A meta-analysis comparing efficacy and safety between proton beam therapy versus carbon ion radiotherapy.

BACKGROUND: This study aimed to compare the outcomes of proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) by a systematic review and meta-analysis of the existing clinical evidence. METHODS: A systematic literature search was performed to identify studies comparing the clinical outcomes of PBT and CIRT. The included studies were required to report oncological outcomes (local control [LC], progression-free survival [PFS], or overall survival [OS]) or adverse events. RESULTS: Eighteen articles comprising 1857 patients (947 treated with PBT and 910 treated with CIRT) were included in the analysis. The pooled analysis conducted for the overall population yielded average hazard ratios of 0.690 (95% confidence interval (CI), 0.493-0.967, p = 0.031) for LC, 0.952 (95% CI, 0.604-1.500, p = 0.590) for PFS, and 1.183 (0.872-1.607, p = 0.281) for OS with reference to CIRT. The subgroup analyses included patients treated in the head and neck, areas other than the head and neck, and patients with chordomas and chondrosarcomas. These analyses revealed no significant differences in most outcomes, except for LC in the subgroup of patients treated in areas other than the head and neck. Adverse event rates were comparable in both groups, with an odds ratio (OR) of 1.097 (95% CI, 0.744-1.616, p = 0.641). Meta-regression analysis for possible heterogeneity did not demonstrate a significant association between treatment outcomes and the ratio of biologically effective doses between modalities. CONCLUSION: This study highlighted the comparability of PBT and CIRT in terms of oncological outcomes and adverse events.

Radiation-induced skin and heart toxicity in patients with breast cancer treated with adjuvant proton radiotherapy: a comparison with photon radiotherapy.

This study aimed to investigate the dose parameters and incidence of radiotherapy (RT)-associated toxicity in patients with left breast cancer (LBC) treated with proton-RT, compared with photon-RT. We collected data from 111 patients with LBC who received adjuvant RT in our department between August 2021 and March 2023. Among these patients, 24 underwent proton-RT and 87 underwent photon-RT. In addition to the dosimetric analysis for organs at risk (OARs), we measured NT-proBNP levels before and after RT. Our data showed that proton-RT improved dose conformity and reduced doses to the heart and lungs and was associated with a lower rate of increased NT-proBNP than did photon-RT. Regarding skin toxicity, the Dmax for 1 c.c. and 10 c.c. and the average dose to the skin-OAR had predictive roles in the risk of developing radiation-induced dermatitis. Although pencil beam proton-RT with skin optimization had a dose similar to that of skin-OAR compared with photon-RT, proton-RT still had a higher rate of radiation dermatitis (29%) than did photon RT (11%). Using mice 16 days after irradiation, we demonstrated that proton-RT induced a greater increase in interleukin 6 and transforming growth factor-ß1 levels than did photon-RT. Furthermore, topical steroid ointment reduced the inflammatory response and severity of dermatitis induced by RT. In conclusion, we suggest that proton-RT with skin optimization spares high doses to OARs with acceptable skin toxicity. Furthermore, prophylactic topical steroid treatment may decrease radiation dermatitis by alleviating proton-induced inflammatory responses in vivo.

A multicenter retrospective analysis of patients with salivary gland carcinoma treated with postoperative radiotherapy alone or chemoradiotherapy.

BACKGROUND: The aim of this study was to interrogate if the use of postoperative chemoradiotherapy (POCRT) correlated with superior oncological outcomes for certain subgroups of patients with high-risk salivary gland carcinoma (SGC), compared with postoperative radiotherapy (PORT) alone. METHODS: This multicenter retrospective study included 411 patients with surgically resected SGC who underwent PORT (n = 263) or POCRT (n = 148) between 2000 and 2015. Possible correlations of clinical parameters with outcomes were examined using the Kaplan-Meier analysis and Cox proportional-hazards regression model. RESULTS: The median follow-up of survivors is 10.9 years. For the entire cohort, adding concurrent chemotherapy to PORT was not associated with OS, PFS, or LRC improvement. However, patients with nodal metastasis who underwent POCRT had significantly higher 10-year OS (46.2% vs. 18.2%, P = 0.009) and PFS (38.7% vs. 10.0%, P = 0.009) rates than those treated with PORT alone. The presence of postoperative macroscopic residual tumor (R2 resection) was identified as an independent prognosticator for inferior OS (P = 0.032), PFS (P = 0.001), and LRC (P = 0.007). Importantly, POCRT significantly correlated with higher 10-year LRC rates in patients with R2 resection (74.2% vs. 40.7%, P = 0.034) or adenoid cystic carcinoma (AdCC, 97.6% vs. 83.6%, P = 0.039). On multivariate analyses, the use of POCRT significantly predicted superior OS (P = 0.037) and PFS (P = 0.013) for node-positive patients and LRC for patients with R2 resection (P = 0.041) or AdCC (P = 0.005). CONCLUSIONS: For surgically resected SGC, POCRT was associated with improved long-term OS and PFS for patients with nodal metastasis and superior LRC for patients with R2 resection or AdCC.

