Comparison of therapeutic outcomes in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A prospective observational cohort study.

BACKGROUND: Patients with locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoradiotherapy (nCRT) may not always receive resection despite the possible achievement of a pathologic complete response (pCR) being associated with superior survival benefit. We aimed to compare outcomes among ESCC patients with or without pCR and those refusing surgery. METHODS: In total, 111 medically operable, non-cervical ESCC patients after the same protocol of nCRT (platinum/5-fluorouracil plus radiation 50Gy) were prospectively enrolled between 2011 and 2021. Eighty-three of them underwent esophagectomy comprising pCR (n = 32) and non-pCR (n = 51), while 28 operable patients declined surgery (refusal-of-surgery group). Predictors and survival data were analyzed. RESULTS: In terms of esophagectomy, 38.5% (32/83) patients achieved pCR. The pCR group exhibited better pretreatment performance status than the non-pCR group (adjusted odds ratio: 0.11, 95% confidence interval: 0.03-0.58; p = 0.01). Among pCR, non-pCR, and refusal-of-surgery groups, the 5-year overall survival (OS) rates were 56%, 29% and 50% (p = 0.08) and progression-free survival (PFS) rates were 52%, 28% and 36% (p = 0.07) respectively. The pCR group had significantly better OS and PFS than the non-PCR group (adjusted hazard ratio: 2.33 and 1.93, p = 0.02 and 0.049 respectively) but not the refusal-of-surgery group. CONCLUSION: Better pretreatment performance status is associated with higher chance of pCR. Consistent with previous studies, we found attainment of pCR confers the best OS and PFS. Suboptimal OS in the refusal-of-surgery group reflects some of them would have residual disease in addition to complete remission. Further studies are needed to identify prognostic factors of pCR to select candidates who could validly decline esophagectomy.

Higher pre-treatment skin sympathetic nerve activity and elevated resting heart rate after chemoradiotherapy predict worse esophageal cancer outcomes.

BACKGROUND: Chemoradiotherapy (CRT), which might affect the autonomic system, is the mainstay therapy for advanced esophageal squamous cell carcinoma (ESCC). Autonomic dysfunction has been found to possibly lead to cancer mortality in those with elevated resting heart rates (RHR). Skin sympathetic nerve activity (SKNA) is a new method of stimulating electrical signals in skin to evaluate autonomic function from sympathetic tone. In this study, we investigated the association between changes in RHR and autonomic function and ESCC mortality. METHODS: Thirty-nine stage II-IV ESCC patients receiving CRT between March 2019 and November 2020 were prospectively enrolled and carefully selected, followed up and received the same meticulous supportive care. Serial RHR was recorded every two weeks from before CRT to eight weeks after CRT and average SKNA were recorded before and four weeks after CRT. All-cause mortality was defined as primary outcome. RESULTS: We found the RHR of ESCC patients to be significantly elevated and peaking at four weeks after CRT (p < 0.001) and then to gradually decrease. Those with an elevated RHR above the cutoff level (18 beat-per-minute) at eight weeks after CRT had worse overall survival. In addition, those with higher baseline sympathetic tone (average SKNA ≥ 0.86 µV) also had poor outcome. CONCLUSIONS: Increased pre-treatment sympathetic tone and elevated RHR after CRT are alarm signs of poor ESCC outcome. Further exploration of the mechanisms underlying these associations could potentially lead to intervention strategies for reducing mortality. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier: NCT03243448.

DNA Repair Protein Rad51 Induces Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma via a p38/Akt-Dependent Pathway.

BACKGROUND: Rad51 is a protein which plays a vital role in DNA double-strand break repair and maintenance of telomeres. However, the underlying mechanism for its action in esophageal squamous cell carcinoma (ESCC) remains unclear. PATIENTS AND METHODS: Eighty-seven patients with ESCC were enrolled in this study. Expression of Rad51 in ESCC was determined by immunohistochemistry and correlated with clinicopathological variables by Chi square test. The role of Rad51 in patient survival was determined by Kaplan-Meier estimates. The effects of Rad51 knockdown and overexpression on esophageal cancer growth, migration, and invasion were examined using TE8, CE81T, and KYSE70 cells. The mechanisms involved were also analyzed. Nude mice models were used for assessment of tumor growth. RESULTS: Rad51 staining was predominantly observed in ESCC patients. ESCC patients with high Rad51 expression had significantly decreased survival (P < 0.001) combined with increased tumor size (P = 0.034) and lymph node metastasis (P = 0.039). Rad51 overexpression promoted, while its knockdown attenuated, esophageal cancer cell viability through cell cycle entry and migration/invasion via epithelial-mesenchymal transition. Moreover, Rad51 overexpression increased colony formation in vitro and tumor growth in vivo. In addition, high Rad51 expression increased cancer progression through the p38/Akt/Snail signaling pathway. CONCLUSIONS: This study indicates a new biological role for Rad51 in ESCC progression. Rad51 may serve as a potential prognostic biomarker and therapeutic target for ESCC patients.

