Role of vitamin D3 in tumor aggressiveness and radiation response for hepatocellular carcinoma.

Locoregional control is a significant prognostic factor for hepatocellular carcinoma (HCC). Historically, the use of radiotherapy (RT) for HCC was limited owing to the low radiotolerance of the liver and the need for high RT doses for disease control. We aimed to examine if 1α,25-dihydroxyvitamin D3 (calcitriol) has a role in the tumor inhibition and the radiation response of HCC in vitro and in vivo, and explore the underlying mechanisms. The human and murine liver cancer cell lines were selected for cellular and animal experiments to investigate the changes in tumor characteristics and the radiation response after calcitriol supplementation. The effects induced by calcitriol supplementation on interleukin-6 (IL-6) signaling and the tumor immune microenvironment following RT were also examined. Our data revealed that calcitriol supplementation attenuated tumor aggressive behavior, decrease IL-6 expression, and augmented radiation-induced tumor inhibition. The biological changes following calcitriol treatment included suppressed epithelial-mesenchymal transition, attenuated cancer stem cell-like properties and increased radiation-induced reactive oxygen species and cell death in vitro. Regarding immune microenvironment, calcitriol attenuated the recruitment of myeloid-derived suppressor cell (MDSC) recruitment and increased the infiltration of cytotoxic T cells in tumor following RT. Furthermore, When the primary liver tumor was irradiated with larger dose per fraction, calcitriol induced a smaller size of synchronous unirradiated tumor in mice, which linked with attenuated IL-6 signaling and MDSC recruitment. In conclusion, calcitriol treatment reduced tumor aggressiveness and enhanced the radiation response. The inhibited IL-6 signaling and subsequently enhanced antitumor immunity might be responsible to augment radiation-induced tumoricidal effect induced by calcitriol. Based on our results, we suggest that calcitriol could exert the antitumor and radiosensitization effects for HCC, especially for multifocal tumors.

MicroRNA-29a Manifests Multifaceted Features to Intensify Radiosensitivity, Escalate Apoptosis, and Revoke Cell Migration for Palliating Radioresistance-Enhanced Cervical Cancer Progression.

Radioresistance remains a major clinical challenge in cervical cancer therapy and results in tumor relapse and metastasis. Nevertheless, the detailed mechanisms are still largely enigmatic. This study was conducted to elucidate the prospective impacts of microRNA-29a (miR-29a) on the modulation of radioresistance-associated cervical cancer progression. Herein, we established two pairs of parental wild-type (WT) and radioresistant (RR) cervical cancer cells (CaSki and C33A), and we found that constant suppressed miR-29a, but not miR-29b/c, was exhibited in RR-clones that underwent a dose of 6-Gy radiation treatment. Remarkably, radioresistant clones displayed low radiosensitivity, and the reduced apoptosis rate resulted in augmented surviving fractions, measured by the clonogenic survival curve assay and the Annexin V/Propidium Iodide apoptosis assay, respectively. Overexpression of miR-29a effectively intensified the radiosensitivity and triggered the cell apoptosis in RR-clones. In contrast, suppressed miR-29a modestly abridged the radiosensitivity and abolished the cell apoptosis in WT-clones. Hence, ectopically introduced miR-29a into RR-clones notably attenuated the wound-healing rate and cell migration, whereas reduced miR-29a aggravated cell mobilities of WT-clones estimated via the in vitro wound-healing assay and time-lapse recording assay. Notably, we further established the in vivo short-term lung locomotion metastasis model in BALB/c nude mice, and we found that increased lung localization was shown after tail-vein injection of RR-CaSki cells compared to those of WT-CaSki cells. Amplified miR-29a significantly eliminated the radioresistance-enhanced lung locomotion. Our data provide evidence suggesting that miR-29a is a promising microRNA signature in radioresistance of cervical cancer cells and displays multifaceted innovative roles involved in anti-radioresistance, escalated apoptosis, and anti-cell migration/metastasis. Amalgamation of a nucleoid-based strategy (miR-29a) together with conventional radiotherapy may be an innovative and eminent strategy to intensify the radiosensitivity and further protect against the subsequent radioresistance and the potential metastasis in cervical cancer treatment.

