Standard Chemoradiation Research Articles

Magnetic resonance imaging features of tumor and lymph node to predict clinical outcome in node-positive cervical cancer: a retrospective analysis

BackgroundCurrent chemoradiation regimens for locally advanced cervical cancer are fairly uniform despite a profound diversity of treatment response and recurrence patterns. The wide range of treatment responses and prognoses to standardized concurrent chemoradiation highlights the need for a reliable tool to predict treatment outcomes. We investigated pretreatment magnetic resonance (MR) imaging features of primary tumor and involved lymph node for predicting clinical outcome in cervical cancer patients.MethodsWe included 93 node-positive cervical cancer patients treated with definitive chemoradiotherapy at our institution between 2006 and 2017. The median follow-up period was 38 months (range, 5–128). Primary tumor and involved lymph node were manually segmented on axial gadolinium-enhanced T1-weighted images as well as T2-weighted images and saved as 3-dimensional regions of interest (ROI). After the segmentation, imaging features related to histogram, shape, and texture were extracted from each ROI. Using these features, random survival forest (RSF) models were built to predict local control (LC), regional control (RC), distant metastasis-free survival (DMFS), and overall survival (OS) in the training dataset (n = 62). The generated models were then tested in the validation dataset (n = 31).ResultsFor predicting LC, models generated from primary tumor imaging features showed better predictive performance (C-index, 0.72) than those from lymph node features (C-index, 0.62). In contrast, models from lymph nodes showed superior performance for predicting RC, DMFS, and OS compared to models of the primary tumor. According to the 3-year time-dependent receiver operating characteristic analysis of LC, RC, DMFS, and OS prediction, the respective area under the curve values for the predicted risk of the models generated from the training dataset were 0.634, 0.796, 0.733, and 0.749 in the validation dataset.ConclusionsOur results suggest that tumor and lymph node imaging features may play complementary roles for predicting clinical outcomes in node-positive cervical cancer.

The cortisol level, depression anxiety stress score, and quality of life in patient with advance stage cervical cancer after two years of psychorative intervention

Background: Cervical cancer is the second most cancer in women after breast cancer. Emotional stress is the most common comorbid attacking women with advanced-stage cervical cancer, where 13- 40% are depressed which can increase mortality by 39%. Management of cervical cancer has so far focused on standard chemoradiation treatment, but has paid less attention to other aspects such as cognitive, psychological, spiritual and physical. The study aims to determine cortisol levels, Depression Anxiety Stress (DAS) score and quality of life for patients with advanced-stage cervical cancer after two years of psychocurative interventionMethods: The pretest-posttest group design experimental study, continued previous studies, 30 subjects with advanced-stage cervical cancer patients, divided into 15 subjects received standard and psychocurative treatments, the other 15 as controls only received standard therapy. Psychocurative is done independently three times a week for two years based on psychocurative smart books. Home visits are conducted once per week to monitor, motivate the subject to do the psychocurative independently properly and discipline. Cortisol levels, DAS scores and quality of life were measured before and after treatment, the data were analysed by paired t-tests in the SPSS 25 program.Results: One control group subject died before the study was completed. Before and after psychocurative, cortisol levels in the treatment group were 12.29 ± 4.36 and 6.71 ± 3.88 with p<0.05. The Depressive scores were 14.13 ± 3.02 and 8.46 ± 3.07 with p<0.05. The Anxiety scores 12.13 ± 1.64 and 6.73 ± 2.40 with p<0.05. The Stress scores were 14.40 ± 2.64 and 7.27 ± 2.81 with p<0.05. The quality of life score of the physical domain were 55.00 ± 6.54 and 62.67 ± 8.63 with p <0.05. The Psychical domain was 57.00 ± 9.41 and 65.66 ± 8.42 with p <0.05. The Social domain was 33.67 ± 9.15 and 41.67 ± 10.29 with p <0.05. The Environmental domain was 63.00 ± 1.93 and 69.33 ± 7.76 with p <0.05Conclusions: Psychocurative decreases serum cortisol levels, decreases depression, anxiety, and stress scores and improves the quality of life of the physical, psychological, social and environmental domains.