Enteral nutrition and quality of life in patients undergoing chemoradiotherapy for esophageal carcinoma: a comparison of nasogastric tube, esophageal stent, and ostomy tube feeding.

BACKGROUND AND AIMS: This study prospectively recruited esophageal squamous cell carcinoma patients who received esophageal stent, nasogastric tube (NGT), or jejunostomy/gastrostomy feeding to compare the changes in nutritional status and quality of life during chemoradiation therapy (CRT). METHODS: In total, 81 patients were analyzed (stent, 7; surgical ostomy, 26; NGT, 19; oral intake, 29). An NGT was inserted when, despite medication, dysphagia or pain worsened with oral feeding during CRT. Serial body weight and daily narcotic demand were recorded. Changes in serum albumin level and quality of life were also assessed. In subgroup analysis comparing NGT and prophylactic surgical ostomy feeding, 5 patients with total occlusion in the ostomy group were excluded. RESULTS: Patients in all groups had similar decreases in mean body weight with an overall change of -6.41% ± 5.21% at the end of CRT. The stent group had significantly worse pain, decreased albumin (-1.03 ± .9 mg/dL), and decreased quality of life across CRT compared with the other groups. In subgroup analysis the stent group had significantly higher weight loss, whereas the NGT group had higher narcotic demand and slightly worse quality of life. Two patients (7.7%) had ileus days after jejunostomy creation. Five patients (23.8%) among those received prophylactic ostomy creation and scarcely used it. CONCLUSIONS: These preliminary results raise concerns that use of esophageal stents may be less suitable in patients undergoing CRT. Tube feeding by means of transnasal or percutaneous routes appear to be comparably effective during CRT, but both have advantages and disadvantages. We suggest a careful endoscopic evaluation to select the population more appropriate for NGT feeding on an as-needed basis during CRT.

Association between proteinuria and the development of malignant middle cerebral artery infarction: A retrospective cohort study.

A disrupted blood-brain barrier (BBB) with extravasation of macromolecules plays a critical role in the development of malignant middle cerebral artery infarction (MMI). Proteinuria is considered a marker of generalized endothelial dysfunction, including BBB disruption. This study aimed to clarify whether proteinuria identified in the acute stage of stroke is associated with MMI development. Patients with infarctions involving the middle cerebral artery territory were reviewed. Urine samples collected within 8 hours after stroke were analyzed using urine dipsticks. Patients were divided into proteinuria (urine dipstick reading of 1 + to 4+) and nonproteinuria groups. MMI was present if either signs of uncal herniation or a progressive conscious disturbance were recorded along with a midline shift > 5 mm identified on follow-up computed tomography (CT). Among the 1261 patients identified between January 2010 and June 2019, 138 were eligible for final analyses. Patients in the MMI group had lower Alberta Stroke Program Early CT Scores (ASPECTS), higher National Institutes of Health Stroke Scale scores, and a greater proportion of proteinuria than those in the non-MMI group. Four multivariate logistic regression models were used to clarify the role of proteinuria in MMI development. In model 1, proteinuria was significantly associated with MMI after adjusting for age, sex, dyslipidemia and ASPECTS (OR = 2.987, 95% CI = 1.329-6.716, P = .0081). The risk of developing MMI in patients with proteinuria remained significant in model 2 (OR = 3.066, 95% CI = 1.349-6.968, P = .0075) after adjusting for estimated glomerular filtrate rate (eGFR) < 60ml/min/1.73 m2 in addition to variables in model 1. In model 3, proteinuria was still significantly associated with MMI after adjusting for age, sex, dyslipidemia, ASPECTS, hypertension, diabetes, and atrial fibrillation (OR = 2.521, 95% CI = 1.075-5.912, P = .0335). In model 4, the risk of developing MMI in patients with proteinuria remained significant (OR = 2.579, 95% CI = 1.094-6.079, P = .0304) after adjusting for eGFR < 60ml/min/1.73 m2 in addition to variables in model 3. Proteinuria is independently associated with MMI development. Proteinuria may be a clinically accessible predictor of MMI development.

