Advanced gastric cancer achieving major pathologic regression after chemoimmunotherapy combined with hypofractionated radiotherapy: A case report.

BACKGROUND: Currently, chemotherapy combined with immunotherapy is the established first-line standard treatment for advanced gastric cancer (GC). In addition, the combination of radiotherapy and immunotherapy is considered a promising treatment strategy. CASE SUMMARY: In this report, we present a case of achieving nearly complete remission of highly advanced GC with comprehensive therapies. A 67-year-old male patient was referred to the hospital because he presented with dyspepsia and melena for several days. Based on fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), endoscopic examination and abdominal CT, he was diagnosed with GC with a massive lesion and two distant metastatic lesions. The patient received mFOLFOX6 regimen chemotherapy, nivolumab and a short course of hypofractionated radiotherapy (4 Gy × 6 fractions) targeting the primary lesion. After the completion of these therapies, the tumor and the metastatic lesions showed a partial response. After having this case discussed by a multidisciplinary team, the patient underwent surgery, including total gastrectomy and D2 lymph node dissection. Postoperative pathology showed that major pathological regression of the primary lesion was achieved. Chemoimmunotherapy started four weeks after surgery, and examination was performed every three months. Since surgery, the patient has been stable and healthy with no evidence of recurrence. CONCLUSION: The combination of radiotherapy and immunotherapy for GC is worthy of further exploration.

Immunotherapy and tumor mutational burden in cancer patients with liver metastases: A meta and real word cohort analysis.

Background: The predictive effects of liver metastases for immune-checkpoint inhibitors (ICIs) and the relationship between tumor mutational burden (TMB) and liver metastases (LM) remain unclear. Methods: A systematic review and meta-analysis were conducted to explore the heterogeneity of ICIs efficacy between patients with or without LM. A pan-cancer cohort of 1,661 patients who received ICIs was downloaded and analyzed to assess the association between TMB and LM. Results: Of 21053 studies identified in our search, eight single-arm studies and 24 randomized controlled trials were included. Overall, 17957 patients with advanced or metastatic cancers (4805 patients (26.8%) with LM and 13151 patients (73.2%) without LM) were enrolled. The pooled objective response rate (ORR) was 8.5% (95% CI 4%-13%) in the LM group versus 21% (95% CI 16%-21%) in the non-LM group. The pooled hazard ratio (HR) for death was 0.85 (95% CI 0.80-0.90) in the LM group treated with ICIs compared with the standard of care. In patients without LM who were treated with ICIs, the pooled HR for death was 0.78 (95% CI 0.73-0.82) compared with the standard of care. The difference in efficacy between patients with or without LM treated with ICIs was significant (p=0.04). Pan-cancer analysis revealed that the TMB-high rate was 10.8% in liver metastatic lesions versus 21.4% in other metastatic lesions (p=0.004). In addition, TMB was also significantly associated with OS as a binary cutoff (p=0.05) and was an independent prognostic variable (HR=0.98, P=0.047) as a continuous variable in patients with LM. Conclusions: In patients with LM, the efficacy of immunotherapy was attenuated, but TMB-high could predict better survival outcomes.

Aneuploidy of chromosome 8 and mutation of circulating tumor cells predict pathologic complete response in the treatment of locally advanced rectal cancer.

Identifying patients who may or may not achieve pathologic complete response (pathCR) allows for treatment with alternative approaches in the preoperative setting. The aim of the current study was to investigate whether aneuploidy of chromosome 8 and mutations of circulating tumor cells (CTCs) could predict the response of patients with rectal cancer to preoperative chemoradiotherapy. A total of 33 patients with locally advanced rectal cancer (cT3-T4 and/or cN+) treated with neoadjuvant chemoradiotherapy between September 2014 and March 2015 were recruited. Blood samples were collected from 33 patients with pre-chemoradiotherapy rectal cancer. It was demonstrated that ≥5 copies of chromosome 8 was associated with pathCR (univariate logistic regression, P=0.042). Of the 6 patients whose CTCs had <5 copies of chromosome 8, 3 achieved pathCR (3/6, 50%), and of the 27 patients whose CTCs had ≥5 copies of chromosome 8 obtained 3 pathCR (3/27, 11.1%; Chi-square test, P=0.0255). Of the 33 patients with mutations assessed, 8 significant nonsynonymous mutations in CTCs were identified as associated with pathCR (Chi-square test, P-values range, 0.0004-0.0298; mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 and AR). These results suggest that ≥5 copies of chromosome 8 and 8 nonsynonymous mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 AR in CTCs were associated with pathCR. This conclusion should be validated further in larger prospective studies and the long-term follow-up survival data of this study will also be reported in the future.