Induction Chemotherapy in Patients With Anal Canal Cancer: A Pilot Study

PurposeTo investigate the role of induction chemotherapy (IC) followed by definitive chemoradiotherapy in people with anal canal cancer with bulky disease at diagnosis. Patients and MethodsWe assessed patient acceptability and treatment feasibility of IC in patients with bulky anal canal malignant lesions. ResultsTheoretical IC advantages may include tumor downsizing and early micrometastasis eradication, without affecting compliance with subsequent standard chemoradiotherapy regimens, as a result of improvement of oxygenation and higher intramural concentration of cytotoxic drugs. ConclusionThe study design should be proven feasible, with a satisfactory patient acceptance rate and an optimized work flow. To our knowledge, this study is the first trial to investigate the use of IC in the population of patients with bulky anal canal cancer.

Cancer Imaging Phenomics via CaPTk: Multi-Institutional Prediction of Progression-Free Survival and Pattern of Recurrence in Glioblastoma.

PURPOSETo construct a multi-institutional radiomic model that supports upfront prediction of progression-free survival (PFS) and recurrence pattern (RP) in patients diagnosed with glioblastoma multiforme (GBM) at the time of initial diagnosis.PATIENTS AND METHODSWe retrospectively identified data for patients with newly diagnosed GBM from two institutions (institution 1, n = 65; institution 2, n = 15) who underwent gross total resection followed by standard adjuvant chemoradiation therapy, with pathologically confirmed recurrence, sufficient follow-up magnetic resonance imaging (MRI) scans to reliably determine PFS, and available presurgical multiparametric MRI (MP-MRI). The advanced software suite Cancer Imaging Phenomics Toolkit (CaPTk) was leveraged to analyze standard clinical brain MP-MRI scans. A rich set of imaging features was extracted from the MP-MRI scans acquired before the initial resection and was integrated into two distinct imaging signatures for predicting mean shorter or longer PFS and near or distant RP. The predictive signatures for PFS and RP were evaluated on the basis of different classification schemes: single-institutional analysis, multi-institutional analysis with random partitioning of the data into discovery and replication cohorts, and multi-institutional assessment with data from institution 1 as the discovery cohort and data from institution 2 as the replication cohort.RESULTSThese predictors achieved cross-validated classification performance (ie, area under the receiver operating characteristic curve) of 0.88 (single-institution analysis) and 0.82 to 0.83 (multi-institution analysis) for prediction of PFS and 0.88 (single-institution analysis) and 0.56 to 0.71 (multi-institution analysis) for prediction of RP.CONCLUSIONImaging signatures of presurgical MP-MRI scans reveal relatively high predictability of time and location of GBM recurrence, subject to the patients receiving standard first-line chemoradiation therapy. Through its graphical user interface, CaPTk offers easy accessibility to advanced computational algorithms for deriving imaging signatures predictive of clinical outcome and could similarly be used for a variety of radiomic and radiogenomic analyses.

Estrogen Attenuates the Growth of Human Papillomavirus-Positive Epithelial Cells.

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that are significant risk factors in the development of cancer, and HPV accounts for approximately 5% of all worldwide cancers. Recent studies using data from The Cancer Genome Atlas (TCGA) have demonstrated that elevated levels of estrogen receptor alpha (ERα) are associated with improved survival in oropharyngeal cancers, and these elevated receptor levels were linked with human papillomavirus-positive cancers (HPV+cancers). There has been a dramatic increase in HPV-related head and neck squamous cell carcinomas (HPV+HNSCCs) over the last 2 decades, and therapeutic options for this ongoing health crisis are a priority; currently, there are no antiviral therapeutics available for combatting HPV+cancers. During our TGCA studies on head and neck cancer, we had also discovered the overexpression of ERα in HPV+cancers. Here, we demonstrate that 17β-estradiol (estrogen) attenuates the growth/cell viability of HPV+cancers in vitro, but not HPV-negative cancer cells. In addition, N/Tert-1 cells (foreskin keratinocytes immortalized with human telomerase reverse transcriptase [hTERT]) containing human papillomavirus 16 (HPV16) have elevated levels of ERα and growth sensitivity after estrogen treatment compared with parental N/Tert-1 cells. Finally, we demonstrate that there are potentially two mechanisms contributing to the attenuation of HPV+ cell growth following estrogen treatment. First, estrogen represses the viral transcriptional long control region (LCR) downregulating early gene expression, including E6/E7. Second, expression of E6 and E7 by themselves sensitizes cells to estrogen. Overall, our results support the recent proposal that estrogen could be exploited therapeutically for the treatment of HPV-positive oral cancers.IMPORTANCE Human papillomaviruses cause around 5% of all human cancers, yet there are no specific antiviral therapeutic approaches available for combatting these cancers. These cancers are currently treated with standard chemoradiation therapy (CRT). Specific antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ERα) is overexpressed in HPV+HNSCC and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combatting HPV+cancers. Here, we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.