Postoperative radiotherapy alone is as effective as postoperative chemoradiotherapy in patients with pT4aN0 gingival cancer with negative surgical margins.

Background and purpose: This study compared the survival outcomes following postoperative chemoradiotherapy (CCRT) and postoperative radiotherapy (RT) alone for patients with gingival cancer with negative surgical margins and only bone invasion. Materials and methods: Of the 2579 gingival cancer cases reviewed from 2002 to 2018, 156 were enrolled in the study (CCRT: 63 patients; RT: 93 patients). The primary endpoints were the impact of adjuvant treatment (RT vs. CCRT) on overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). Subgroup analyses were conducted based on surgical margins (<5 mm vs. ≥ 5 mm) and different adjuvant treatments (RT vs. CCRT). Results: Median follow-up time, age, and invasion depth were 88.5 months, 57 years, and 14 mm, respectively. More patients undergoing adjuvant CCRT had surgical margins < 5 mm (47.6% vs. 21.5%, p < 0.01) than those undergoing RT. No significant difference was observed in the 5-year OS, LRRFS, and DMFS of patients undergoing adjuvant RT and CCRT. Although adjuvant RT alone and CCRT provided similar local control for patients with surgical margins ≥ 5 mm, worse LRRFS trends were observed in patients with surgical margins < 5 mm (hazards ratio, 6.15, 95% confidence interval 0.92-41.13, p = 0.06). Conclusion: Postoperative RT alone may be effective for patients with gingival cancer with negative surgical margins (≥5 mm) and only bone invasion, while postoperative CCRT may result in better LRRFS than RT alone for patients with surgical margins < 5 mm.

The relationship of nutritional status with anticancer immunity and its prognostic value for head and neck cancer.

Malnutrition has been reported to be associated with reduced survival and deficient anticancer immunity, and undernourishment is a frequent comorbidity in head and neck cancer (HNC) patients. In this study, we evaluated the relationship between nutritional status and immunologic factors, and its prognostic value for HNC. We retrospectively reviewed 212 HNC patients who had undergone a nutrition evaluation based on the Patient-Generated Subjective Global Assessment (PG-SGA) and curative radiotherapy (RT). The role of nutritional status in the prognosis of HNC and its correlation with anticancer immune response was assessed in HNC patients, and in the 4-nitroquinoline 1-oxide (4NQO)-induced tongue tumor animal model. Our data revealed that malnutrition (high PG-SGA scores) was significantly associated with more advanced disease, lower body mass index, lower RT completion rates, and reduced survival. Patients in the group with high PG-SGA scores had a higher neutrophil-to-lymphocyte ratio, higher proportion of myeloid-derived suppressor cells (MDSCs), and elevated IL-6 levels in the peripheral circulation. Patients with increased PG-SGA scores following treatment were more likely to developing locoregional failure. In the 4NQO-induced tumor model, nutritional supplementation decreased the rate of invasive tumor formation and attenuated the immune-suppressive microenvironment. Following ectopic tumor implantation in an immunocompetent host, nutrition supplements decreased tumor growth in association with attenuated MDSC recruitment and lower IL-6 expression. In conclusion, malnutrition by PG-SGA was associated with poor prognosis in HNC patients. Based on the data of HNC patients and the 4NQO-tumor model, adequate nutritional supplementation might improve the prognosis associated with augmented anticancer immunity.

Clinical Determinants of Extraurinary Tract Recurrence and Survival after Radical Surgery for pT2 Upper Tract Urothelial Carcinoma.