The association between white matter changes and development of malignant middle cerebral artery infarction: A case-control study.

ABSTRACT: Disrupted blood-brain barrier (BBB) in patients with ischemic stroke plays a critical role in malignant middle cerebral artery infarction (MMI) development.Cerebral white matter changes (WMC), particularly in the deep subcortical area or in severe one, may be also underlain by disrupted BBB. It is unclear whether the presence of WMC with potential premorbid disruption of BBB makes patients susceptible to MMI. Therefore, this study aimed to clarify any putative relationship between the MMI and WMC in terms of their severity and locations.In this case-control study, patients with infarction in the middle cerebral artery territory were retrospectively reviewed. Brain magnetic resonance images were analyzed according to Fazekas scale, and identified WMC were divided into periventricular WMC (PV-WMC) and deep subcortical WMC (deep-WMC). Patients were scored as having WMC, PV-WMC, deep-WMC, severe PV-WMC, and severe deep-WMC according to the severity and locations. Patients were defined as having MMI if either a progressive conscious disturbance or signs of uncal herniation was recorded in combination with a midline shift >5 mm identified on the follow-up computed tomography.Among 297 patients admitted between July 2009 and February 2015, 92 patients were eligible for final analysis. Compared to patients without MMI, patients with MMI had a higher score of National Institutes of Health Stroke Scale, a larger infarct volume, and an increasingly greater proportion of severe PV-WMC, deep-WMC, and severe deep-WMC, respectively. After adjustment for sex, age, infarct volume, and history of hypertension, severe deep-WMC (odds ratio [OR] = 6.362, 95% confidence interval [CI] = 1.444-28.023, P = .0144) and severe PV-WMC (odds ratio = 5.608, 95% confidence interval = 1.107-28.399, P = .0372) were significantly associated with MMI development.MMI and WMC are significantly associated such that MMI development is more likely when PV-WMC or deep-WMC is more severe. We hypothesize that Fazekas scale-defined severe deep-WMC and PV-WMC may be considered as clinically approachable predictors of MMI development. These findings support that the WMC with potential premorbid disrupted BBB may make patients susceptible to MMI, and further prospective study should be conducted to clarify this hypothesis.

Excision repair cross-complementing group 2 upregulation is a potential predictive biomarker for oral squamous cell carcinoma recurrence.

Oral cancer is the fourth most common type of cancer among males in Taiwan, and the prognosis for patients with advanced-stage oral squamous cell carcinoma (OSCC) remains poor. The present study investigated the prognostic value of three DNA repair genes, namely excision repair cross-complementing group 1 (ERCC1), ERCC2 and X-ray repair cross-complementing group 1 (XRCC1) in OSCC. The protein expression levels of XRCC1, ERCC1 and ERCC2 in oral cell lines were analyzed via western blotting and immunohistochemistry using samples from 98 patients with biopsy-proven OSCC, while the χ2 test was used to analyze the clinicopathological association. Kaplan-Meier estimates were used to determine the prognostic value of XRCC1, ERCC1 and ERCC2 for overall survival, and the log-rank test was used to evaluate the significance of differences. Multivariate analysis revealed a positive association between ERCC2 expression and OSCC recurrence (19.64-fold; 95% CI, 5.00-77.1; P<0.001). In addition, the high protein expression levels of XRCC1, ERCC1 and ERCC2 were associated with poor disease-free and overall survival rates. Therefore, the present study suggested that high ERCC2 expression may be a risk factor for OSCC recurrence.

Post-radiation sinusitis is associated with recurrence in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.