Comparison of neoadjuvant treatments followed by radical surgery or chemoradiation on quality of life in patients with stage IB2-IIA cervical cancer

ObjectiveTo compare quality of life (Qol) of patients with stage IB2-IIA cervical cancer treated by neoadjuvant treatments followed by radical surgery (NTS) or standard chemoradiation (CRT). MethodsPatients with stage IB2-IIA cervical cancer during 2006–2012 were treated with NTS or CRT and were invited to participate. The Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) Questionnaire was used to assess patient Qol. A multivariable linear regression analysis was performed to identify factors associated with Qol. ResultsIn total, 90 (78.3%) out of 115 eligible patients completed the questionnaires. No significant differences were found in Qol between treatment groups, except that patients after NTS reported higher scores in the social/family well-being (e.g. satisfaction with sexual life, close relationships with partner or friends, and support from friends) than those after CRT, in particular, during 2–3 years after treatment. Results of multivariate analysis indicated that NTS was associated with better social/family functioning, while advanced stage of cervical cancer, lower family income and lower education were associated with impaired Qol in different domains. ConclusionsAlthough self-reported Qol after treatment were not significantly different, NTS treated patients reported better social/family functioning than CRT treated patients, such as satisfaction with their sexual life and close relationships with partner or friends, during 2–3 years post treatment. These results were helpful for physicians to make treatment decisions while considering treatment-related Qol, and moreover, for rehabilitation and supportive care of patients after treatment. Further validation of our findings in randomized, controlled clinical trials is warranted.

Sequential chemotherapy followed by radical thoracic radiotherapy (50 Gy in 25 fractions) in limited stage small cell lung cancer.

IntroductionFor limited stage small cell lung cancer (LS-SCLC) where concurrent chemoradiotherapy is inappropriate due to tumour bulk, co-morbidities or performance status, sequential treatment using chemotherapy followed by radiotherapy is the standard of care. The outcomes are not well established; we assessed in a single institution, the survival of these patients, prognostic factors and compared to the limited existing literature.Materials and MethodRetrospective data was collected on all 59 patients diagnosed with LS-SCLC from 2011 to 2016 who received chemotherapy consisting of Carboplatin or Cisplatin + Etoposide followed by thoracic radiotherapy (50 Gy in 25 fractions) +/- prophylactic cranial irradiation (PCI).ResultsMedian age at diagnosis was 66 years (range 46–90). Patients received a median of four cycles of chemotherapy (range: 1–6) and all the patients completed a full course of radiotherapy with only one patient experiencing grade >2 radiation induced toxicity. With a median follow up of 20.6 months, 45 patients had died with a median survival of 20.6 months. 2-year overall survival (OS) rates were 42%. Age using a cut-off of 65 was prognostic (median OS 25.6 months ≤65 years versus 14.1 months >65 years, p = 0.013) but gender, stage and receipt of PCI were not.ConclusionsMost of the literature reporting outcome from sequential treatment in LS-SCLC is old and used a variety of radiotherapy regimens. Our data shows inferior outcomes to the gold standard concurrent chemoradiotherapy but support its usage in less fit patients with reasonable outcome observed.

Locally Advanced, Unresectable Non-Small Cell Lung Cancer.

Treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) has recently been revolutionized by the incorporation of immunotherapy to standard platinum-based concurrent chemoradiation. This review examines the current standard practices and ongoing studies on the management of locally advanced, unresectable NSCLC. Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC. However, chemoradiation can be associated with high therapy-related toxicities, and risk of disease relapse remains significantly elevated despite treatment with curative intent. Durvalumab, a PD-L1 inhibitor, was recently approved as consolidation therapy following concurrent chemoradiation; this agent represents a major advancement in treatment of unresectable stage III NSCLC. Several clinical trials are currently underway to evaluate the benefit of different immunotherapy sequencing and other biomarker-driven strategies in this disease setting. Multiple trials are presently ongoing to assess novel immunotherapy and targeted therapy strategies to improve outcomes and decrease treatment-associated toxicities in patients with locally advanced NSCLC.