A prospective nutritional assessment using Mini Nutritional Assessment-short form among patients with head and neck cancer receiving concurrent chemoradiotherapy.

BACKGROUND: No gold standard of nutritional assessment is established among patients with head and neck cancer (HNC) receiving concurrent chemoradiotherapy (CCRT). This study aimed to evaluate the clinical significance of pre-treatment nutritional status using the Mini Nutritional Assessment-short form (MNA-SF) among HNC patients receiving CCRT. METHODS: A total of 461 consecutive patients with newly diagnosed HNC treated with definitive CCRT at three medical institutes were prospectively enrolled. Nutritional status was assessed using MNA-SF within 7 days before CCRT initiation. Patients were classified as having normal nutrition, at risk of malnutrition, and malnourished groups according to MNA-SF for comparison. RESULTS: The 1-year overall survival rates were 89.8%, 76.8%, and 67.7% in the normal nutrition, at risk of malnutrition, and malnourished groups, respectively. Patients with normal nutrition had significantly lower rates of uncompleted radiotherapy and chemotherapy (4.5% and 4.1%, respectively) compared with patients at risk for malnutrition (14.1% and 11.5%, respectively) and those malnourished (11.1% and 11.1%, respectively). Patients with normal nutrition had significantly lower treatment-related complication rates regarding emergency room visits, hospital admission, and need for tubal feeding than those with at risk of malnutrition and malnourished. Patients with normal nutrition had significantly fewer severe hematologic toxicities (p = 0.044) and severe non-hematologic toxicities (p = 0.012) of CCRT than those malnourished. CONCLUSION: Pre-CCRT nutritional status identifies HNC patients vulnerable to treatment interruption and treatment complications. We suggest that nutritional assessment with MNA-SF should be incorporated in pre-CCRT evaluation for all HNC patients.

Real-world experience with Ropeginterferon-alpha 2b (Besremi) in Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND/PURPOSE: Ropeginterferon alpha-2b (Ropeg) is a novel pegylated interferon-alpha recently approved for the treatment of polycythemia vera (PV) in Europe. However, other than data from clinical trials, little is known about this agent in real world practice. METHODS: A compassionate use program employing Ropeg for treating patients with unmet medical need was initiated in Taiwan in 2017. Herein, we collected clinical data and assessed the safety as well as efficacy of Ropeg in nine patients treated in this program. RESULTS: Collectively, among evaluable patients, both the molecular response and complete blood count remission rates were 62.5%. Most therapy-related side effects were mild, and there was no treatment discontinuation attributable to intolerable adverse events. The agent also showed efficacy in symptom amelioration and spleen size reduction. Although no specific patterns of cytokine level alteration could be identified, significantly attenuated plasma levels of inflammation markers were observed in one particular patient who happened to have normalized spleen size and most remarkable reduction in JAK2 mutant allele burden, indicating all-around improvement in every aspect of this case. Furthermore, plasma hepcidin levels increased in two-thirds of PV patients, illustrating the potential of Ropeg to restore normal regulation of erythropoiesis. Using RNA sequencing on pre- and post-treatment samples from one patient, we demonstrated altered expression of genes participating in IFN response, inflammation, apoptosis, and cellular differentiation. CONCLUSION: Conclusively, observed signs of efficacy and safety in our real-world experience prove Ropeg as a promising option for the treatment of MPN.

Molecular heterogeneity unravelled by single-cell transcriptomics in patients with essential thrombocythaemia.

Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single-cell RNA sequencing (scRNA-Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple-negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra-individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA-Seq extended our knowledge of clonal diversity and inter-individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.

External validation of the Besançon nomogram in Asian patients with advanced pancreatic cancer receiving second-line chemotherapy: A multi-institute experience in Taiwan.

