Topical Antibiotic Prophylaxis for Preventing Surgical Site Infections of Clean Wounds: A Systematic Review and Meta-Analysis.

Background: Topical antibiotic agents are not generally indicated for preventing of surgical site infections (SSIs) in clean incisions, and the drug concentrations that should be delivered to local incision sites remain uncertain. The aim of this study was to critically assess the efficacy of topical antibiotic agents in comparison with non-antibiotic agents for preventing SSIs in clean incisions by performing a systematic review and meta-analysis. Methods: We conducted a search of literature in PubMed, Embase, and Cochrane Databases and included randomized controlled trials (RCTs) on topical antibiotic use for patients with clean post-surgical incisions. The primary outcome was the incidence of SSI, presented as the event rate. Eleven RCTs were included. Results: Using random-effects modeling, the pooled risk ratio (RR) of developing a post-surgical incisions infection was 0.83 (95% confidence interval [CI], 0.61-1.16; I2, 0%). In subgroup analyses, no reductions in SSI were observed when topical antibiotic agents were used to treat incisions due to spinal (RR, 0.75; 95% CI, 0.40-1.38; I2, 0%), orthopedic (RR, 0.69; 95% CI, 0.37-1.29; I2, 0%), dermatologic (RR, 0.77; 95% CI, 0.39-1.55; I2, 65%), or cardiothoracic surgeries (RR, 1.31; 95% CI, 0.83-2.06; I2: 0%). The incidence of SSI across different operative phases did not differ for the application of topical antibiotic agents compared with non-antibiotic agents (RR, 0.80; 95% CI, 0.56-1.14; I2, 0%). Conclusions: The results of this meta-analysis show that topical antibiotic agents provide no clinical benefit for preventing SSI in clean incisions.

Effects of Fracture Liaison Service on Outcomes of Patients with Hip Fracture in Rural Area of an Asian Country.

Introduction: Fracture Liaison Services (FLS) has been proven effective in reducing subsequent fractures and related mortality. However, more research is needed on the impact of FLS on the 30-day readmission rate and its effectiveness in rural hospitals. This study aims to assess the impact of FLS on clinical outcomes including readmission rates, subsequent fractures, and fracture-related mortality in rural areas of an Asain country. Materials and methods: In a rural hospital in Taiwan, we conducted a two-year prospective cohort study on elderly individuals with fragility hip fractures. The study compared the clinical outcomes between the control group and the FLS-cohort group. Logistic regression analysis was used to identify factors contributing to 1-year mortality after injury. Results: 556 patients were enrolled. (304 in the control group and 252 in the FLS group) The mean age was 79.8 years. The findings revealed that the introduction of FLS did not result in significant differences in mortality, readmission, complication, subsequent fractures, or secondary hip fractures. However, there were notable improvements in the length of hospital stay and the proportion of patients receiving surgery within 48 h following the implementation of FLS. Subgroup analysis showed that FLS patients who received anti-osteoporotic treatment had lower mortality and 30-day readmission rates. Factors associated with higher 1-year mortality included male, high ASA level, and delayed surgery. Discussion: This study provides the real-life evidence of the effect of intensive FLS model in a rural hospital in an Asian country. Conclusion: While FLS did not show significant differences in certain clinical outcomes, it led to shorter hospital stays and increased timely surgeries. FLS patients receiving anti-osteoporotic treatment had better mortality and readmission rates. Further research is necessary to gain a comprehensive understanding of the impact of FLS care in rural areas of Asia.

Age as a modifier of the effects of sarcopenia on survival among colon cancer patients after surgery.