Total Neoadjuvant Therapy in Rectal Cancer

The addition of induction chemotherapy to concomitant neoadjuvant chemoradiation in locally advanced rectal cancer could increase pathological downstaging and act on occult micrometastatic disease, leading ultimately to a better outcome. A systematic review was carried out of the existing literature on the treatment outcomes of total neoadjuvant therapy (TNT) on locally advanced rectal cancer. TNT was defined as chemotherapy using cycles of induction and/or consolidation in conjunction with standard chemoradiotherapy prior to surgery. A systematic search of PubMed, Embase, and the Cochrane Library was performed according to the PRISMA statement up until January 2019. The primary endpoints were complete pathologic response (pCR), disease-free survival, and overall survival rates. A total of 28 studies (3 retrospective and 25 prospective for a total of 3579 patients) were included in the final analysis (n = 2688 treated with TNT and n = 891 with neoadjuvant chemoradiotherapy therapy). The pooled pCR rate was 22.4% (95% CI 19.4%-25.7%) in all patients treated with TNT (n = 27 studies with data available). In n = 10 comparative studies with data available, TNT was found to increase the odds of pCR by 39% (1.40, 95% CI 1.08-1.81, P = 0.01). The addition of induction or consolidation chemotherapy to standard neoadjuvant chemoradiotherapy results in a higher pCR rate. Given that the comparative analysis was derived from few randomized publications, large confirmatory trials should be carried out before a strong recommendation is made in favor of TNT.

Regular aspirin intake and prognosis of TxN2-3M0 nasopharyngeal carcinoma: A cohort study based on propensity score matching

Distant metastasis is the leading cause of death in patients with N2-3 nasopharyngeal carcinoma (NPC). And aspirin is found to reduce metastasis and improve prognosis in some other malignancies, such as colorectal cancer. This study aimed to evaluate the clinical value of regular aspirin intake (RAI) in N2-3 NPC treated with standard chemoradiotherapy. Totally 2064 patients diagnosed with TxN2-3M0 NPC from Jan. 2008 to Dec. 2015 and treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy were involved. According to RAI, these patients were divided into 2 groups between which a propensity score matching was made, with a ratio of 1:3 and a series of clinical characteristics (age, gender, T stage, N stage and EBV DNA) as covariates. Then survivals and acute toxicities were compared in the 464 matched patients. RAI appeared to bring better overall (87.7% vs. 79.6%, P=0.031), metastasis-free (87.8% vs. 76.5%, P=0.017) and disease-free (85.9% vs. 75.5%, P=0.033) survivals. It simultaneously increased total incidences of myelosuppression (55.2% vs. 32.2%, P<0.001), oral mucositis (60.3% vs. 38.2%, P<0.001), cervical dermatitis (60.3% vs. 38.5%, P<0.001) and xerostomia (49.1% vs. 33.3%, P=0.002). But RAI failed to affect incidence of any grade 3/4 toxicity. Post-diagnosis RAI might be a tolerable approach to control distant metastasis and provide survival benefit for N2-3 NPC in combination with standard chemoradiotherapy.

Phase II study of trifluridine/tipiracil (FTD/TPI) and oxaliplatin as induction chemotherapy (IC) in resectable esophageal and gastroesophageal junction adenocarcinoma (EGAC).

TPS464 Background: Neoadjuvant chemoradiation (CRT) followed by surgery is a standard approach for localized EGAC. Despite multimodality treatment, 5-year overall survival (OS) is less than 50%, with pathologic complete response (pCR) rates of 20%. Achievement of pCR is associated with an improved OS. We propose to use a novel combination of FTD/TPI and oxaliplatin as IC. We hypothesize that IC before CRT will increase the pCR rate in localized EGAC. Methods: This is an open-label, multicenter phase II trial. Patients (pts) with potentially resectable loco-regional EGAC are eligible. Pts. should have adequate organ function, ECOG performance status of 0 –1, age &lt; 76 years, and endoscopic ultrasound-determined node-positive disease with any T-stage, or T3-T4a with any N stage. Pts. with T4b or M1 disease will be excluded. Pts. will receive three cycles of IC with FTD/TPI and oxaliplatin. Based on the maximum tolerated dose (MTD) observed in a phase I trial, FTD/TPI will be administered 35 mg/m² BID, days 1–5 every 14 days, with a fixed dose of oxaliplatin 85 mg/m² (day 1). Pts will then undergo concurrent CRT (standard radiation dose of 5040 cGY will be utilized) with weekly Carboplatin (AUC 2) and Paclitaxel (50 mg/m2) for 6 weeks followed by surgery. Our primary objective is to evaluate the pCR rate. The secondary objectives include evaluation of 2-year disease-free survival (DFS), 2-year OS, and assessment of toxicities of the IC. As a correlative endpoint, circulating tumor DNA level will be correlated with disease recurrence and metabolic response on PET CT. Assuming a historic pCR rate of 20% with standard CRT, 41 pts (enrollment of up to 45 pts accounting for non-evaluable pts) are needed to show a 15% increase in pCR with IC with 80% power at one-sided significance level of α = 0.1. In stage 1, n1= 22 evaluable pts will be enrolled. If there is 5 or more pCRs, an additional n2= 19 pts will be enrolled in stage 2. If 12 or more pCRs are observed in the total n = 41 evaluable pts, then the proposed treatment regimen will be considered promising for further study. We anticipate accrual over a 2-year period from 3 sites. Clinical trial information: NCT04097028.