BACKGROUND: Oncologic outcomes for pT2N0M0 upper tract urothelial carcinoma (UTUC) after nephroureterectomy are not well defined, with most previous studies focused on a heterogeneous population. Therefore, we aimed to investigate the clinical determinants of extraurinary tract recurrence and survival after radical surgery in patients with localized UTUC. METHODS: We retrospectively identified 476 patients with pT2N0M0 UTUC who underwent radical nephroureterectomy or ureterectomy between October 2002 and March 2022. To evaluate the prognostic impact, patients were divided into renal pelvic, ureteral, and both-region (renal pelvis plus synchronous ureter) groups based on tumor location. The outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Associations were evaluated using multivariable Cox regression analyses for prognostic factors and Kaplan-Meier analyses for survival curves. RESULTS: The renal pelvic, ureteral, and both-region groups consisted of 151 (31.7%), 314 (66.0%), and 11 (2.3%) patients, respectively. Kaplan-Meier analyses comparing the three tumor types showed significant differences in 5-year RFS (83.6% vs. 73.6% vs. 52.5%, p = 0.013), CSS (88.6% vs. 80.7% vs. 51.0%, p = 0.011), and OS (83.4% vs. 70.1% vs. 45.6%, p = 0.002). Multivariable analyses showed that age >60 years, previous bladder cancer history, ureteral involvement (ureteral and both-regional groups), and positive surgical margins were significant negative prognostic factors for the studied outcomes. CONCLUSIONS: Patients with pT2 UTUC and presence of ureteral involvement had more frequent disease relapse. Subsequent adjuvant therapy regimens and close follow-up in patients with negative prognostic factors are warranted despite complete pathological removal of the tumor.

Appraisal of lung cancer survival in patients with end-stage renal disease.

Introduction: The survival outcome of lung cancer patients with end-stage renal disease has been poorly studied in the literature. In this study, we evaluated the effect of end-stage renal disease on lung cancer survival. Material and methods: A retrospective, multicenter, matched-cohort study of lung cancer patients with end-stage renal disease under renal replacement therapy (WITH-ESRD) and without end-stage renal disease (WITHOUT-ESRD) was performed. One WITH-ESRD patient was matched to four WITHOUT-ESRD patients. Results: Baseline clinical characteristics did not differ statistically significantly after matching between the WITH-ESRD and WITHOUT-ESRD groups. WITH-ESRD included 133 patients and WITHOUT-ESRD included 532 patients. Kaplan-Meier survival analysis demonstrated no significant difference in median overall survival between WITH-ESRD patients and WITHOUT-ESRD patients (7.36 months versus 12.25 months, respectively, p = 0.133). Lung cancer WITH-ESRD patients receiving medical treatment had a median overall survival of 5.98 months (95% CI: 4.34-11.76) compared to 14.13 months (95% CI: 11.30-16.43) for WITHOUT-ESRD patients, p = 0.019. Although patients receiving surgical treatment compared to those receiving medical treatment had an improvement of survival by 46% (HR = 0.54, 95% CI: 0.19-1.53, p = 0.243), the difference did not reach statistical significance. Cox regression analysis revealed that male gender and stage IIIA-IV were independent factors associated with poor outcome for WITH-ESRD patients. Conclusions: In our limited experience, the survival for lung cancer with ESRD is not inferior to lung cancer patients without ESRD. The reasons for poor survival for the WITH-ESRD medical treatment group and late diagnosis despite frequent medical visits merit further investigation.

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.

Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era.

BACKGROUND: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients. METHODS: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively. RESULTS: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality (p = 0.003) and a 48% reduction in risk of recurrence (p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend (p = 0.058) towards worse recurrence-free survival. CONCLUSIONS: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Streptococcus mutans promotes tumor progression in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is an aggressive head and neck cancer. Evidence showed that some pathogenic bacteria are associated with periodontitis and oral cancer. The change in oral microbiome composition and the role of the specific periodontal pathogen Streptococcus mutans in OSCC were investigated. We analyzed the microbiome of oral biofilms to identify if the oral microbiome composition was associated with OSCC. The role of S. mutans with clinical prognosis for OSCC was also examined. We further examined the role of S. mutans infection in OSCC progression in preclinical experiments. The microbiome assay by oral biofilms revealed that there was different microbiota composition between OSCC patients and health participants. Furthermore, the microbiota profiles showed that S. mutans abundance was associated with the development of OSCC development. Using the 16S rRNA PCR analysis, the presence of S. mutans was associated with advanced clinical stage and poor disease control. Furthermore, in the 4-nitroquinoline 1-oxide-induced mouse model, the presence of S. mutans was associated with elevated invasive oral cancer incidence. By cellular and xenograft tumor model using oral cancer cells, S. mutans infection was associated with the increased tumor aggressiveness, the epithelial-mesenchymal transition and interleukin-6 (IL-6) production; it also correlated with the recruitment of myeloid-derived-suppressor cells. When IL-6 signaling inhibited, the effects of S. mutans on tumor aggressiveness were attenuated. In conclusion, S. mutans may have the additive effect on oral cancer development and progression. Good oral hygiene to eradicate S. mutans or targeting IL-6 signaling could be a promising strategy for OSCC associated with S.mutans infection.

