Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal tract associated with high rates of malignant transformation. Most GISTs present asymptomatically. They are best identified by computed tomography (CT) scan and most stain positive for CD117 (C-Kit), CD34, and/or DOG-1. There have been many risk stratification classifications systems which are calculated based on tumor size, mitotic rate, location, and perforation. The approaches to treating GISTs are to resect primary low-risk tumors, resect high-risk primary or metastatic tumors with imatinib 400 mg daily for 12 months, or if the tumor is unresectable, neoadjuvant imatinib 400 mg daily followed by surgical resection is recommended. Sunitinib is required for KIT exon 9, 13, and 14 mutations, while ponatinib is used for exon 17 mutations and regorafenib for highly refractory tumors. High-risk tumors should be monitored for recurrence with serial abdominal CT scans. Radiofrequency ablation has shown to be effective when surgery is not suitable. Newer therapies of ipilimumab, nivolumab, and endoscopic ultrasound alcohol ablation have shown promising results. This report addresses the epidemiology, clinical presentation, diagnostic imaging, histologic diagnosis, classification and risk stratification, staging and grading, surgical treatment, adjuvant treatment, and metastasis of GISTs.

/pdf/gastrointestinal-stromal-tumors-a-comprehensive-review-59jewifayd.pdf

Gastrointestinal stromal tumors: a comprehensive review.

Frailty, an age-related condition of increased vulnerability to acute endogenous or exogenous stressors, is a key barrier to successful treatment of cancer in older people. In this group of patients, assessment of frailty is required before starting a new treatment. According to guidelines, the gold standard to assess frailty in older adults with cancer is geriatric screening followed by geriatric assessment (GA) across essential GA-domains (social status, physical function, nutrition, cognition, emotion, co-morbidity, polypharmacy). GA enables tailoring of both oncological therapy and non-oncological interventions to the patient's vulnerabilities. Large clinical trials recently have demonstrated that the feasibility and tolerability of systemic cancer treatment in older patients are significantly improved by such GA-guided management. Indications and optimal tools for frailty monitoring during the course of cancer treatment have not yet been defined in greater detail. New technologies such as wearable sensors or apps offer promising new opportunities to further develop frailty monitoring. This review describes the current standards and perspectives for the assessment and monitoring of frailty in elderly patients with cancer. 

/pdf/frailty-and-cancer-current-perspectives-on-assessment-and-3p1yidqi.pdf

Frailty and Cancer: Current Perspectives on Assessment and Monitoring

https://escholarship.org/content/qt391190g0/qt391190g0.pdf?t=qaewdh

Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations.

Background The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. Objective The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Methods Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. Results In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. Conclusion In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome.

INTRODUCTION AND PURPOSE
In gall bladder cancers, even after curative surgery, survivals are dismal and loco-regional failure accounts for 40-86%. Although these are considered radio-resistant, adjuvant radiation, with or without chemotherapy, has been tried to improve loco-regional control and overall survival rates. With an aim to evaluate the natural history of gall bladder cancers, role of radiation therapy (RT) and prognostication, a retrospective analysis was undertaken.


MATERIALS AND METHODS
Between 1991-2000, 60 patients with gall bladder cancer, treated with radical intent, were evaluated. Patients details including history, physical examination, liver function tests, ultrasonography of the abdomen and chest X-ray; and CT scan Abdomen if done, were noted. In patients who underwent surgery, surgical details, histopathology and pathological staging, were recorded. The details of post-operative adjuvant treatment, including radiation therapy details, as well as chemotherapeutic agents, number of cycles and type of infusion [bolus/infusion], were noted.


RESULTS
Sixty patients underwent surgery. On histopathological staging, 28 patients (46.5%) had stage II, 19 (32%) had stage III, 12 (20%) had stage-I and 1 patient had stage IV disease. Thirteen (21%) patents did not receive any adjuvant treatment, 32 (53%) patients received adjuvant RT alone, 8(14%) received post-operative CT+RT and 7 (12%) patients received CT alone. With a median follow-up of 18 months (12-124 months), 27 (45%) patients were disease free, 11 (19%) had local failures, 7 (11%) had loco-regional, 7 (11%) loco-regional+distant, 4 (7%) distant and 4 (7%) patients had local+distant failures. The Overall Disease Free Survival (DFS) and overall survival was 30% and 25%, at 5 years, respectively. Stage grouping ('P' = 0.007), Pathological T ('P' = 0.01) had significant impact on DFS on univariate analysis, where as histological grade ('P' = 0.06) showed trend towards significance.


CONCLUSION
Gall bladder cancers are aggressive and lethal. Early diagnosis and curative surgery, followed by appropriate adjuvant radiation therapy, may improve survivals, with no established consensus till date. Following curative surgery, pathological T stage and stage grouping, are the significant prognostic factors for outcome.