BACKGROUND: Studies have been conducted to evaluate whether sarcopenia is a predictor for survival in patients with colon cancer postsurgery, but findings have been inconsistent, and effects of age were seldom evaluated. METHODS: We recruited 133 patients with resectable colon cancer who underwent surgery between January 2014 and December 2017 at a teaching hospital to evaluate the effects of sarcopenia on survival, after adjusting for age and other potential predictors, including visceral adiposity (VA). RESULTS: Preoperative sarcopenia was associated with worse overall survival (OS: 62.3% vs. 83.8%, p = 0.04) and longer hospital stay (20.6 vs. 14.9 days, p < 0.01) while VA was not. Cox proportional hazards regressions showed that sarcopenia was associated with an adjusted hazard ratio (HR) of 2.91 (95% confidence interval [CI]: 1.08-7.86) after adjustment for other independent risk factors, but was not associated with disease free survival. In stratified analyses, we found that sarcopenia was an independent factor for worse OS (adjusted HR = 1.94; 95% CI: 1.11-3.38) among patients >70 years, but not among patients ≤70 years (HR = 0.48; 95% CI: 0.55-4.55). CONCLUSIONS: Age appeared to be a modifier of the effects of sarcopenia on OS among colon cancer patients postsurgery.

Anticancer Therapy and Mortality of Adult Patients with Hematologic Malignancy and COVID-19: A Systematic Review and Meta-Analysis.

Coronavirus disease 2019 (COVID-19) might affect cancer treatment outcomes. This systematic review and meta-analysis identified the prognostic predictors of adult patients with hematologic malignancies and COVID-19, and evaluated the effect of anticancer therapy on mortality. We performed a literature search of electronic databases and identified additional studies from the bibliographies of the articles that were retrieved. Two investigators independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. We evaluated study quality using the Newcastle-Ottawa Scale and performed a meta-analyses in order to evaluate the effect of anticancer therapy on mortality among adult patients with hematologic malignancies and COVID-19. Heterogeneity was assessed with the I2 statistic. The meta-analysis included 12 studies. The overall mortality rate was 36.3%. The pooled risk difference (RD) in mortality between patients receiving and not receiving anticancer therapy was 0.14 (95% confidence interval [CI]: 0.02-0.26; I2 = 76%). The pooled RD in mortality associated with chemotherapy was 0.22 (95% CI: 0.05-0.39; I2 = 48%), and with immunosuppression was 0.20 (95% CI: 0.05-0.34; I2 = 67%). In the subgroup analyses, anticancer-therapy-associated mortality was higher in females (RD = 0.57; 95% CI: 0.29-0.85; I2 = 0%) than in males (RD = 0.28; 95% CI: 0.04-0.52; I2 = 0%). Among patients with hematologic malignancies and COVID-19, those receiving anticancer therapy had a higher mortality risk, regardless of sex. The mortality risk was higher in females than in males. These results indicate that caution should be exercised when administering anticancer therapy to patients with hematologic malignancies and COVID-19.

MiR-455-5p suppresses PDZK1IP1 to promote the motility of oral squamous cell carcinoma and accelerate clinical cancer invasion by regulating partial epithelial-to-mesenchymal transition.

BACKGROUND: Lymph node and distant metastasis contribute to poor outcomes in patients with oral squamous cell carcinoma (OSCC). The mechanisms regulating cancer migration and invasion play a key role in OSCC. METHODS: We determined migration and invasion ability of OSCC by wound-healing assay, two-chamber transwell invasion assay and cell mobility tracking and evaluated tumor metastasis in vivo. Western blot (WB), qRT-PCR, RNA-seq, dual-luciferase reporter assays and nuclear/cytoplasmic fractionation were performed to investigate the potential mechanism. Immunohistochimical (IHC) staining determined vimentin and PDZK1IP1 expression in OSCC tissues. RESULTS AND CONCLUSION: In this study, we determined that miR-455-5p was associated with lymph node metastasis and clinical invasion, leading to poor outcomes in patients with OSCC. MiR-455-5p promoted oral cancer cell migration and invasion and induced epithelial-to-mesenchymal transition (EMT). We also identified a new biomarker, PDZK1IP1 (MAP17), that was targeted by miR-455-5p. PDZK1IP1 knockdown led to migration, metastasis, EMT, and increased transforming growth factor-ß signaling in OSCC. In addition, miR-455-5p overexpression and PDZK1IP1 inhibition promoted collective OSCC cell migration. According to data from the Cancer Genome Atlas database and the NCKU-OrCA-40TN data set, miR-455-5p and PDZK1IP1 are positively and negatively correlated, respectively, with partial EMT score. High miR-455-5p expression was associated with high vimentin levels and low MAP17 H-scores. The patients with low MAP17 expression had higher rates of disease recurrence than did patients with high MAP17 expression, especially for patients with clinical invasion risk factors and low MAP17 expression. These results suggest that miR-455-5p suppresses PDZK1IP1 expression and mediates OSCC progression. MiR-455-5p and PDZK1IP1 may therefore serve as key biomarkers and be involved in regulating partial EMT in OSCC cells. PDZK1IP1 expression may also serve as an independent factor that impacts outcomes in patients with clinical risk factors for recurrence.