Perioperative Complications and Oncologic Outcomes after Radical Cystectomy in End-Stage Renal Disease Patients with Bladder Cancer Obtained Using a Standardized Reporting System.

Background: We investigated the use of a standardized reporting system to study perioperative complications and oncologic outcomes after radical cystectomy in end-stage renal disease (ESRD) patients with bladder cancer. Methods: We reviewed retrospective outcomes in 141 ESRD patients with bladder cancer who underwent radical cystectomy between 2004 and 2015. Complications were graded using the Clavien−Dindo classification system with 0−2 classified as "No Major Complications" and Clavien 3−5 as "Major Complications". Low-volume surgeons were classified as those performing fewer than nine cases during the study. Fisher's exact test along with the chi-squared test, two-tailed t tests, logistic regression, and the Cox proportional hazard model were used to evaluate all clinically meaningful covariates. Results: Ninety-nine (99, 70.2%) patients had no major complications, and forty-two (29.8%) patients had major complications. Patients in the major complications group were older, had a higher Charlson comorbidity index (CCI), and had a longer hospitalization duration than those in the no major complications group (all, p < 0.05). Major complications were also more common when the procedure was performed by low-volume surgeons (p = 0.003). In multivariate logistic regression models, CCI ≥ 5 (p = 0.006) and low-volume surgeon (p = 0.004) were independent predictors of major complications. According to multivariate analysis with the Cox hazards regression, male sex, age > 70 years, CCI ≥ 5, bladder cancer stage ≥ 3, lymphovascular invasion, and experiencing major complications were significant poor prognostic factors for overall survival (all, p < 0.05). Conclusions: Accurate reporting of complications is necessary for preoperative counseling, identifying modifiable risk factors, and planning risk mitigation strategies. High comorbidity and low-volume surgeons were interrelated as notable risk factors for major complications. In addition to tumor-related factors, male sex, older age, and major complications significantly influence overall survival.

Survival Impact of Nephroureterectomy for De Novo Stage IV Nonmetastatic and Metastatic Upper Tract Urothelial Carcinoma.

Background: Whether nephroureterectomy (NU) provides survival benefits in patients with stage IV upper tract urothelial carcinoma (UTUC) remains unclear. We compared the effect of chemotherapy (CT) alone with that of CT combined with NU (CT + NU) on the overall survival (OS) of patients with stage IV nonmetastatic UTUC (nmUTUC) and metastatic UTUC (mUTUC). Patients and Methods: This multicenter retrospective cohort study included the data of patients with UTUC undergoing CT alone or CT + NU from the Chang Gung Cancer Database (2002-2015) and followed them until August 2017. OS and hazard ratios (HRs) were assessed using the Kaplan-Meier method and Cox proportional hazards model, respectively. Results: This study included 308 patients with stage IV UTUC, comprising 139 with nmUTUC and 169 with mUTUC. Moreover, 91 (74.6%) patients with nmUTUC and 31 (25.4%) patients with mUTUC received NU. The CT + NU group had a higher 3-year OS rate (41.0.% vs 16.7%, p < 0.001), longer median OS duration (20.7 vs 9.0 months, p < 0.001), and lower risk of death (HR, 0.48; 95% confidence interval, 0.36-0.66; p < 0.001) than did the CT-alone group. Similarly, patients with mUTUC who underwent CT + NU had a longer median OS duration (25.0 vs 7.8 months, p < 0.001) and lower risk of death (HR, 0.37; 95% confidence interval, 0.23-0.59; p < 0.001) than did those who received CT alone. Conclusion: Compared with CT alone, NU + CT can provide survival benefits to patients with nonmetastatic and metastatic stage IV UTUC.

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.

Prospective Evaluation of Taste Function in Patients With Head and Neck Cancer Receiving Intensity-Modulated Radiotherapy.

