Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

A systematic scoping review of group reflection in medical education.

BACKGROUND: Reviewing experiences and recognizing the impact of personal and professional views and emotions upon conduct shapes a physician's professional and personal development, molding their professional identity formation (PIF). Poor appreciation on the role of reflection, shortages in trained tutors and inadequate 'protected time' for reflections in packed medical curricula has hindered its integration into medical education. Group reflection could be a viable alternative to individual reflections; however, this nascent practice requires further study. METHODS: A Systematic Evidence Based Approach guided Systematic Scoping Review (SSR in SEBA) was adopted to guide and structure a review of group reflections in medical education. Independent searches of articles published between 1st January 2000 and 30th June 2022 in bibliographic and grey literature databases were carried out. Included articles were analysed separately using thematic and content analysis, and combined into categories and themes. The themes/categories created were compared with the tabulated summaries of included articles to create domains that framed the synthesis of the discussion. RESULTS: 1141 abstracts were reviewed, 193 full-text articles were appraised and 66 articles were included and the domains identified were theories; indications; types; structure; and benefits and challenges of group reflections. CONCLUSIONS: Scaffolded by current approaches to individual reflections and theories and inculcated with nuanced adaptations from other medical practices, this SSR in SEBA suggests that structured group reflections may fill current gaps in training. However, design and assessment of the evidence-based structuring of group reflections proposed here must be the focus of future study.

Mentoring as a complex adaptive system - a systematic scoping review of prevailing mentoring theories in medical education.

BACKGROUND: Effective mentorship is an important component of medical education with benefits to all stakeholders. In recent years, conceptualization of mentorship has gone beyond the traditional dyadic experienced mentor-novice mentee relationship to include group and peer mentoring. Existing theories of mentorship do not recognize mentoring's personalized, evolving, goal-driven, and context-specific nature. Evidencing the limitations of traditional cause-and-effect concepts, the purpose of this review was to systematically search the literature to determine if mentoring can be viewed as a complex adaptive system (CAS). METHODS: A systematic scoping review using Krishna's Systematic Evidence-Based Approach was employed to study medical student and resident accounts of mentoring and CAS in general internal medicine and related subspecialties in articles published between 1 January 2000 and 31 December 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles underwent thematic and content analysis, with the themes identified and combined to create domains, which framed the discussion. RESULTS: Of 5,704 abstracts reviewed, 134 full-text articles were evaluated, and 216 articles were included. The domains described how mentoring relationships and mentoring approaches embody characteristics of CAS and that mentorship often behaves as a community of practice (CoP). Mentoring's CAS-like features are displayed through CoPs, with distinct boundaries, a spiral mentoring trajectory, and longitudinal mentoring support and assessment processes. CONCLUSION: Recognizing mentorship as a CAS demands the rethinking of the design, support, assessment, and oversight of mentorship and the role of mentors. Further study is required to better assess the mentoring process and to provide optimal training and support to mentors.

Professional identity formation amongst peer-mentors in a research-based mentoring programme.

BACKGROUND: Mentoring plays a pivotal yet poorly understood role in shaping a physician's professional identity formation (PIF) or how they see, feel and act as professionals. New theories posit that mentoring nurtures PIF by functioning as a community of practice through its structured approach and its support of a socialisation process made possible by its assessment-directed personalized support. To test this theory and reshape the design, employ and support of mentoring programs, we evaluate peer-mentor experiences within the Palliative Medicine Initiative's structured research mentoring program. METHODS: Semi-structured interviews with peer mentors under the Palliative Medicine Initiative (PMI) at National Cancer Centre Singapore were conducted and triangulated against mentoring diaries to capture longitudinal data of their PMI experiences. The Systematic Evidence-Based Approach (SEBA) was adopted to enhance the trustworthiness of the data. SEBA employed concurrent content and thematic analysis of the data to ensure a comprehensive review. The Jigsaw Perspective merged complementary themes and categories identified to create themes/categories. The themes/categories were compared with prevailing studies on mentoring in the Funnelling Process to reaffirm their accuracy. RESULTS: Twelve peer-mentors participated in the interviews and eight peer-mentors completed the mentoring diaries. The domains identified were community of practice and identity work. CONCLUSIONS: The PMI's structured mentoring program functions as a community of practice supporting the socialisation process which shapes the peer-mentor's belief system. Guided by a structured mentoring approach, stage-based assessments, and longitudinal mentoring and peer support, peer-mentors enhance their detection and evaluation of threats to their regnant belief system and adapt their self-concepts of identity and personhood to suit their context. These insights will help structure and support mentoring programs as they nurture PIF beyond Palliative Medicine.