NSABP FR-2: Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer.

TPS264 Background: Clinical improvements for locally advanced rectal cancer have been relatively static over the past few decades. While immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling with intent to proceed to surgical resection after CRT. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.

Chemoradiation in locally advanced Ca Cx: Effect on NGAL levels.

Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to be unregulated in many cancers and to suppress tumor suppressor genes like p53 leading to cell proliferation. Studies to report its relationship with carcinoma cervix (Ca Cx) are still scant. Serum NGAL levels were analyzed in 30 patients of histopathologically proven locally advanced Ca Cx at the time of diagnosis and 3 weeks after standard chemoradiation by enzyme-linked immunosorbent assay. These patients underwent either brachytherapy or supplementary external beam radiotherapy (EBRT) depending on the response of treatment. The results were analyzed statistically by applying Student's paired t-test. No statistically significant difference (P > 0.05) was observed in patients of Ca Cx before and after treatment or when compared stage wise, histopathological grade wise, or response wise. But the levels were found to increase when duration of treatment was ≥8 weeks (P = 0.040) and to decrease significantly when duration of treatment was <8 weeks (P = 0.0052). The NGAL levels also increased significantly after treatment in patients who received EBRT and supplementary radiotherapy (P = 0.019) while the pre- and post-treatment difference in NGAL levels was not statistically significant in patients who received EBRT + intracavitary brachytherapy (P > 0.05). As the duration as well as modality of treatment is quite important in Ca Cx, shorter duration associated with better results and lower NGAL levels, NGAL might prove to be a useful biomarker although further studies are needed to support the claim.

Survival after reoperation for recurrent glioblastoma

Determining which patients will benefit from reoperation for recurrent glioblastoma remains difficult and the impact of the volume of FLAIR signal hyperintensity is not well known. The primary purpose of this study is to analyze the impact of preoperative volume of FLAIR hyperintensity on prognosis. 37 patients who underwent a reoperation for recurrent glioblastoma after initial gross total resection followed by standard chemoradiation were retrospectively reviewed. Volumetric analysis of preoperative MR images from the initial and second surgery was performed and correlated with clinical data. Survival probabilities were estimated using the Kaplan-Meier method and Cox regression to assess the effect of risk factors on time to reoperation (TTR), progression-free survival (PFS) after reoperation, and overall survival (OS). The volumes of FLAIR signal hyperintensity prior to the initial surgery and reoperation were not associated with prognosis. TTR and OS were significantly affected by the preoperative enhancement volume at the initial surgery, with increasing volumes yielding poorer prognosis. Patients with tumor in critical/eloquent areas were found to have a worse prognosis. Median TTR was 11 months, median PFS after reoperation was 3 months, and OS in patients undergoing a reoperation was 21 months. The results suggest FLAIR signal change seen in patients with glioblastoma does not influence time to reoperation, progression-free survival, or overall survival. These findings suggest the amount of FLAIR signal change should not greatly influence a surgeon’s decision to perform a second surgical resection compare to other factors, and when appropriate, aggressive surgical intervention should be considered.