BACKGROUND: This study investigated the impact of post-radiation sinusitis on the prognosis of nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiation therapy (IMRT). METHODS: Two hundred and thirty patients with non-metastatic NPC were analyzed in terms of freedom from local failure (FFLF), freedom from distant failure (FFDF), overall survival (OS), and disease-free survival (DFS). For each patient, the status of the sinus mucosa was flexibly assessed by documenting mucosal changes as indicated by differences between images obtained before radiotherapy and more than 6 months post-radiation. RESULTS: With a median follow-up of 39.7 months (8 to 81 months), 19 (8.26%) patients relapsed locally, 13 (5.65%) patients failed in the neck, and 26 (11.3%) patients developed distant metastases. The presence of sinusitis noted in images post-radiation was a significant predictor for DFS (p = 0.001), FFLF (p = 0.004), and FFDF (p = 0.015), in addition to having high negative predictive value for local relapse (97.5%). CONCLUSIONS: This is the first study to investigate the prognostic value of post-radiation sinusitis in NPC patients treated with IMRT. Post-radiation sinusitis was found to be a significant predictor for DFS, FFLF, and FFDF, and was also found to have high negative predictive value for local recurrence (97.5%). It may thus be used as an additional tool for clinicians to determine the possibility of recurrence.

Randomized double-blind, placebo-controlled trial evaluating oral glutamine on radiation-induced oral mucositis and dermatitis in head and neck cancer patients.

BACKGROUND: Glutamine is the primary fuel for the gastrointestinal epithelium and maintains the mucosal structure. Oncologists frequently encounter oral mucositis, which can cause unplanned breaks in radiotherapy (RT). OBJECTIVES: The aim of this study was to explore the association between oral glutamine and acute toxicities in patients with head and neck cancer undergoing RT. METHODS: This was a parallel, double-blind, randomized, placebo-controlled Phase III trial conducted in a university hospital. A central randomization center used computer-generated tables to allocate interventions to 71 patients with stages I-IV head and neck cancers. The patients, care providers, and investigators were blinded to the group assignment. Eligible patients received either oral glutamine (5 g glutamine and 10 g maltodextrin) or placebo (15 g maltodextrin) 3 times daily from 7 d before RT to 14 d after RT. The primary and secondary endpoints were radiation-induced oral mucositis and neck dermatitis, respectively. These were documented in agreement with the National Cancer Institute Common Terminology Criteria for Adverse Events version 3. RESULTS: The study included 64 patients (placebo n = 33; glutamine n = 31) who completed RT for the completers' analysis. Based on multivariate analysis, glutamine had no significant effect on the severity of oral mucositis (OR: 0.3; 95% CI: 0.05, 1.67; P = 0.169). Only the change in body mass index (BMI) was significant in both multivariate completers (OR: 0.41; 95% CI: 0.20, 0.84; P = 0.015) and per-protocol analysis (OR: 0.40; 95% CI: 0.20, 0.83; P = 0.014). No difference was found in the incidence and severity of neck dermatitis between the two arms. CONCLUSIONS: The decrease in BMI was strongly related to the severity of oral mucositis in the head and neck cancer patients under RT, but not to the use of glutamine. This trial was registered at clinicaltrials.gov as NCT03015077.

Prognosis of Hippocampal Function after Sub-lethal Irradiation Brain Injury in Patients with Nasopharyngeal Carcinoma.

This work emphasizes the value of assessing hippocampal function by making a timely MRI-based prognosis following a minor dose of hippocampal irradiation after nasopharyngeal carcinomas (NPC) radiotherapy. A quasi-experiment with case-control design and functional assessments (e.g., neuroimaging analysis with fMRI) was conducted to assess hippocampal function after radiotherapy. We delivered 70 Gy of irradiation to nasopharyngeal carcinomas by 6MV helical radiotherapy and collected data from twenty NPC patients and 24 healthy age-matched subjects. Inevitably, hippocampi also received an average dose of 6.89 Gy (range, 2.0-14 Gy). Seed-based functional connectivity of the hippocampus was applied to estimate the cognitive alteration by time before, one month, and four months after irradiation. Afterward, longitudinal-and-cross-sessional statistical inference was determined with time-dependent measurement analysis of variance (ANOVA) with controlled covariance. Over time, there were longitudinal changes in the functional connectivity of hippocampal-related cortices, including the right middle frontal lobe, left superior temporal lobe, and left postcentral gyrus. The findings indicate the presence of functional plasticity, demonstrating how minor irradiation affects functional performance during the early delayed phase of irradiation-induced brain injury.