Assessing the effects of a mentoring program on professional identity formation.

BACKGROUND: Medical education has enjoyed mixed fortunes nurturing professional identity formation (PIF), or how medical students think, feel and act as physicians. New data suggests that structured mentoring programs like the Palliative Medicine Initiative (PMI) may offer a means of developing PIF in a consistent manner. To better understand how a well-established structured research mentoring program shapes PIF, a study of the experiences of PMI mentees is proposed. METHODOLOGY: Acknowledging PIF as a sociocultural construct, a Constructivist approach and Relativist lens were adopted for this study. In the absence of an effective tool, the Ring Theory of Personhood (RToP) and Krishna-Pisupati Model (KPM) model were used to direct this dual Systematic Evidence-Based Approach (Dual-SEBA) study in designing, employing and analysing semi-structured interviews with PMI mentees and mentoring diaries. These served to capture changes in PIF over the course of the PMI's mentoring stages. Transcripts of the interviews and mentoring diaries were concurrently analysed using content and thematic analysis. Complementary themes and categories identified from the Split Approach were combined using the Jigsaw Approach and subsequently compared with mentoring diaries in the Funnelling Process. The domains created framed the discussion. RESULTS: A total of 12 mentee interviews and 17 mentoring diaries were analysed, revealing two domains-PMI as a Community of Practice (CoP) and Identity Formation. The domains confirmed the centrality of a structured CoP capable of facilitating longitudinal mentoring support and supporting the Socialisation Process along the mentoring trajectory whilst cultivating personalised and enduring mentoring relationships. CONCLUSION: The provision of a consistent mentoring approach and personalised, longitudinal mentoring support guided along the mentoring trajectory by structured mentoring assessments lay the foundations for more effective mentoring programs. The onus must now be on developing assessment tools, such as a KPM-based tool, to guide support and oversight of mentoring relationships.

A systematic scoping review of reflective writing in medical education.

BACKGROUND: Reflective writing (RW) allows physicians to step back, review their thoughts, goals and actions and recognise how their perspectives, motives and emotions impact their conduct. RW also helps physicians consolidate their learning and boosts their professional and personal development. In the absence of a consistent approach and amidst growing threats to RW's place in medical training, a review of theories of RW in medical education and a review to map regnant practices, programs and assessment methods are proposed. METHODS: A Systematic Evidence-Based Approach guided Systematic Scoping Review (SSR in SEBA) was adopted to guide and structure the two concurrent reviews. Independent searches were carried out on publications featured between 1st January 2000 and 30th June 2022 in PubMed, Embase, PsychINFO, CINAHL, ERIC, ASSIA, Scopus, Google Scholar, OpenGrey, GreyLit and ProQuest. The Split Approach saw the included articles analysed separately using thematic and content analysis. Like pieces of a jigsaw puzzle, the Jigsaw Perspective combined the themes and categories identified from both reviews. The Funnelling Process saw the themes/categories created compared with the tabulated summaries. The final domains which emerged structured the discussion that followed. RESULTS: A total of 33,076 abstracts were reviewed, 1826 full-text articles were appraised and 199 articles were included and analysed. The domains identified were theories and models, current methods, benefits and shortcomings, and recommendations. CONCLUSIONS: This SSR in SEBA suggests that a structured approach to RW shapes the physician's belief system, guides their practice and nurtures their professional identity formation. In advancing a theoretical concept of RW, this SSR in SEBA proffers new insight into the process of RW, and the need for longitudinal, personalised feedback and support.

A systematic scoping review on patients' perceptions of dignity.

BACKGROUND: A socioculturally appropriate appreciation of dignity is pivotal to the effective provision of care for dying patients. Yet concepts of dignity remain poorly defined. To address this gap in understanding and enhance dignity conserving end-of-life care, a review of current concepts of dignity is proposed. METHODS: To address its primary research question "How do patients conceive the concept of dignity at the end of life?", this review appraises regnant concepts and influences of dignity, and evaluates current dignity conserving practices. To enhance accountability, transparency and reproducibility, this review employs the Ring Theory of Personhood (RToP) as its theoretical lens to guide a Systematic Evidence Based Approach guided Systematic Scoping Review (SSR in SEBA) of patient perspectives of dignity. Three independent teams of reviewers independently analysed included articles from a structured search of PubMed, Embase, PsycINFO, Scopus, CINAHL and Cochrane Databases using thematic and content analyses. The themes and categories identified were compared and combined using the Funnelling Process to create domains that guide the discussion that follows. RESULTS: Seventy-eight thousand five hundred seventy-five abstracts were identified, 645 articles were reviewed, and 127 articles were included. The three domains identified were definitions of dignity, influences upon perceptions of dignity, and dignity conserving care. CONCLUSIONS: This SSR in SEBA affirms the notion that dignity is intimately entwined with self-concepts of personhood and that effective dignity conserving measures at the end of life must be guided by the patient's concept of dignity. This SSR in SEBA posits that such personalised culturally sensitive, and timely support of patients, their family and loved ones may be possible through the early and longitudinal application of a RToP based tool.

