standardized incidence rates and observed survival rates of NETs diagnosed in Taiwan from January 1, 1996 to December 31, 2008 were calculated using data of the Taiwan Cancer Registry (TCR) and compared to those of the Norwegian Registry of Cancer (NRC) and the US Surveillance, Epidemiology, and End Results (SEER) program. RESULTS: During the study period, a total of 2,187 NET cases were diagnosed in Taiwan, with 62% males and a mean age of 57.9 years-old. The age-standardized incidence rate of NETs increased from 0.30 per 100,000 in 1996 to 1.51 per 100,000 in 2008. The most common primary sites were rectum (25.4%), lung and bronchus (20%) and stomach (7.4%). The 5-year observed survival was 50.4% for all NETs (43.4% for men and 61.8% for women, P

BACKGROUND: Second cancers have been reported to occur in 10-20% of patients with neuroendocrine tumors (NETs). However, most published studies used data from a single institution or focused only on specific sites of NETs. In addition, most of these studies included second cancers diagnosed concurrently with NETs, making it difficult to assess the temporality and determine the exact incidence of second cancers. In this nationwide population-based study, we used data recorded by the Taiwan Cancer Registry (TCR) to analyze the incidence and distribution of second cancers after the diagnosis of NETs. METHODS: NET cases diagnosed from January 1, 1996 to December 31, 2006 were identified from the TCR. The data on the occurrence of second cancers were ascertained up to December 31, 2008. Standardized incidence ratios (SIRs) of second cancers were calculated based on the cancer incidence rates of the general population. Cox-proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of second cancers associated with sex, age, and primary NET sites. RESULTS: A total of 1,350 newly diagnosed NET cases were identified according to the selection criteria. Among the 1,350 NET patients, 49 (3.63%) developed a second cancer >3 months after the diagnosis of NET. The risk of second cancer following NETs was increased compared to the general population (SIR = 1.48, 95% CI: 1.09-1.96), especially among those diagnosed at age 70 or older (HR = 5.08, 95% CI = 1.69-15.22). There appeared to be no preference of second cancer type according to the primary sites of NETs. CONCLUSIONS: Our study showed that the risk of second cancer following NETs is increased, especially among those diagnosed at age 70 or older. Close monitoring for the occurrence of second cancers after the diagnosis of NETs is warranted.