Adjuvant chemotherapy for patients with ypT0-2N0-category after neoadjuvant chemoradiotherapy for rectal cancer.

Locally advanced rectal cancer patients with ypT0-2N0 have good prognosis and may not require as many cycles of adjuvant chemotherapy as patients with a poor (ypT3-4 or N+) response. The aim of the present study was to evaluate the three-year disease-free and overall survival between patients with ypT0-2N0 rectal adenocarcinoma who received 0-3 cycles of 5-fluorouracil-based adjuvant chemotherapy and those who received >3 cycles. A total of 106 patients with locally advanced rectal cancer, classified as ypT0-2N0 after surgery at the Fudan University Shanghai Cancer Center (Shanghai, China) between 2006 and 2012, were identified. The patients were divided into two groups depending on the number of cycles of adjuvant chemotherapy: Group 1 received 0-3 cycles (n=32) and group 2 received ≥4 cycles of adjuvant chemotherapy (n=74). The three-year disease-free survival and overall survival rates were 86.8 and 93.1% for group 1 (P=0.633), and 88.5 and 96.8% for group 2 (P=0.381). No statistically significant difference was observed between the two groups, suggesting that patients with ypT0-2N0 status may not require more than three cycles of post-operative chemotherapy. Further evaluation in prospective studies is urgently recommended.

The recommended treatment strategy for locally advanced gastric cancer in elderly patients aged 75 years and older: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: As patients aged 75 years and older are often underrepresented in randomized clinical trials, the external validity of clinical trials-based recommendations in older gastric patients was still controversial. The aim of this study is to explore the recommended treatment strategy for locally advanced gastric cancer in elderly patients. METHODS: We designed our study to specifically evaluate the cancer-specific survival (CSS) of four subgroups of patients according to four different treatment modalities: adjuvant radiation (RT), surgery only, RT only and no surgery/no RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. RESULTS: The 5-year CSS was 43.8 % in adjuvant RT, 28.5 % in surgery only, 14.9 % in RT only and 1.4 % in no surgery/no RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Moreover, we observed significant survival benefits in adjuvant RT group in all age categories, including age 75-79 years, age 80-84 years and age ≥85 years (all P < 0.001). CONCLUSIONS: Surgery and adjuvant RT may be the recommended treatment strategy in elderly patients with locally advanced gastric cancer, especially for patients medically fit for the combined modality therapy.

Sex, Race, and Age Disparities in the Improvement of Survival for Gastrointestinal Cancer over Time.

There have been notable improvements in survival over the past 2 decades for gastrointestinal (GI) cancer. However, the degree of improvement by age, race, and sex remains unclear. We analyzed data from 9 population-based cancer registries included in the SEER program of the National Cancer Institute (SEER 9) in 1990 to 2009 (n = 288,337). The degree of survival improvement over time by age, race, and sex was longitudinally measured. From 1990 to 2009, improvements in survival were greater for younger age groups. For patients aged 20 to 49 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.74 (95% CI, 0.66-0.83), 0.49 (95% CI, 0.37-0.64), 0.69 (95% CI, 0.65-0.76), 0.62 (95% CI, 0.54-0.69), and 0.56 (95% CI, 0.42-0.76), for cancer of the stomach, small intestine, colon, rectum and anus, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. Compared with African Americans, whites experienced greater improvement in small intestinal and anal cancer survival. Female anal cancer and regional anal cancer patients experienced no improvement. Our data suggest that different improvement in survival in age, sex and race exists.

YpT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer.

Pathologic T1-2N0 rectal cancer shows an excellent prognosis without preoperative or postoperative chemoradiation. However, oncologic outcome of ypT1-2N0 remains unclear and undetermined. Thus, the aim of this study was to compare the survival of ypT1-2 and pT1-2 rectal cancer patients after radical resection and identify risk factors of ypT1-2 rectal cancer in Surveillance, Epidemiology, and End Results Program (SEER)-registered rectal cancer patients. The results showed that ypT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer and mucinous/signet-ring cancer and less than 12 lymph nodes retrieval were two risk factors in ypT1-2 patients. These results suggest that ypT1-2 patients with one or two risk factors may benefit from postoperative adjuvant chemotherapy.

Implications for determining the optimal treatment for locally advanced rectal cancer in elderly patients aged 75 years and older.