Clinicopathologic Characteristics and Survival of Patients with Gastroenteropancreatic Neuroendocrine Neoplasm in a Multi-Ethnic Asian Institution.

BACKGROUND: Epidemiological evidence suggests there are differences in gastroenteropancreatic neuroendocrine neoplasm (GEPNEN) among population groups. We aimed to contribute to the current evidence by evaluating the clinicopathological characteristics of GEPNEN in a multi-ethnic Asian group. MATERIALS AND METHODS: This was a retrospective chart review of patients diagnosed with GEPNEN at a tertiary medical institution at Singhealth Outram Campus, Singapore, between 1995 and 2015. RESULTS: Two hundred ninety-five patients were included in the evaluation, comprising Chinese (74.6%), Malay (4.4%), Indian (9.5%) and other (11.5%) ethnic backgrounds. The median age at diagnosis was 59 years; 52.5% were males. Distribution of disease stage at diagnosis was: localised (42.4%), regional (15.3%) and distant (38.0%). The three most common primary tumour sites were located in the pancreas (38.6%), rectum (19.7%) and stomach (9.5%), which varied significantly with ethnic background and age at diagnosis. Malay patients were younger (median 42 years) at diagnosis than Chinese (60 years). Patients with an appendiceal neuroendocrine neoplasm (NEN) (48 years) were younger compared to oesophageal NEN (66 years). Disease stage correlated with primary tumour site and grade (p < 0.001). Median overall survival (OS) for all GEPNEN was 10.2 years. Age at diagnosis, disease stage and grading were prognostic factors of OS in multivariable analyses. CONCLUSION: Our findings correspond with other studies that focus on GEPNEN incidences in Asian countries, with the pancreas, rectum and stomach being the most common primary tumour sites. Our findings suggest racial differences in primary tumour site and age at diagnosis. Further prospective population-based registries are required to understand these epidemiological differences.

Postoperative serum methylation levels of TAC1 and SEPT9 are independent predictors of recurrence and survival of patients with colorectal cancer.

BACKGROUND: Serum carcinoembryonic antigen (CEA) is the only marker recommended for surveillance of colorectal cancer (CRC) recurrence; its sensitivity and specificity, however, are suboptimal. This study sought to evaluate the values of postoperative serum methylation levels of 7 genes for prognostication and especially for recurrence detection after curative resection. METHODS: This prospective cohort study included 150 patients with stage I-III CRC from whom 3 consecutive blood sampling was taken 1 week before, and 6 months and 1 year after operation. Methylation levels of 7 genes were evaluated via quantitative methylation-specific polymerase chain reaction. Serum CEA was measured in parallel. Univariate and multivariate survival analyses were followed by construction of receiver operating characteristic curves for recurrence detection. RESULTS: After a median follow-up of 59 months, 43 patients (28.7%) developed recurrent lesions. High serum methylation levels of TAC1 in serum at 6-month follow-up (6M-FU), and SEPT9 at 1-year follow-up (1Y-FU) were independent predictors for tumor recurrence and unfavorable cancer-specific survival (CSS) (P < .05 in all tests). Serum NELL1 methylation levels were significant alone for CSS at both 6M-FU and 1Y-FU, but not for disease-free survival. Dynamic changes of TAC1 and SEPT9 with methylation increment were also independently predictive for recurrence (P < .05 in all tests). More importantly, TAC1 at 6M-FU and SEPT9 at 1Y-FU exhibited earlier detection of potential recurrences compared with concurrent serum CEA. CONCLUSIONS: Levels of TAC1 and SEPT9 methylation detected in postoperative sera of patients with CRC appear to be novel promising prognostic markers and may probably be considered for monitoring of CRC recurrence.

The impact of online education during the Covid-19 pandemic on the professional identity formation of medical students: A systematic scoping review.