BACKGROUND: Determining survival outcome in advanced pancreatic ductal adenocarcinoma (aPDAC) patients receiving second-line (L2) chemotherapy is important for clinical decision-making. The Besançon group from France recently proposed a prognostic nomogram to predict overall survival (OS) for aPDAC patients receiving L2 chemotherapy. The present study aimed to externally validate the performance of the Besançon nomogram in predicting OS in an Asian cohort. METHODS: We retrospectively enrolled 349 patients who received L2 chemotherapy for aPDAC between 2010 and 2016 at four institutes in Taiwan. The performance of the Besançon model in this cohort was evaluated with C-index and calibration plots. RESULTS: The median OS time in our patient cohort was 4.5 months (95% confidence interval [CI], 3.0-5.0). Using the Besançon nomogram-predicted risk groups, the median OS times in the low, intermediate, and high-risk groups were 6.7 (95% CI, 5.3-8.2), 3.2 (95% CI, 2.4-3.9), and 1.7 months (95% CI, 0.6-2.7), respectively. The C-index of the predicted six- and 12-month survival probabilities for the Besançon nomogram were 0.766 (95% CI, 0.715-0.816) and 0.698 (95% CI, 0.641-0.754), respectively. The calibration plot showed that the observed six-month survival probability was close to the diagonal line, while that for 12-month survival deviated below the diagonal line compared to the survival probability predicted by the Besançon nomogram. CONCLUSIONS: Although the Besançon nomogram tended to over-estimate the 12-month survival probability, our study demonstrated that the nomogram is a reliable and readily applicable model to estimate survival outcomes of aPDAC patients receiving L2 chemotherapy.

Development and validation of a prognostic nomogram to predict survival in patients with advanced pancreatic cancer receiving second-line palliative chemotherapy.

BACKGROUND AND AIM: Given that a wide variation in tumor response rates and survival times suggests heterogeneity among the patients with advanced pancreatic cancer (APC) who underwent second-line (L2) chemotherapy, it is a challenge in clinical practice to identify patients who will receive the most benefit from L2 treatment. METHODS: We selected 183 APC patients who received L2 palliative chemotherapy between 2010 and 2016 from a medical center as the development cohort. A Cox proportional hazard model was used to identify the prognostic factors and construct the nomogram. An independent cohort of 166 patients from three other hospitals was selected for external validation. RESULTS: The nomogram was based on eight independent prognostic factors from the multivariate Cox model: sex, Eastern Cooperative Oncology Group performance status, reason for first-line treatment discontinuation, duration of first-line treatment, neutrophil-to-lymphocyte ratio, tumor stage, body mass index, and serum carbohydrate antigen 19-9 levels at the beginning of L2 treatment. The model exhibited good discrimination ability, with a C-index of 0.733 (95% confidence interval, 0.681-0.785) and 0.724 (95% confidence interval, 0.661-0.787) in the development and validation cohorts, respectively. The calibration plots of the development and validation cohorts showed optimal agreement between model prediction and actual observation in predicting survival probability at 6 months, 1 year, and 2 years. CONCLUSIONS: This study developed and externally validated a prognostic model that accurately predicts the survival outcome of APC patients before L2 palliative chemotherapy, which could assist in clinical decision-making, counseling for treatment, and most importantly, prognostic stratification of patients.

Accelerated Risk of Premature Ischemic Stroke in 5-Year Survivors of Nasopharyngeal Carcinoma.

BACKGROUND: Research on cancer survivorship associated with nasopharyngeal carcinoma (NPC) is rare. We aimed to elucidate the risk of ischemic stroke in 5-year survivors of NPC following radiotherapy (RT) or concurrent chemoradiation therapy (CCRT). SUBJECTS, MATERIALS, AND METHODS: NPC survivors, defined as those who survived longer than 5 years after diagnosis, were identified and matched at a 1:5 ratio with normal controls from the Longitudinal Health Insurance Database 2005 of Taiwan. The stratified Cox regression models were used to access the risk of ischemic stroke, with adjustment for age, treatment modality, comorbidities, and socioeconomic characteristics. RESULTS: From 2000 to 2005, a total of 3,016 NPC survivors who had received RT (n = 959) or CCRT (n = 2,057) and 15,080 controls were matched for age, sex, income, and urbanization level. The risk of ischemic stroke was significantly higher in the NPC survivor cohort than in the control cohort. Stroke was positively related to death. Moreover, the age onset of stroke for NPC survivors was 10 years earlier than that for the general population. CONCLUSION: Not only was the stroke risk in NPC survivors higher than that in the general population, but the onset age was also 10 years earlier. Future survivorship care should include ischemic stroke as a late complication, for its proper prevention and management. IMPLICATIONS FOR PRACTICE: Nasopharyngeal carcinoma (NPC) is endemic in Taiwan, and its 5-year survival is 65.2%. With the increased 5-year cancer survivors, survivorship has become an important issue. However, research on NPC survivorship is very rare. To the authors' knowledge, this is the first population-based study on long-term NPC survivors. This study's results indicated that not only was the risk of ischemic stroke in NPC survivors at least triple that of the general population, but the onset age was also 10 years earlier. These results may provide solid evidence that survivorship care guidelines should include stroke as a late complication in 5-year NPC survivors, for its proper prevention and management.