Bevacizumab and Atezolizumab for Unresectable Hepatocellular Carcinoma: Real-world Data in Taiwan-Tainan Medical Oncology Group H01 Trial.

BACKGROUND/AIM: The combination of bevacizumab and atezolizumab (Bev-Ate) has been established as a standard first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC) since 2020. This study examined the outcomes of HCC patients who received the combination in southern Taiwan. PATIENTS AND METHODS: All patients were enrolled from four hospitals in Taiwan. They received Bev-Ate therapy for unresectable HCC. RESULTS: Thirty-five patients were included; 28 (80%) had Barcelona Clinic Liver Cancer stage C disease. Hepatitis etiology was chronic hepatitis B and C in 63% and 17% of patients, respectively. Eleven (31%) patients had received prior systemic treatment for unresectable HCC. The response rate was 51%, and the disease control rate was 72% for all patients. The median progression-free survival (PFS) and overall survival (OS) was 5.2 and 22.2 months, respectively. For patients who received prior systemic treatment, the efficacy of Bev-Ate in terms of response rates was similar compared with those without prior systemic treatment. Patients who received lower doses of bevacizumab (<15 mg/kg per dose) had non-inferior PFS and OS compared with those receiving a standard dose of bevacizumab. The incidence of proteinuria of all grades (15.8%) was less common when lower doses of bevacizumab were used. CONCLUSION: Real world data from HCC patients in southern Taiwan disclosed that the efficacy outcomes of Bev-Ate treatment were generally consistent with those of clinical trials in other countries. In patients who were exposed to prior systemic treatment or who received lower doses of bevacizumab, the Bev-Ate regimen retained its clinical efficacy.

Role of high ubiquitin-conjugating enzyme E2 expression as a prognostic factor in nasopharyngeal carcinoma.

The incidence of nasopharyngeal carcinoma (NPC) in Southeast Asia and Taiwan is high due to epidemiological factors. Cisplatin-based chemoradiotherapy is an important treatment strategy with excellent outcomes for patients with NPC. However, the outcomes for patients who are refractory to cisplatin-based therapy are poor. Methods for risk stratification of patients with NPC undergoing cisplatin-based chemoradiotherapy require to be investigated. A previous study indicated that ubiquitin-conjugating enzyme E2 B (UBE2B) was able to regulate alkylating drug sensitivity in NPC cells. In the present study, the clinical significance of UBE2B expression in patients with NPC was analyzed. Analysis of the two available NPC datasets containing the UBE2B expression profile (GSE12452 and GSE68799) was performed to evaluate the UBE2B expression levels in NPC tissues compared with nasopharyngeal mucosal epithelial tissues. Furthermore, immunohistochemical staining was performed using anti-UBE2B antibodies on samples from 124 patients with NPC who underwent cisplatin-based chemoradiotherapy. Disease-specific survival (DSS), distant metastatic-free survival (DMeFS) and local recurrence-free survival (LRFS) of patients with high and low UBE2B expression was analyzed. Furthermore, the associations between UBE2B expression and the biological behavior of NPC cells were investigated in vitro. Using public NPC datasets and in vitro studies, it was identified that UBE2B expression levels were increased in NPC tumor tissues compared with those in mucosal epithelial tissues. The cell proliferation ability was decreased in UBE2B-deficient NPC cells as compared with that in UBE2B-proficient cells. Immunohistochemical analysis of 124 NPC tissues from patients who underwent cisplatin-based chemoradiotherapy indicated that high UBE2B expression levels were associated with poor DSS, DMeFS and LRFS. Multivariate regression analysis of factors influencing survival also confirmed that high UBE2B expression levels were a statistically significant independent risk factor for poor clinical outcomes in terms of DSS [hazard ratio (HR), 1.955; 95% CI 1.164-3.282], DMeFS (HR, 2.141; 95% CI 1.206-3.801) and LRFS (HR, 2.557; 95 CI 1.313-4.981). In vitro analysis indicated that O6-methylguanine-DNA methyltransferase attenuated cisplatin sensitivity induced by knockdown of UBE2B in NPC cells. In conclusion, the present study demonstrated that high UBE2B expression is associated with poor clinical outcomes for patients with NPC treated with cisplatin-based chemoradiotherapy.