Evolving individual, contextual, organizational, interactional and sociocultural factors have complicated efforts to shape the professional identity formation (PIF) of medical students or how they feel, act and think as professionals. However, an almost exclusive reliance on online learning during the COVID-19 pandemic offers a unique opportunity to study the elemental structures that shape PIF and the environmental factors nurturing it. We propose two independent Systematic Evidence-Based Approach guided systematic scoping reviews (SSR in SEBA)s to map accounts of online learning environment and netiquette that structure online programs. The data accrued was analysed using the clinically evidenced Krishna-Pisupati Model of Professional Identity Formation (KPM) to study the evolving concepts of professional identity. The results of each SSR in SEBA were evaluated separately with the themes and categories identified in the Split Approach combined to create richer and deeper 'themes/categories' using the Jigsaw Perspective. The 'themes/categories' from each review were combined using the Funnelling Process to create domains that guide the discussion. The 'themes/categories' identified from the 141 included full-text articles in the SSR in SEBA of online programs were the content and effects of online programs. The themes/categories identified from the 26 included articles in the SSR in SEBA of netiquette were guidelines, contributing factors, and implications. The Funnelling Process identified online programs (encapsulating the content, approach, structures and the support mechanisms); their effects; and PIF development that framed the domains guiding the discussion. This SSR in SEBA identifies the fundamental elements behind developing PIF including a structured program within a nurturing environment confined with netiquette-guided boundaries akin to a Community of Practice and the elemental aspect of a socialisation process within online programs. These findings ought to be applicable beyond online training and guide the design, support and assessment of efforts to nurture PIF.

Serum methylation levels of TAC1. SEPT9 and EYA4 as diagnostic markers for early colorectal cancers: a pilot study.

OBJECTIVE: To identify methylated genes in serum with diagnostic potentials for early colorectal cancer (CRC). METHODS: Serum methylation levels of up to 12 genes were measured in two sets of serum samples with the second set from 26 stage I CRC patients and 26 age/gender-matched controls. RESULTS: Serum methylation levels of TAC1, SEPT9, and EYA4 were significant discriminants between stage I CRC and healthy controls. Combination of TAC1 and SEPT9 rendered 73.1% sensitivity with 92.3% specificity. CONCLUSION: Serum methylation levels of TAC1. SEPT9 and EYA4 may be useful biomarkers for early detection of CRC though a validation study is necessary.

Peptide Receptor Radionuclide Therapy Performed Shortly After Administration of Long-Acting Octreotide.

ABSTRACT: We present a case of a 68-year-old man with metastatic small bowel neuroendocrine tumor who underwent 4 cycles of peptide receptor radionuclide therapy with 177 Lu-DOTATATE. For his first 3 cycles, therapy was performed approximately 4 weeks after his last dose of octreotide LAR. Because of miscommunication in scheduling, his fourth cycle was performed only 48 hours after his last full dose of octreotide LAR. Despite this, we found that the tumoral uptake was not reduced at all, which may add to the increasing evidence on the nonnecessity of stopping somatostatin analogs before peptide receptor radionuclide therapy.

Safety and efficacy of peptide receptor radionuclide therapy in patients with advanced pheochromocytoma and paraganglioma: A single-institution experience and review of the literature.

INTRODUCTION: Despite advances in diagnosis and management, patients with advanced pheochromocytomas and paragangliomas (PPGL) face limited treatment options. This study aims to evaluate the safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with advanced PPGL, based on a single-institution experience and provide a comprehensive review of the literature. METHODS: A retrospective analysis was conducted on patients with advanced pheochromocytoma and paraganglioma who received PRRT at a single institution from April 2012 to March 2022. Clinical characteristics, treatment response, adverse events, and survival outcomes were assessed. A systematic literature review was also performed. RESULTS: A total of 15 patients with advanced PPGL were included, the majority of whom had both metastatic and functional disease. Most patients received four infusions of 177Lu-DOTATATE (73%). The median therapeutic 177Lu-DOTATATE radioactivity for each infusion was 7.4 GBq. Only one patient was treated with one infusion of 90Y-DOTATATE (4.2 GBq) in addition to three infusions of Lu-177 DOTATATE. Overall, PRRT suggests a promising efficacy with disease control rate of 63.6% by RECIST v1.1. The median overall survival (OS) was not reached and the median progression free survival (PFS) was 25.9 months. In terms of safety, PRRT was well tolerated. Review of the literature revealed consistent findings, supporting the efficacy and safety of PRRT in PPGL. CONCLUSION: This study suggests that PRRT is a safe and effective therapeutic option for patients with PPGL. Our findings align with the existing literature, providing additional evidence to support the use of PRRT in this challenging patient population.