The Predictive Value of Pretreatment Neutrophil-To-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been reported to be both a prognostic biomarker for cancer and associated with inflammation, but its predictive role in tumor immunity is not clear. The present study examined the correlations of the NLR and immune suppression with the prognoses in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We performed a retrospective review of 1168 patients who were newly diagnosed with stage T1N(+) and T2-T4 ESCC at our hospital. The NLR of each ESCC patient prior to treatment was calculated, and the associations of the NLR with various clinicopathological parameters and prognoses were then examined. In addition, correlations of the proportion of myeloid-derived suppressor cells (MDSCs) and level of interleukin (IL)-6 with the NLR were assessed in 242 ESCC patients. RESULTS: An elevated NLR was significantly correlated with advanced-stage disease and reduced overall survival (OS) of ESCC patients. Furthermore, the levels of IL-6 in tumors and MDSCs in the peripheral circulation were significantly correlated with the prognoses of ESCC, and the NLR was positively correlated with MDSC levels in the circulation and IL-6 staining intensity in tumor specimens. Moreover, a high NLR was significantly associated with reduced OS in the 926 patients treated with concomitant chemoradiotherapy, but not in the 242 patients who underwent surgical intervention. CONCLUSION: The NLR may represent a clinically useful biomarker to guide ESCC treatment decisions. Patients with a higher NLR may be an optimal subgroup for IL-6- and MDSC-targeted therapy.

Role of ALDH1 in the prognosis of esophageal cancer and its relationship with tumor microenvironment.

Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and significantly increased in cancer stem-like cells. In the present study, the role of ALDH1 in esophageal squamous cell carcinoma (ESCC) was investigated. We retrospectively analyzed the clinical outcomes of 148 ESCC and examined its correlation with ALDH1 levels. Furthermore, we preformed cellular and animal experiments to investigate the role of ALDH1 in tumor progression and microenvironment. Our data revealed that ALDH1 staining was positively linked to a higher clinical stage, higher loco-regional failure rate, and shorter survival time. Furthermore, there was a positive link between ALDH1 expression and IL-6 signaling according to the data of clinical specimens and cellular experiments. Using animal model, ALDH1-positive tumors were associated with aggressive tumor growth, increased IL-6, augmented epithelial-mesenchymal transition (EMT), and activation of myeloid-derived suppressor cells (MDSCs). Blockade of COX-2 attenuated the aggressive tumor growth of ALDH1-positive cancer cells. In conclusion, our findings suggested that ALDH1 played an important role in tumor aggressiveness and associated with a tumor-promoting microenvironment in esophageal cancer. Directly targeting ALDH1 or using a COX-2 inhibitor could be a promising strategy for the treatment of ESCC.

Incidence and risk factors for central venous access port-related infection in Chinese cancer patients.

BACKGROUND/PURPOSE: Cytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy. METHODS: Between January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors. RESULTS: The overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both p < 0.001) and less infection-free catheter longevity (p < 0.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (p < 0.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida. CONCLUSION: Infection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.

IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus.