Importance: The majority of the patients with head and neck cancer (HNC) experience taste dysfunction (TD) during or after radiotherapy (RT). However, prospectively collected data for taste dysfunction have been limited, especially in the era of intensity-modulated RT (IMRT). Objective: To evaluate the taste function in patients with HNC receiving IMRT by investigating the association between time course and recovery of TD in both acute and late phases. Design, Setting, and Participants: From August 2017 to November 2020, patients treated at the Chang Gung Memorial Hospital with curative or postoperative IMRT for HNC were enrolled in this prospective cohort study. The data analysis was performed from March 2021 to January 2022. Exposures: IMRT with and without concurrent chemotherapy. Main Outcomes and Measures: Taste function was measured using the whole-mouth solution method for 4 tastes (salt, sweet, sour, and bitter). Subjective evaluations (National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03] and Subjective Total Taste Acuity scale) were used. Patient self-reported quality of life was evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-H&N35). Results: A total of 87 patients (78 [90%] men and 9 [10%] women; mean [range] age, 58 [31-80] years) were enrolled. Overall TD rates were 79 of 86 (91.9%), 63 of 83 (75.9%), 27 of 81 (33.3%), 5 of 56 (8.9%), and 2 of 30 (6.7%) during RT, and 1 week, 3 months, 6 months, and 1 year after RT, respectively. Positive correlation occurred between objectively measured taste loss for the 4 taste qualities and subjective perception of taste loss. Only oral cavity mean dose 4000 cGy or greater predicted TD 3 months after RT. The mean oral cavity doses to the predicted 15% (D15), 25% (D25), and 50% (D50) probabilities were 25, 38, and 60 Gy at 3 months and 57, 60, and 64 Gy at 6 months, respectively. Conclusions and Relevance: In this cohort study, most patients still experienced TD during and at 3 months after RT. Only a few patients experienced long-term TD. A high oral cavity dose was associated with TD in patients with HNC receiving IMRT. Reducing oral cavity dose may promote early recovery of taste function after IMRT.

Risk of critical limb ischemia in long-term uterine cancer survivors: A population-based study.

BACKGROUND: The risk of critical limb ischemia (CLI) which causes ischemic pain or ischemic loss in the arteries of the lower extremities in long-term uterine cancer (UC) survivors remains unclear, especially in Asian patients, who are younger at the diagnosis of UC than their Western counterparts. AIM: To conduct a nationwide population-based study to assess the risk of CLI in UC long-term survivors. METHODS: UC survivors, defined as those who survived for longer than 5 years after the diagnosis, were identified and matched at a 1:4 ratio with normal controls. Stratified Cox models were used to assess the risk of CLI. RESULTS: From 2000 to 2005, 1889 UC survivors who received surgery alone or surgery combined with radiotherapy (RT) were classified into younger (onset age < 50 years, n = 894) and older (onset age ≥ 50 years, n = 995) groups. While compared with normal controls, the younger patients with diabetes, hypertension, and receiving hormone replacement therapy (HRT) were more likely to develop CLI. In contrast, the risk of CLI was associated with adjuvant RT, obesity, hypertension, and HRT in the older group. Among the UC survivors, those who were diagnosed at an advanced age (> 65 years, aHR = 2.48, P = 0.011), had hypertension (aHR = 2.18, P = 0.008) or received HRT (aHR = 3.52, P = 0.020) were at a higher risk of CLI. CONCLUSION: In this nationwide study, we found that the risk factors associated with CLI were similar in both cohorts except for adjuvant RT that was negligible in the younger group, but positive in the older group. Among the survivors, hypertension, advanced age, and HRT were more hazardous than RT. Secondary prevention should include CLI as a late complication in UC survivorship programs.

Treatment Strategy for Dialysis Patient with Urothelial Carcinoma.