Original Article - Adjuvant radiation therapy in gall bladder cancers: 10 years experience at Tata Memorial Hospital

IMPORTANCE The Cancer Aging Research Group (CARG) toxicity score is used to assess toxicity risk in geriatric patients receiving chemotherapy. OBJECTIVE The primary aim was to validate the CARG score in geriatric patients treated with curative intent chemotherapy in predicting grade 3-5 toxicities. DESIGN This was a longitudinal prospective observational study. SETTING Tata Memorial Hospital, Mumbai, India, a tertiary cancer care referral centre. PARTICIPANTS Patients, aged ≥65 years, with gastrointestinal, breast or gynaecological stage I-III cancers being planned for curative intent chemotherapy. A total of 270 patients were required for accrual in the study. EXPOSURES Total risk score ranged from 0 (lowest toxicity risk) to 19 (highest toxicity risk). MAIN OUTCOMES AND MEASURES The primary endpoint of the study was to evaluate whether the CARG risk score predicted for grade 3-5 toxicities. RESULTS The study cohort of 270 patients had a mean age of 69 (65-83) years, with the most common cancers being gastrointestinal (79%). Fifty-two per cent of patients had atleast one grade 3-5 toxicity. The risk of toxicity was increased with an increasing risk score (42% low risk, 51% medium risk and 79% high risk; p<0.001). There was no association between either Eastern Cooperative Oncology Group (ECOG) performance status (p=0.69) or age-adjusted Charlson Comorbidity Index (p=0.79) risk categories and grade 3-5 chemotherapy toxicities. CONCLUSIONS AND RELEVANCE This study validates the CARG risk score in predicting for grade 3-5 toxicities in geriatric oncology patients receiving curative intent chemotherapy and can be considered as the standard of care before planning chemotherapy in every elderly patient. TRIAL REGISTRATION NUMBER CTRI/2016/10/007357; Results.

https://bmjopen.bmj.com/content/bmjopen/11/6/e047376.full.pdf

Cancer Aging Research Group (CARG) score in older adults undergoing curative intent chemotherapy: a prospective cohort study.

Data on adjuvant chemotherapy with gemcitabine–cisplatin (GC) in resected gallbladder cancers (GBC) are scarce. Patients who underwent upfront curative resection for GBC from 2010 to 2016 were analyzed. Patients with stage II–III GBC treated with adjuvant GC were analyzed. A total of 242 patients were evaluated, of whom 125 patients received GC regimen as adjuvant chemotherapy. The median age was 50 years (range 31–74), majority were female (77.6%), and 37 patients (29.6%) had raised CA 19.9 levels at baseline. One hundred and thirteen patients (90.4%) underwent radical cholecystectomy with R0 resections. Median number of GC administered was 6, with completion rates of 84%. Toxicity data were comprehensively available for 110 patients, with common grade 3 and grade 4 being neutropenia (9.9%), fatigue (7.3%) and febrile neutropenia (3.6%), respectively. With a median follow-up of 36.88 months, 3-year RFS was 60.3%. Patients with stage II (28%; n = 35), stage IIIA (28%; n = 35) and stage IIIB GBC (44%; n = 55) had a 3-year OS of 91.9, 67 and 58.1% (p = 0.001), respectively. Patients with stage II–III GBC undergoing R0 resections receiving adjuvant GC have good tolerance, high completion rates and encouraging outcomes in a non-trial high GBC prevalence scenario.

Gemcitabine-cisplatin (GC) as adjuvant chemotherapy in resected stage II and stage III gallbladder cancers (GBC): a potential way forward.

Background: The exon 11 KIT mutant gastrointestinal stromal tumors (GIST) is a heterogeneous cohort with variable biological behavior based on different mutational subtypes. Methods: Patients with histologically prove n GIST with KIT exon 11 mutations were selected from a prospectively maintained database, and evaluated for clinical characteristics and event free survival (EFS). Patients were divided into mutations upstream to codon 557 (G1), mutations involving codon 557-558 (G2) and mutation downstream to codon 558 (G3). Results: A total of 90 patients satisfied the inclusion criteria for study. Substitutions, indels and duplications were seen in 23 patients. Deletions were seen in 67 patients, of which 44 patients had large deletions (>6 base pairs), while 23 has small deletions ( vs . 55 months), but this did not achieve statistical significance (univariate analysis: P=0.075). On multivariate analysis, patients undergoing radical intent surgery vs . no surgery (58 vs . 55 months; P=0.005) and G1 or G3 vs . G2 cohort (P=0.058) showed trend towards improved EFS. Conclusions: In patients with GIST exon 11 codon 557-558 mutation subset there is a trend towards an inferior survival even when treated with Imatinib mesylate (IM).

/pdf/early-outcomes-of-exon-11-mutants-in-gist-treated-with-4nfpssr0rq.pdf

Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

Background Evidence suggests that intestinal type (IT) and pancreatobiliary (PB) subtypes of ampullary adenocarcinoma (AC) may have different outcomes. The current study evaluated differences in outcomes between these subtypes and the benefit of adjuvant chemotherapy (AT). Methods A prospectively maintained database of patients who underwent upfront resection for AC from January 2012 to March 2016 was conducted. A dedicated pathologist reported differentiation between IT and PB subtypes. Results 214 patients were included for analysis: 105 PB subtype and 109 IT subtype. With a median follow up of 46.3 months, estimated 4 year overall survival (OS) was 65.8%. In patients with stage II–III disease, lymph-node ratio (LNR)  Conclusions AC-IT and AC-PB did not have a different OS when treated with resection and adjuvant gemcitabine, though adjuvant therapy benefitted both subtypes individually.

Clinico-pathological correlates and survival outcomes in 214 resected ampullary adenocarcinomas - are outcomes different in intestinal and pancreatobiliary subtypes with adjuvant gemcitabine?

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Cancer Aging Research Group (CARG) score in older adults undergoing curative intent chemotherapy: a prospective cohort study.

Gemcitabine-cisplatin (GC) as adjuvant chemotherapy in resected stage II and stage III gallbladder cancers (GBC): a potential way forward.

Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

Clinico-pathological correlates and survival outcomes in 214 resected ampullary adenocarcinomas - are outcomes different in intestinal and pancreatobiliary subtypes with adjuvant gemcitabine?