Epigenetic Deregulation of Protein Tyrosine Kinase 6 Promotes Carcinogenesis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers and causes considerable morbidity and mortality. Epigenetic deregulation is a common mechanism underlying carcinogenesis. DNA methylation deregulation is the epigenetic change observed during the transformation of normal cells to precancerous and eventually cancer cells. This study investigated the DNA methylation patterns of PTK6 during the development of OSCC. Bisulfite genomic DNA sequencing was performed to determine the PTK6 methylation level. OSCC animal models were established to examine changes in PTK6 expression in the different stages of OSCC development. The DNA methylation of PTK6 was decreased during the development of OSCC. The mRNA and protein expression of PTK6 was increased in OSCC cell lines compared with human normal oral keratinocytes. In mice, the methylation level of PTK6 decreased after treatment with 4-nitroquinoline 1-oxide and arecoline, and the mRNA and protein expression of PTK6 was increased. PTK6 hypomethylation can be a diagnostic marker of OSCC. Upregulation of PTK6 promoted the proliferation, migration, and invasion of OSCC cells. PTK6 promoted carcinogenesis and metastasis by increasing STAT3 phosphorylation and ZEB1 expression. The epigenetic deregulation of PTK6 can serve as a biomarker for the early detection of OSCC and as a treatment target.

Single-Cell RNA Sequencing Analysis for Oncogenic Mechanisms Underlying Oral Squamous Cell Carcinoma Carcinogenesis with Candida albicans Infection.

Oral squamous cell carcinoma (OSCC) carcinogenesis involves heterogeneous tumor cells, and the tumor microenvironment (TME) is highly complex with many different cell types. Cancer cell-TME interactions are crucial in OSCC progression. Candida albicans (C. albicans)-frequently pre-sent in the oral potentially malignant disorder (OPMD) lesions and OSCC tissues-promotes malignant transformation. The aim of the study is to verify the mechanisms underlying OSCC car-cinogenesis with C. albicans infection and identify the biomarker for the early detection of OSCC and as the treatment target. The single-cell RNA sequencing analysis (scRNA-seq) was performed to explore the cell subtypes in normal oral mucosa, OPMD, and OSCC tissues. The cell composi-tion changes and oncogenic mechanisms underlying OSCC carcinogenesis with C. albicans infec-tion were investigated. Gene Set Variation Analysis (GSVA) was used to survey the mechanisms underlying OSCC carcinogenesis with and without C. albicans infection. The results revealed spe-cific cell clusters contributing to OSCC carcinogenesis with and without C. albicans infection. The major mechanisms involved in OSCC carcinogenesis without C. albicans infection are the IL2/STAT5, TNFα/NFκB, and TGFß signaling pathways, whereas those involved in OSCC carcinogenesis with C. albicans infection are the KRAS signaling pathway and E2F target down-stream genes. Finally, stratifin (SFN) was validated to be a specific biomarker of OSCC with C. albicans infection. Thus, the detailed mechanism underlying OSCC carcinogenesis with C. albicans infection was determined and identified the treatment biomarker with potential precision medicine applications.

Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. SIGNIFICANCE: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Investigation of the incidence trend of follicular lymphoma from 2008 to 2017 in Taiwan and the United States using population-based data.

BACKGROUND: The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. MATERIALS AND METHODS: We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. RESULTS: The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of -2.1. We found no significant change for the blacks (APC, -1.5%), Hispanics (APC, -0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, -3.8%) and then stabilized after 2012 (APC, -0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. CONCLUSION: We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites.

Association between sarcopenia and survival in patients with gynecologic cancer: A systematic review and meta-analysis.