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

BackgroundGlioblastoma (GBM) is a highly malignant brain neoplasm with poor survival. Despite its aggressive nature, metastatic spread of GBM is identified only rarely. While the molecular alterations associated with GBM and its subtypes are well-described, there remains a gap in understanding which alterations may predispose towards metastasis. In this report, we present a case of GBM with multi-organ metastases and discuss its genomic alterations.Case presentationA 74-year-old woman was diagnosed with left occipital glioblastoma (IDH-wildtype, MGMT-unmethylated), for which she underwent resection, standard chemoradiation, and then stereotactic radiosurgery (SRS) for local recurrence. One month after SRS, work-up for a pathologic hip fracture revealed a left breast mass, lytic lesions involving pelvic bones, and multiple pulmonary and hepatic lesions. Biopsies of the breast and bone lesions both demonstrated metastatic IDH-wildtype GBM. For worsening neurologic symptoms, the patient underwent debulking of a large right temporal lobe recurrence and expired shortly thereafter. Autopsy confirmed metastatic GBM in multiple systemic sites, including bilateral lungs, heart, liver, thyroid, left breast, small bowel, omentum, peritoneal surfaces, visceral surfaces, left pelvic bone, and hilar lymph nodes. Targeted sequencing was performed on tissue samples obtained pre- and postmortem, as well as on cell cultures and an orthotopic mouse xenograft derived from premortem surgical specimens. A BRCA1 mutation (p.I571T) was the only variant found in common among the primary, recurrence, and metastatic specimens, suggesting its likely status as an early driver mutation. Multiple subclonal ARID1A mutations, which promote genomic instability through impairment of DNA mismatch repair, were identified only in the recurrence. Mutational spectrum analysis demonstrated a high percentage of C:G to T:A transitions in the post-treatment samples but not in the primary tumor.ConclusionThis case report examines a rare case of widely metastatic IDH-wildtype GBM with a clonal somatic mutation in BRCA1. Post-treatment recurrent tumor in the brain and in multiple systemic organs exhibited evidence of acquired DNA mismatch repair deficiency, which may be explained by functional loss of ARID1A. We identify a potential role for immune checkpoint and PARP inhibitors in the treatment of metastatic GBM.

Locally Advanced Rectal Cancer: Treatment Approach in Elderly Patients.

Independently of age, evidence-based guidelines recommend a multidisciplinary treatment approach in patients with locally advanced rectal cancer (LARC). But actually, elderly patients are grossly underrepresented in clinical trials, accounting < 10% of enrolled cases. Therefore, LARC management in elderly patients remains a crucial issue in daily practice, especially due to their frailty. Multiple clinical factors, including general health status, cognitive status, co-morbidity, disability, and life expectancy should be considered to understand the complexities of geriatric assessment and then define therapy. We use a patient-centered approach in order to tailor the optimal treatment strategy. We treat fit elderly patients as younger patients, including neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy. Whereas, in vulnerable and frail patients, we propose standard CRT (vulnerable patients) or radiotherapy alone (frail patients).

Effect of chemoradiotherapy on anti-tumor immunity of glioblastoma patients and treatment enlightement

Glioblastoma (GBM) is the most malignant primary brain tumor, and it has very poor prognosis. In recent years, the immunotherapy has become a hot issue in the treatment of malignancies. The traditional treatment regimen combined with immunotherapy might make a progress in the diagnosis and treatment of GBM. This paper reviews the explanation of the traditional chemoradiotherapy affecting the body's anti-tumor and immunity mechanism, and the current achievement of standard chemoradiotherapy combined with immunotherapy, to explore the potential benefits to GBM patients. Key words: Glioblastoma; Immunotherapy; Drug therapy, combination; Radiotherapy

Postoperative standard chemoradiotherapy benefits primary glioblastoma patients of all ages.

BackgroundGlioblastoma is the most malignant tumor of the central nervous system. Several prediction models have been produced to aid in prognosis assessment. Age, a primary decision factor for prognosis, is associated with increased genomic alterations, however the exact link between increased age and poor prognosis is unknown.ObjectiveIn this study, we aimed to reveal the underlying cause of poor prognosis in elderly patients.MethodsThis study included data on 616 primary GBM tumor samples from the CGGA and TCGA databases and 41 nontumor brain tissue samples obtained from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53890. Hallmarks and clinicopathological characteristics were evaluated in both tumor and nontumor brain tissues. The association between choice of treatment regimen and age was measured using ANOVA and Student's t test.ResultsAge was a robust predictor of poor prognosis in glioma. No age‐related hallmarks of cancer were detected, including pathological characteristics or mutations. However, treatment choice was strongly significantly different between old and young patients. Combined chemo‐radiation therapy could benefit old and young GBM patients, however, old patients are currently less likely to choose it.ConclusionThe vast divergence in prognosis between young and old GBM patients is largely caused by choice of treatment rather than age‐related tumor genomic characteristics. Postoperative standard radio‐ and chemotherapy provide strong benefits to primary glioblastoma patients of all ages.