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The aim of this study was to highlight the significance of IL-6 in esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively analyzed the clinical outcomes of 173 patients with esophageal SCC, and examined the correlation between IL-6 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression. RESULTS: In clinical outcome analysis, positive IL-6 staining and poor treatment response was significantly associated with shorter survival. Furthermore, the frequency of IL-6 immunoreactivity was significantly higher in esophageal cancer specimens than in non-malignant epithelium, and this staining was positively linked to the development of distant metastasis (p = 0.0003) and lower treatment response rates (p = 0.0001).By ELISA analysis, IL-6 serum levels were significantly elevated in patients developing disease failure.When IL-6 expression was inhibited, aggressive tumor behavior and radiation resistance could be overcome in vitro and in vivo. The underlying changes included increased cell death, less epithelial-mesenchymal transition and attenuated STAT3 activation. IL-6 inhibition was also associated with attenuated angiogenesis in tumor-bearing mice. CONCLUSIONS: IL-6 was significantly associated with poor prognosis in patients with esophageal cancer. Targeting this cytokine could be a promising strategy for treatment of esophageal cancer, as evidenced by inhibition of aggressive tumor behavior and treatment resistance.

Effect of Proton Therapy on Tumor Cell Killing and Immune Microenvironment for Hepatocellular Carcinoma.

Radiotherapy with proton therapy (PT) has dosimetric advantages over photon therapy, which helps to enlarge the therapeutic window of radiotherapy for hepatocellular carcinoma (HCC). We evaluated the response of HCC to PT and examined the underlying mechanisms. The human liver cancer cell lines HepG2 and HuH7 and the murine liver cancer cell line Hepa1-6 were selected for cell and animal experiments to examine the response induced by PT irradiation. Biological changes and the immunological response following PT irradiation were examined. In vitro experiments showed no significant difference in cell survival following PT compared with photon radiotherapy. In a murine tumor model, the tumors were obviously smaller in size 12 days after PT irradiation. The underlying changes included increased DNA damage, upregulated IL-6 levels, and a regulated immune tumor microenvironment. Protein analysis in vitro and in vivo showed that PT increased the level of programmed cell death ligand 1 (PD-L1) expressed in tumor cells and recruited myeloid-derived suppressor cells (MDSCs). The increase in PD-L1 was positively correlated with the irradiation dose. In Hepa1-6 syngeneic mouse models, the combination of PT with anti-PD-L1 increased tumor growth delay compared with PT alone, which was associated with increased tumor-infiltrating T cells and attenuated MDSC recruitment in the microenvironment. Furthermore, when PT was applied to the primary HCC tumor, anti-PD-L1 antibody-treated mice showed smaller synchronous unirradiated tumors. In conclusion, the response of HCC to PT was determined by tumor cell killing and the immunological response in the tumor microenvironment. The combination with the anti-PD-L1 antibody to enhance antitumor immunity was responsible for the therapeutic synergism for HCC treated with PT. Based on our results, we suggest that PT combined with anti-PD-L1 may be a promising therapeutic policy for HCC.

The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma.

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P = .002) and reduced survival rates (P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance.

A multiple-center phase II study of weekly docetaxel and oxaliplatin as first-line treatment in patients with advanced gastric cancer.

BACKGROUND: Docetaxel and oxaliplatin are active agents for advanced gastric cancer (GC). The combination of these two drugs in a triweekly schedule is an active and attractive regimen for gastric cancer but with significant hematological toxicities. A multicenter phase II study was designed to establish an active regimen with good tolerability by using a weekly docetaxel-oxaliplatin (DO) combination in GC patients. METHODS: Eligible patients had histologically confirmed stage IV gastric cancer without previous palliative chemotherapy; age ≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; at least one measurable lesion; and adequate hematological, renal, and liver functions. All patients received premedications with dexamethasone and 5-HT3 antagonist before the chemotherapy. Docetaxel (Taxotere®; Sanofi-Aventis) 30 mg/m(2) followed by oxaliplatin (Eloxatin®; Sanofi-Aventis) 65 mg/m(2) were administered on days 1 and 8 of each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, or consent withdrawal. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. Tumor responses were evaluated every 2 cycles by the Response Evaluation Criteria in Solid Tumors Guidelines. RESULTS: From May 2007 to December 2008, a total of 47 patients were enrolled. There were 8 females and 39 males with a median age of 57 years (range 26-76). Forty-three patients were evaluable for response. Two patients obtained a complete response (4.7%) and 12 patients had a partial response (27.9%), with an overall response rate of 32.6% (95% confidence interval [CI] 19.1-48.5); 20 patients experienced stable disease (46.5%), and the disease progressed in 9 patients (20.9%). Median time to disease progression was 4.2 months and median overall survival was 8.3 months. All 47 patients were assessable for toxicity. Major grade 3/4 hematological toxicities were anemia (5 patients, 10.6%), neutropenia (2 patients, 4.3%), and leukopenia (1 patient, 2.1%). The most common grade 3/4 non-hematological toxicities were fatigue (3 patients, 6.4%) and aspartate aminotransferase (AST) elevation in 3 patients (6.4%). CONCLUSIONS: The combination of weekly DO demonstrated a well-tolerated profile with moderate activity in the treatment of advanced gastric cancer. Further studies of the combination together with a fluoropyrimidine are warranted.