Background: Despite prior attempts to evaluate the effects of sarcopenia on survival among patients with gynecologic cancer, the results of these studies have not been consistent. The present study evaluated the association between sarcopenia and survival among patients with gynecologic cancer by aggregating multiple studies. Methods: We performed a literature search using computerized databases and identified additional studies included in the bibliographies of retrieved articles. The quality of each study was evaluated using the Newcastle-Ottawa Scale, and meta-analyses were performed to evaluate overall survival (OS) and progression-free survival (PFS). We constructed a forest plot for each outcome and assessed publication bias using Begg's test. Heterogeneity was assessed using I2 statistics. Results: From the 5,933 initially identified articles, 16 studies describing 2,031 participants with a mean age of 60.34 years were included in the meta-analysis. We found that compared with patients with gynecologic cancer but without sarcopenia, patients with sarcopenia had worse OS, with a pooled hazard ratio (HR) of 2.61 (95% confidence interval [CI]:1.52-4.46), and worse PFS (HR: 1.37, 95% CI: 1.09-1.73). The quality of studies was generally good, and no publication bias was detected among studies for either OS or PFS. Although 4 of 12 studies were of fair quality, we conducted a sensitivity analysis excluding studies or fair quality and obtained similar results. Conclusions: These meta-analysis results suggest that sarcopenia is associated with worse OS and PFS among patients with gynecologic cancer. The use of different case definitions appeared to be a major source of heterogeneity among the studies. Further studies remain necessary to confirm our findings, especially those examining OS and PFS, because publication bias was identified.

Effect of diabetes mellitus comorbidity on outcomes in stages II and III colorectal cancer.

AIM: The effects of diabetes mellitus (DM) on the outcomes of colorectal cancer (CRC) are controversial. This retrospective study evaluated the effects of DM on American Joint Committee on Cancer (AJCC, 7th) Stages II and III CRC patients who received curative surgery. METHODS: We reviewed the records of CRC patients who were treated from January 2008 to December 2014 and identified the presence of DM and hypertension prior to CRC diagnosis. Cox proportional hazards analyses were used for prognostic factor determination, and survival was analyzed using the Kaplan-Meier method with the log-rank test. RESULTS: Total of 1066 consecutive eligible patients with stage II/III CRC were enrolled. There were 326 (30.6%) patients diagnosed with DM, and 311 (29.2%) CRC patients had recurrence. Patients with DM did not have a higher recurrence risk (p = 0.183) but had higher mortality (adjusted hazard ratio [aHR] = 1.381; 95% conference interval [CI], 1.069-1.782). In addition, HbA1c (≥7 vs. <7) was not associated with recurrence (p = 0.365). Patients with DM had more hypertension than patients without DM (69.1% vs. 37.6%, p < 0.001). A lower recurrence risk was noted in patients with hypertension (p = 0.002), but the overall survival (OS) did not reach statistical significance (aHR = 0.910; 95% CI, 0.707-1.169). CONCLUSION: In our study, DM was a poor prognostic factor for survival in curative CRC patients. More studies are required to elucidate the effects that DM and other metabolic disorders, such as hypertension, have on the prognosis of patients with CRC.

Incidence of second primary malignancies in women with different stages of breast cancer.

Introduction: Breast cancer (BC) is the most common cancer in women worldwide. Because of the extended survival of patients with BC, the occurrence of second primary malignancies (SPMs) after BC is an important issue. Methods: We identified female patients with BC in the Breast Cancer Health Database of Taiwan, which includes four cancer registry datasets between 2002 and 2014 from Taiwan Cancer Registry. We compared the incidence of SPM between patients who received chemotherapy and/or radiotherapy with those who did not. Stratified analyses were performed according to the American Joint Committee on Cancer (AJCC) stage. The Cox regression model was used to identify the risk factors for SPM and evaluate their effects. Results: We enrolled 85,947 eligible patients with BC, and 2,656 (3.09%) patients developed SPM. The median duration of SPM was 2.70 (1.14-5.14) years. Radiotherapy was administered in 40,946 (47.64%) patients, and chemotherapy was administered in 52,120 (60.64%). The most common SPMs were digestive tract cancers (876, 31.89%). The risk factors for SPM included the AJCC stage, chemotherapy, radiotherapy, age, and underlying comorbidities. Neither chemotherapy nor radiotherapy was associated with an increased risk of SPM in any stage. In contrast, after adjusting for other risk factors, patients at stage III/IV who received both therapies had lower risks of SPM compared with those who did not (p = 0.047). Conclusion: The risk of SPM was different across BC stages. Neither chemotherapy nor radiotherapy was associated with an increased risk of SPM in women with BC.