ANGI-01 ALTERATION IN IMMUNE REGULATORY CELLS BEFORE AND AFTER TREATMENT BY STUPP REGIMEN WITH OR WITHOUT BEVACIZUMAB FOR GLIOBLASTOMA

BACKGROUNDIn our previous study, bevacizumab (Bev), a humanized anti- vascular endothelial growth factor monoclonal antibody, downregulated the expression of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint molecules, suppressed the infiltration of immunosuppressing cells such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and induces cytotoxic T lymphocytes (CTL) infiltration. To explore the possibility that inhibition of immunosuppressive cell infiltration and induction of CTL were attributed to not only Bev alone but also radiation (RT) or temozolomide (TMZ), we re-evaluated those alterations in the tumor tissue obtained from patients before and after the treatment using Stupp regimen (RT concomitant with TMZ) without Bev therapy.MATERIALS & METHODSWe analyzed 10 tumor tissues from 5 patients with GBMs, which were paired samples of pre- and post- standard chemoradiotherapy (Stupp regimen: RT plus concomitant and adjuvant TMZ). Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue of 10 tumors. The sections were stained with anti-Ki-67, anti-VEGF-A, anti-VEGFR1, anti-VEGFR2, anti-CD34, anti-HIF1 alpha, anti-CA9, anti-nestin, anti-PD-1, anti-PD-L1, anti-CD4, anti-CD8, anti-Foxp3, and anti-CD163 antibodies. All expressions were assessed by authors with blinded clinical information.RESULTSImmunohistochemical analyses demonstrated that the expression levels of immune regulatory molecules such as Foxp3, CD163, PD-1, PD-L1, CD4, and CD8 were not significantly changed after the treatment using the Stupp regimen, compared with combinational usage of Bev. In addition, expressions of VEGF/VEGFR, hypoxic markers, and stem cell marker were not altered before and after Stupp regimen, either. Bev persistently inhibited immune suppressive cells and immune checkpoint molecules via down-regulation of VEGF pathway. In contrast, Stupp regimen did not affect immune regulations and tumor microenvironment.CONCLUSIONThese results suggested that immunosupportive effect was caused by Bev administration, leading to the novel combinational treatment strategies, in addition to Stupp regimen.

IMT-05 PHASE III RANDOMIZED CLINICAL TRIAL OF AFTV FOR NEWLY DIAGNOSED GLIOBLASTOMA

BACKGROUNDThe highly fatal glioblastoma has an extremely poor prognosis and development of a new treatment is desired. Local treatment is limited due to its high invasiveness, and immunotherapy utilizing self-immune mechanism is theoretically expected. An autologous formalin-fixed tumor vaccine (AFTV) is a vaccine that is prepared using formalin-fixed tumor tissue and recognizes tumor antigen peptides to induce cytotoxic T cells. We have previously conducted three clinical trials using AFTV for patients with newly diagnosed glioblastoma since 2004. The third trial was a double-blind multicenter phase IIb/III trial with 63 case registries, which did not make a significant difference in OS (study group 25 months, placebo group 31 months), the total removal group showed excellent clinical results (3-year survival rate; 65%, median survival; not reached). Since the study was designed to go to Phase III if the test group was not inferior to the placebo group, so it went on to go to Phase III.METHODSTarget patients will be 80 patients with newly diagnosed glioblastoma undergoing pathologic diagnosis, who have undergone total removal of contrast-enhanced lesions and receive standard chemoradiation therapy.STUDY DESIGNDouble-blind, 3-year enrollment period, 18-month observation period. Stratification factor: Photodynamic therapy (PDT), facility, age, KPS. Administration method: After standard chemoradiotherapy, in parallel with maintenance chemotherapy, a total of 9 times intradermal administration of vaccine. Primary endpoint: PFS of FAS patients, Secondary endpoints: 18 months PFS of the FAS patient, OS, PFS of the ITT analysis target case. Based on the results of the IIb trial, we limited the registered patients with total tumor removal, and in view of the fact that the prognosis of patients with combined PDT and AFTV were excellent, PDT was added to the stratification factor. We outline our efforts and problems aimed at clinical approval of AFTV for glioblastoma.