Incidence and patterns of second primary malignancies following oral cavity cancers in a prevalent area of betel-nut chewing: a population-based cohort of 26,166 patients in Taiwan.

OBJECTIVE: The incidence of oral cavity cancers is increasing rapidly in South-East Asia, which may be attributable to tobacco smoking, alcohol and betel-nut chewing. However, the actual incidence and risk of second primary malignancies after oral cavity cancers have not been well established in this region. A population-based study was therefore conducted. METHODS: Standardized incidence ratios and cumulative incidences were calculated for second primary cancers using the Taiwan Cancer Registry database for the period 1979-2003, which included 26 166 cases having an initial diagnosis of oral cavity cancers. RESULTS: A 3.11-fold increase in risk for second cancer at all sites was observed after oral cavity cancers compared with the general population (standardized incidence ratio = 3.11, 95% confidence interval: 2.97-3.25). Of nine sites with excess risks of developing a second cancer, the frequency was highest in the oral/pharynx (60%), followed by lung (7.2%) and esophagus (5.5%). Second esophageal and lung cancers had a greater impact on survival compared with other types of second cancer. Notably, the risk excess was more prominent for patients with a follow-up interval of ≤ 1 year and a first primary cancer diagnosed at age of ≤ 40. These patients may justify closer surveillance. CONCLUSIONS: This is the largest population-based study with a homogeneous patient population focusing on oral cavity cancers within a high-incidence area. We found that oral cavity cancers are associated with an increased risk of nine second malignancies, which had a negative impact on survival.

Role of Nutritional Status in the Treatment Outcome for Esophageal Squamous Cell Carcinoma.

Undernourishment is reported to impair treatment response, further leading to poor prognosis for cancer patients. We aimed to investigate the role of nutritional status on the prognosis of squamous cell carcinoma (SCC) of the esophagus, and its correlation with anticancer immune responsiveness. We retrospectively reviewed 340 esophageal-SCC patients who completed curative treatment and received a nutrition evaluation by the Patient-Generated Subjective Global Assessment (PGSGA) score at the beginning and completion of neoadjuvant treatment at our hospital. The correlation between the nutritional status and various clinicopathological parameters and prognosis were examined. In addition, the role of nutritional status in the regulation of the anticancer immune response was also assessed in cancer patients and in a 4-nitroquinoline 1-oxide (4NQO)-induced esophageal tumor model. Our data revealed that malnutrition (patients with a high PGSGA score) was associated with advanced stage and reduced survival rate. Patients in the group with a high PGSGA score were correlated with the higher neutrophil-to-lymphocyte ratio, higher proportion of myeloid-derived-suppressor cells (MDSC) and increased IL-6 level. Furthermore, surgical resection brought the survival benefit to patients in the low PGSGA group, but not for the malnourished patients after neoadjuvant treatment. Using a 4NQO-induced tumor model, we found that nutrition supplementation decreased the rate of invasive tumor formation and attenuated the immune-suppressive microenvironment. In conclusion, malnutrition was associated with poor prognosis in esophageal-SCC patients. Nutritional status evaluated by PGSGA may be useful to guide treatment decisions in clinical practice. Nutritional supplementation is suggested to improve prognosis, and it might be related to augmented anticancer immune response.