Assessment of pegylated arginine deiminase and modified FOLFOX6 in patients with advanced hepatocellular carcinoma: Results of an international, single-arm, phase 2 study.

BACKGROUND: Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. METHODS: This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . RESULTS: In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. LAY SUMMARY: Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Age as a modifier of the effects of chemoradiotherapy with infusional 5-fluorouracil after D2 dissection in gastric cancer.

Adjuvant concurrent chemoradiotherapy (CCRT) is the standard care for patients with resected advanced gastric cancer, but its survival benefits remain undetermined in patients undergoing D2 lymph node dissection (D2 dissection). We evaluated safety and efficacy of adjuvant CCRT with 5-fluorouracil (5-FU) versus chemotherapy alone in 110 gastric cancer patients with D2 dissection treated in Taiwan between January 2009 and January 2013. All the 71 patients receiving adjuvant CCRT were treated with daily infusional 5-FU and radiotherapy. Adjuvant CCRT was associated with higher risks of major hematologic (56.3% vs. 23.8%, p = 0.002) and gastrointestinal (46.9% vs. 14.3%, p = 0.027) toxicities and death (12.5% vs. 0.0%, p = 0.041) in patients above 70 years old, but this was not the case in those ≤70 years of age. Univariate Cox proportional regressions identified adjuvant CCRT as a factor for better overall survival (OS) (hazard ratio [HR]=0.52; 95% confidence interval [CI]: 0.27-0.99) and disease-free survival (DFS) (HR=0.46, 95% CI: 0.24-0.88), but it was not a significant factor for OS or DFS after adjusting for other factors in the multivariate analysis. However, in stratified analyses by age, we found adjuvant CCRT was an independent prognostic factor for better OS (HR=0.07; 95% CI: 0.01-0.38) in patients ≤70 years old, but not in those above 70 years of age. Therefore, it was concluded that age may to be a modifier of the effects of adjuvant CCRT.

Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature.

Anti-epithelial growth factor receptor or anti-vascular endothelial growth factor agents combined with chemotherapy were the standard of treatment for metastatic colorectal cancer (CRC). However, increasing evidence of molecularly stratified treatment makes the complexity of treatment. Anaplastic lymphoma kinase (ALK) gene alternation is one of potential target for biomarker-guided therapy for CRC. We present a case of a 56-year-old man who suffered from advanced ascending colon cancer, harboring echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion gene E21; A20 variant, a rare variant in EML4-ALK fusion gene in lung cancer. We also detected this fusion gene from different tissue types including circulating tumor DNA (ctDNA) and ascites fluid. The patient was offered alectinib, an ALK inhibitor, with partial response in lung, liver, and peritoneal metastasis for 8 months. Tumor heterogeneity, especially in gastrointestinal tract cancer, raise our interest in comprehensive genetic profiling in clinical practice. Convenience and reliability of next-generation sequencing, including using ctDNA, help physicians deal with clinical dilemma. ALK-positive CRC is rare. However, advanced CRC with ALK gene alteration responds to ALK inhibitor. It is reasonable to check ALK gene alteration in clinical practice for CRC.

O6-methylguanine-DNA methyltransferase modulates cisplatin-induced DNA double-strand breaks by targeting the homologous recombination pathway in nasopharyngeal carcinoma.