To investigate postoperative complications and oncologic outcomes of prophylactic nephroureterectomy and/or cystectomy in dialysis patients with urothelial carcinoma (UC), we retrospectively reviewed the records of dialysis patients with UC and a final status of complete urinary tract extirpation (CUTE, i.e., the removal of both kidneys, ureters, and bladder) between January 2004 and December 2015. Patients undergoing dialysis after initial radical nephroureterectomy and/or cystectomy were excluded. Eighty-four and 27 dialysis patients, undergoing one-stage and multi-stage CUTE, were enrolled in this study, respectively. Demographic, medical, perioperative, and pathologic features were collected to determine variables associated with oncologic outcomes. Although there was no significant difference in mortality between the 2 groups (p = 0.333), all 5 (4.5%) patients with Clavien-Dindo grade 5 complications were from the one-stage CUTE group. On multivariate logistic regression analysis, advanced age (p = 0.042) and high Charlson comorbidity index (CCI) (p = 0.000) were related to postoperative major complications. Compared with multi-stage CUTE, one-stage CUTE had no overall, cancer-specific, and recurrence-free survival benefits (all p > 0.05). According to multivariate analysis with Cox regression, age > 70 years (HR 2.70, 95% CI 1.2-6.12; p = 0.017), CCI ≥ 5 (HR 2.16, 95% CI 1.01-4.63; p = 0.048), and bladder cancer stage ≥ 3 (HR 12.4, 95% CI 1.82-84.7; p = 0.010) were independent, unfavorable prognostic factors for the overall survival. One-stage CUTE is not associated with superior oncologic outcomes, and all perioperative mortalities in our series occurred in the one-stage CUTE group. Our data do not support prophylactic nephroureterectomy and/or cystectomy for uremic patients with UC.

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.

Survival of Patients with Lung Cancer in the Setting of Liver Cirrhosis: A Multicenter Propensity Score Matching Study.

PURPOSE: The survival outcome of lung cancer patients with coexisting liver cirrhosis has thus far received limited attention in the literature. In this study, we evaluated whether liver cirrhosis is an independent risk factor for the survival of patients with lung cancer. MATERIALS AND METHODS: We conducted a retrospective, multicenter, propensity-matched study of lung cancer patients with and without liver cirrhosis. To determine differences in survival, we sought to identify risk factors associated with poor outcomes using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: There were no statistically significant differences in the baseline clinical characteristics of patients between the cirrhosis and non-cirrhosis groups. The median overall survival of patients with and without cirrhosis was 13.07 months (95% confidence interval [CI]: 10.56-16.84) and 13.67 months (95% CI: 10.42-16.91), respectively (p=0.76). Cox proportional hazards regression analysis revealed that liver cirrhosis was not an independent risk factor for poor outcome (hazard ratio [HR]: 1.057, 95% CI: 0.805-1.388, p=0.690). In patients with cirrhosis, lower serum albumin levels, higher Charlson Comorbidity Index score, advanced-stage lung cancer, and treatment modality were factors associated with poor outcome. Increase in serum albumin by 1 g was associated with a 30% reduction in the risk of mortality (HR: 0.700, 95% CI: 0.494-0.993, p=0.045). While every point increase in the Charlson Comorbidity Index score by 1 point was linked to a 9% higher risk of mortality (HR: 1.090, 95% CI: 1.023-1.161, p=0.007). CONCLUSION: The survival rates of lung cancer patients with and without cirrhosis did not differ significantly. Higher serum albumin levels and lower Charlson Comorbidity Index scores were associated with improved survival.

Effect of 1α,25-Dihydroxyvitamin D3 on the Radiation Response in Prostate Cancer: Association With IL-6 Signaling.

Radiotherapy (RT) is the main treatment modality for prostate cancer (PCa). This study investigated the role of IL-6 in biological sequelae following irradiation and highlighted the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on the radiation response of PCa and its relationship with IL-6 signaling. Human and murine PCa cell lines were used to examine the response to irradiation in vitro and in vivo. The relationship of IL-6 expression with clinicopathologic characteristics in 104 PCa patients treated with definite RT was also examined. We also investigated the changes in radiation response after calcitriol supplementation and the relationship between calcitriol and IL-6 signaling by conducting cellular and animal experiments. Based on clinical samples, the positivity of IL-6 staining is a significant predictor of biochemical failure-free survival for PCa patients treated with definite RT. Data from preclinical models showed that inhibition of IL-6 increased the response of PCa to radiation, which was associated with increased oxidative DNA damage, attenuated EMT and MDSC recruitment, and decreased tumor regrowth. Moreover, increased vitamin D3 levels by calcitriol supplementation or induction by UVB-radiation was associated with inhibited IL-6 signaling and increased the response to irradiation observed in animal models. These data demonstrate that IL-6 play a critical role in the radiation response of PCa, which involved tumor cell killing and altering the tumor microenvironment. Directly targeting IL-6 signaling or vitamin D3 supplement with oral or light treatment could be a promising strategy to increase the response of PCa to radiation.