Decreasing recurrence and increasing survival rates in patients of ethmoid or sphenoid intestinal-type adenocarcinomas: Systematic review and meta-analysis with 1126 cases.

BACKGROUND: Ethmoid or sphenoid intestinal-type adenocarcinomas (ITACs) form a distinct subtype of sinonasal adenocarcinomas that occur less than 1 case/100,000/yr. They have obvious exposure relationship to hardwood or leather dusts, infrequent metastasis, but a relatively high local-recurrence rate. They locate at sinuses close to vital structures listed as high-risk areas in surgeries. Even in expert hands, a craniofacial resection is associated with non-negligible mortality and morbidity. Management of these tumors, first or recurrent, needs to weigh these consequences versus the survival, regional-recurrence, and distant-recurrence rates. Due to the rareness of ethmoid or sphenoid ITACs, accurate overall survival and local- or regional-recurrence rates across diverse treatments are unclear. The aim of this study is to report the overall statistics of this cancer and the relationship between enrollment year versus age, recurrence, and survival. METHODS: Systemic review and meta-analysis with 1126 cases across various treatments in the literature. RESULTS: Here, we show that patients of ethmoid or sphenoid ITACs had overall local-, regional-, and distant-recurrence rates of 32.2%, 2.2%, and 10.3%, respectively, with a 5-year overall survival rate of 66.2%. The results present a significant correlation between age, local-recurrent rate, or overall survival rate versus enrollment year. CONCLUSION: This suggests that recent patients of ethmoid or sphenoid ITACs may present at an older mean age, have a lower local-recurrence rate, and have a better 5-year survival rate than before. There was a shifting trend of treating ethmoid ITACs from external approach to endoscopic resection. Clinicians may want to weigh mortality and morbidity rates of external surgeries and these data to share or decide a solution.

Acute leukemia presenting with extramedullary diseases and completely normal hemogram: an extremely unusual manifestation unique to pre-B ALL.

Acute lymphoblastic leukemia (ALL) is a clonal hematological disease characterized by inadequate normal hematopoiesis secondary to excessive proliferation of leukemic blasts and their impaired differentiation. As a result, patients usually manifest symptoms related to bone marrow failure. It's very uncommon for ALL patients to present with normal hemogram. Herein, we describe two patients who presented with excruciating bone pain at orthopedic clinics. Osteopathy involving multiple bones was noted initially, but acute leukemia was never considered as one of the differential diagnoses because of the completely normal hemogram in both cases. Consequently, the diagnosis of leukemia was slightly delayed. Upon literature review, we found that ALL patients with solely extramedullary diseases and nearly normal hemogram had exclusively pre-B disease. We also propose a putative hypothesis for this interesting finding.

Radiotherapy Is Associated with an Accelerated Risk of Ischemic Stroke in Oral Cavity Cancer Survivors after Primary Surgery.

The number of oral cavity carcinoma (OCC) survivors continues to increase due to advances in definitive surgery and radiation therapy (RT), however the risk of ischemic stroke is unclear in long-term survivors. In this study, survivors are defined as those who survived for >5 years after a diagnosis of OCC. They were matched at a 1:5 ratio with normal controls. Those who received surgery alone versus surgery+RT were also matched at a 1:1 ratio. From 2000 to 2005, 5172 OCC survivors who received surgery alone (n = 3205) or surgery+RT (n = 1967), and 25,860 matched normal controls were analyzed using stratified Cox regression models. Adjusted HRs (aHR) revealed that the surgery+RT group (aHR = 1.68, p < 0.001) had an elevated risk of stroke, but this was not seen in the surgery alone group (aHR = 0.99, p = 0.953). Furthermore, the age at stroke onset was at least 10 years earlier in the surgery+RT group than in the controls. In conclusion, radiotherapy increased the risk of ischemic stroke by 68% and also accelerated the onset of stroke in long-term OCC survivors after primary surgery compared with matched normal controls. Secondary prevention should include stroke as a late complication in OCC survivorship programs.