BACKGROUND: The homologous recombination (HR) pathway is involved in DNA damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents. O6-methylguanine DNA methyltransferase (MGMT) is associated with cisplatin (CDDP) resistance in cancer cells; however, the underlying mechanisms remain unclear. Here, we explored the interactions between MGMT and the HR pathway in CDDP-activated DDR and their clinical implications in nasopharyngeal carcinoma (NPC). METHODS: Human NPC cells were assessed using loss-of-function approaches in vitro. The expression correlations between MGMT and major proteins of the HR pathway were analyzed through Western blotting, quantitative real-time PCR, and bioinformatic analysis by using a public database. The physical interactions between MGMT and HR proteins were studied using co-immunoprecipitation and immunofluorescence analyses. Cell comet tails and γ-H2AX expression levels were examined to evaluate double-strand break (DSB) formation. Established immunofluorescence and reporter analyses were conducted to measure HR activity. Xenograft and cell viability studies were used to assess the therapeutic potential of MGMT inhibition in combination with CDDP and poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. RESULTS: Among major proteins of the HR pathway, MGMT suppression inhibited CDDP-induced RAD51 expression. Bioinformatic analyses showed a positive correlation between MGMT and RAD51 expression in patients with NPC. Moreover, MGMT physically interacted with BRCA1 and regulated CDDP-induced BRCA1 phosphorylation (ser 988). In functional assays, MGMT inhibition increased CDDP-induced DSB formation through attenuation of HR activity. NPC xenograft studies demonstrated that MGMT inhibition combined with CDDP treatment reduced tumor size and downregulated RAD51 expression and BRCA1 phosphorylation. Furthermore, MGMT suppression increased PARP inhibitor-induced cell death and DSB formation in NPC cells. CONCLUSION: MGMT is crucial in the activation of the HR pathway and regulates DDR in NPC cells treated with CDDP and PARP inhibitor. Thus, MGMT is a promising therapeutic target for cancer treatments involving HR-associated DDR.

Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model.

Oral carcinogenesis involves the progression of the normal mucosa into potentially malignant disorders and finally into cancer. Tumors are heterogeneous, with different clusters of cells expressing different genes and exhibiting different behaviors. 4-nitroquinoline 1-oxide (4-NQO) and arecoline were used to induce oral cancer in mice, and the main factors for gene expression influencing carcinogenesis were identified through single-cell RNA sequencing analysis. Male C57BL/6J mice were divided into two groups: a control group (receiving normal drinking water) and treatment group (receiving drinking water containing 4-NQO (200 mg/L) and arecoline (500 mg/L)) to induce the malignant development of oral cancer. Mice were sacrificed at 8, 16, 20, and 29 weeks. Except for mice sacrificed at 8 weeks, all mice were treated for 16 weeks and then either sacrificed or given normal drinking water for the remaining weeks. Tongue lesions were excised, and all cells obtained from mice in the 29- and 16-week treatment groups were clustered into 17 groups by using the Louvain algorithm. Cells in subtypes 7 (stem cells) and 9 (keratinocytes) were analyzed through gene set enrichment analysis. Results indicated that their genes were associated with the MYC_targets_v1 pathway, and this finding was confirmed by the presence of cisplatin-resistant nasopharyngeal carcinoma cell lines. These cell subtype biomarkers can be applied for the detection of patients with precancerous lesions, the identification of high-risk populations, and as a treatment target.

A nationwide survey of fatigue in cancer patients in Taiwan: an unmet need.

BACKGROUND: Cancer-related fatigue (CRF) is an emerging clinical issue, although its prevalence and impact on quality of life (QOL) in cancer patients in Taiwan remain unclear. The present nationwide cross-sectional study was conducted to provide a thorough overview of the prevalence, related factors and impact of CRF in Taiwan. METHODS: In this multi-center survey, data were collected using the International Classification of Diseases 10th Revision (ICD-10) Fatigue evaluation, Brief Fatigue Inventory-Taiwan (BFI-T), the Chinese version of the Symptom Distressed Scale and a fatigue experience survey. Logistic regression was used to determine the correlations between fatigue characteristics and the factors studied. RESULTS: A total of 1207 cancer patients were recruited from 23 hospitals in Taiwan. Fatigue was the most distressing symptom in Taiwanese cancer patients. The distress score was higher if CRF was diagnosed using ICD-10 compared with BFI-T. Rest and nutritional supplementation were the most common non-pharmacological treatments; blood transfusion was the most common pharmacological treatment. There were 45% of patients reported not receiving a timely intervention for fatigue. CONCLUSIONS: Fatigue is the most bothersome symptom reported by Taiwanese cancer patients. Caregivers should be aware of the impact of CRF on QOL in cancer patients, constantly measure the severity of fatigue and provide appropriate interventions.