Patients were excluded if they were older than 75 years of age in most clinical trials. Thus, the optimal treatment strategies in elderly patients with locally advanced rectal cancer (LARC) are still controversial. We designed our study to specifically evaluate the cancer specific survival of four subgroups of patients according to four different treatment modalities: surgery only, radiation (RT) only, neoadjuvant RT and adjuvant RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. The results showed that the 5-year cancer specific survival (CSS) was 52.1% in surgery only, 27.7% in RT only, 70.4% in neoadjuvant RT and 60.4% in adjuvant RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Thus, the neoadjuvant RT and surgery may be the optimal treatment pattern in elderly patients, especially for patients who are medically fit for the operation.

Implications for preserving neural stem cells in whole brain radiotherapy and prophylactic cranial irradiation: a review of 2270 metastases in 488 patients.

This study delineated the incidence of metastatic involvement of neural stem cell (NSC) regions and further aimed to explore the feasibility of selectively sparing the NSC compartments during whole brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). A total of 2270 intracranial metastases in 488 patients were identified. Lesions were classified according to locations, including lesions in the NSC compartments (subventricular zone, SVZ, or hippocampus) and those in the rest of the brain/brainstem. The incidence of involvement of NSC regions was compared between oligometastatic patients (those with 1-4 lesions) and non-oligometastatic patients (those with 5 or more lesions) using a chi-square test. The volume of the NSC regions accounted for 2.23% of the whole brain, and the overall rate of metastatic lesions in NSC regions was 1.1% in 2270 metastases (25/2270), and 4.7% in 488 patients (23/488). Of the NSC region metastases, 7 (0.3%) involved the hippocampus and 18 (0.8%) occurred in the SVZ. Among the 7 hippocampal metastases identified in this study, 1/7 (14.3%) were found in oligometastatic patients, while 6/7 (85.7%) metastases were in non-oligometastatic patients. For metastases in the SVZ, all lesions occurred in non-oligometastatic patients with none in oligometastatic patients. Metastatic involvement of the NSC compartments was significantly lower in oligometastatic patients (0.15%, 1/670) than in non-oligometastatic patients (1.5%, 24/1600) (P < 0.001). Our retrospective review of 2270 metastases in 488 patients is that the volume of the compartments of NSC regions was 2.23% relative to the whole brain, but the incidence of involvement of the NSC compartments was 1.1%, and the vast majority of NSC lesions were found in non-oligometastatic patients. We believe our data supports selective reduction of doses for these aforementioned structures, when treating oligometastatic patients with WBRT and locally advanced-stage small-cell lung cancer patients with PCI.

A dural arteriovenous fistula in cavernous sinus developed from viral meningitis.

Although hormonal influences, inflammation, trauma, sinus thrombosis, venous hypertension, and congenital origin have been proposed as sources of dural arteriovenous fistulas (DAVFs) in cavernous and sigmoid sinuses, the etiology of these lesions remains controversial. We present a case with a cavernous sinus DAVF developed from viral meningitis which has not been previously described. A 24-year-old male was admitted to our institute because of periorbital pain, decreased vision, pulsatile tinnitus, chemosis, and exophthalmos on the right side after he had suffered viral meningitis four months before. Cerebral angiography demonstrated a cavernous sinus DAVF, which was successfully obliterated with several platinum coils using a transvenous approach. The viral meningitis most likely caused the inflammation, that may be responsible for the occurrence of the cavernous sinus DAVF. Prompt treatment for inflammation may help to prevent the development of DAVFs.

Chronic cerebral hypoperfusion in rats causes proteasome dysfunction and aggregation of ubiquitinated proteins.

The deposition of abnormal protein aggregates is a feature of several neurodegenerative diseases. We have employed a rat model to investigate whether chronic cerebral hypoperfusion (CCH) induces proteasome dysfunction and the accumulation of ubiquitinated proteins and aggregates in the CNS. Protein aggregation was analyzed by ethanolic phosphotungstic acid (EPTA) electron microscopy (EM), immunogold EM, laser-scanning confocal microscopy, and Western blotting. Proteasome peptidase activity was studied by peptidase activity assays. EPTA EM and immunogold EM revealed that CCH led to the accumulation of protein aggregates in rat hippocampal CA1 neurons. High-resolution confocal microscopy demonstrated the presence of ubiquitin-positive protein aggregates surrounding nuclei and along dendrites. Western blotting revealed that levels of free ubiquitin were significantly reduced and that levels of ubiquitinated proteins were markedly increased in the hippocampus of CCH rats. Direct activity measurements revealed that proteasome peptidase activity in the hippocampal region of rats was decreased after CCH induction. These data suggest that reduced proteasome activity following CCH could impair the removal of abnormally folded proteins via the ubiquitin-proteasome pathway, leading to the accumulation of potentially toxic protein aggregates that could contribute to neurodegeneration.

Cognitive impairment and changes of neuronal plasticity in rats of chronic cerebral hypoperfusion associated with cerebral arteriovenous malformations.

A new rat model associated with cerebral arteriovenous malformations (AVMs) was developed to study the effect of chronic cerebral hypoperfusion on cognitive function and neuronal plasticity in rats. Aged-matched animals comprised a control group. Three months after surgery, Morris water waze test was performed to evaluate the cognitive function in rats. Neuronal plasticity was assessed by measuring the protein expression of MAP-2, GAP-43 and synaptophysin in the hippocampal regions of rats with immunohistochemistry and western blotting. The average time of escape latency was significantly longer in the model rats than that in the control rats, and both the time spent in the platform quadrant and the frequency of original platform crossing during space probe trials were less than those in the control animals. The expression levels of MAP-2 and synaptophysin protein in hippocampal areas in the model rats were less than those in the control rats. However there was no difference on the GAP-43 expression between the two groups. These data suggest that chronic cerebral hypoperfusion associated with AVMs could lead to cognitive impairment in rats, which may be partially explained by reduced expression of MAP-2 and synaptophysin at the protein level in the hippocampal area.

Quality of life with special respect to depression after surgical treatment of hypertensive basal ganglia hemorrhage.

BACKGROUND: Hypertensive intracerebral hemorrhage is associated with high mortality and morbidity. Place of surgery in the primary supratentorial intracerebral hemorrhage is uncertain and the data on the long-term functional outcome of surgery in these patients is limited. AIM: The aim of the study was to determine long-term functional outcome of patients undergoing surgical treatment for hypertensive basal ganglia hemorrhage, especially in respect to depression. STUDY DESIGN AND SETTINGS: Retrospective analysis of database of 44 patients undergoing craniotomy for hypertensive basal ganglia hemorrhage between December 2002 and May 2007. MATERIALS AND METHODS: Long-term was defined as at least 18 months after craniotomy. Neurological status of the patients at admission was assessed by National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS). Outcome data consisted of the items including functionality, depression and quality of life. Tests applied included Barthel Index (BI), modified Rankin Scale (mRS), Beck Depression Inventory (BDI) and stroke-specific quality of life (SSQOL) scale. RESULTS: The long-term mortality rate was 29.5% (13/44). Of the 31 survivors, 21 (67.7%) patients had a BI >or= 60, 23 (74.2%) patients had a mRS <4 and 21 (67.7%) patients had a SSQOL >or= 60%, each representing a favorable outcome. In retrospect, 19 (61.3%) patients approved the surgery. Eighteen (58.1%) patients developed depression (BDI > 9), which was related to high NIHSS and low GCS score preoperatively, low BI, high mRS and low SSQOL postoperatively. CONCLUSIONS: The study reveals that depression is a common long-term complication after surgical treatment of hypertensive basal ganglion hemorrhage. Both the NIHSS and GCS scores before operation have critical roles in patient's quality of life associated with depression.

Cognitive dysfunction induced by chronic cerebral hypoperfusion in a rat model associated with arteriovenous malformations.

The relationship between chronic cerebral hypoperfusion and cognitive function has not been completely delineated. In the present studies, we developed an experimental model associated with arteriovenous malformation to investigate the effects of chronic cerebral hypoperfusion on cognitive function and neuropathological changes. The rat model was established by creating a fistula through an end-to-side anastomosis between the right distal external jugular vein and the ipsilateral common carotid artery, followed by ligation of the left vein draining the transverse sinus and bilateral external carotid arteries. Age-matched rats comprised a control group. Three months after surgery, cognitive functions were evaluated by the Morris water maze and hippocampal long-term potentiation (LTP). Neuropathological changes were examined using light and electron microscopic techniques. We found that both learning capacity and spatial memory were significantly impaired in rats with chronic cerebral hypoperfusion concomitant with LTP inhibition and neurodegeneration in the hippocampal CA1 region of model rats compared with control rats. In addition, model rats showed a decrease at the protein level of cyclic AMP response element binding (CREB) phosphorylation in hippocampal tissues. Therefore, cognitive impairment caused by chronic cerebral hypoperfusion associated with arteriovenous malformations may be partially explained by the neurodegeneration and reduction of CREB phosphorylation in rat hippocampus.