Anastomosing Hemangioma on 68Ga-DOTATATE PET/CT: A Potential Pitfall.

ABSTRACT: Anastomosing hemangioma (AH) is a rare benign vascular lesion that primarily involves the genitourinary tract. Cases have also rarely been reported in other organs. AH is often discovered incidentally and resembles angiosarcoma histologically. On imaging, it may mimic other vascular lesions such as renal cell carcinoma and neuroendocrine tumors. We present a case of a 32-year-old woman with incidentally detected AH involving the kidneys, adrenal glands, liver, and retroperitoneum, initially presumed to be neuroendocrine tumors based on imaging findings on CT and 68Ga-DOTATATE PET scans.

Systematic scoping review on moral distress among physicians.

BACKGROUND: Concepts of moral distress (MD) among physicians have evolved and extend beyond the notion of psychological distress caused by being in a situation in which one is constrained from acting on what one knows to be right. With many accounts involving complex personal, professional, legal, ethical and moral issues, we propose a review of current understanding of MD among physicians. METHODS: A systematic evidence-based approach guided systematic scoping review is proposed to map the current concepts of MD among physicians published in PubMed, Embase, PsycINFO, Web of Science, SCOPUS, ERIC and Google Scholar databases. Concurrent and independent thematic and direct content analysis (split approach) was conducted on included articles to enhance the reliability and transparency of the process. The themes and categories identified were combined using the jigsaw perspective to create domains that form the framework of the discussion that follows. RESULTS: A total of 30 156 abstracts were identified, 2473 full-text articles were reviewed and 128 articles were included. The five domains identified were as follows: (1) current concepts, (2) risk factors, (3) impact, (4) tools and (5) interventions. CONCLUSIONS: Initial reviews suggest that MD involves conflicts within a physician's personal beliefs, values and principles (personal constructs) caused by personal, ethical, moral, contextual, professional and sociocultural factors. How these experiences are processed and reflected on and then integrated into the physician's personal constructs impacts their self-concepts of personhood and identity and can result in MD. The ring theory of personhood facilitates an appreciation of how new experiences create dissonance and resonance within personal constructs. These insights allow the forwarding of a new broader concept of MD and a personalised approach to assessing and treating MD. While further studies are required to test these findings, they offer a personalised means of supporting a physician's MD and preventing burn-out.

The Feasibility and Acceptability of a Cognitive Behavioral Therapy-Based Intervention for Patients With Advanced Colorectal Cancer.

CONTEXT: Advanced colorectal cancer and its treatment can bring about challenges associated with psychological distress. OBJECTIVES: The primary aims of this study were to examine the feasibility and acceptability of a cognitive behavioral therapy (CBT)-based intervention to improve coping with the disease. The secondary aim is to evaluate preliminary intervention efficacy. METHODS: Patients with advanced colorectal cancer in Singapore (N = 60) were randomized to either receive a four-session CBT intervention immediately or be waitlisted. Intervention feasibility (i.e., recruitment and intervention adherence) and acceptability (i.e., participant satisfaction and cultural sensitivity) were assessed. Changes in psychological distress and self-efficacy were examined. RESULTS: The study successfully recruited the intended sample (mean age 61; 62% men). A proportion (12%) reported Hospital Anxiety and Depression Scale scores indicative of distress at baseline. Most (88%) completed all sessions. Participants reported high rates of satisfaction (97%), helpfulness (96%), and cultural sensitivity (95%) of the intervention. The intervention group did not show decrease in psychological distress; however, self-efficacy in cancer-related coping (information seeking: effect size [ES] = 0.64; 95% CI = 0.17, 0.85; coping with side effects: ES = 0.69; 95% CI = 0.33, 0.82; and maintaining positive attitude: ES = 0.45; 95% CI = 0.19, 0.79) increased in the intervention group compared with the waitlisted group. CONCLUSION: The CBT-based intervention was feasible and acceptable to patients in Singapore. There is no sufficient evidence to warrant a larger trial in this sample with low baseline distress. Future work should identify and target those who are most in need of support.

What is the value of third-line chemotherapy in advanced gastroesophageal cancer? A 5-year retrospective analysis at a single center.

AIM: The survival benefit of using a non-cross resistant second-line chemotherapy in the third-line setting in metastatic gastroesophageal cancer is unproven. We evaluated the utility of third-line chemotherapy in patients treated at a single institution. METHODS: Between 2010 and 2014, efficacy and toxicity data of patients who received three or more lines of systemic therapies for metastatic gastroesophageal adenocarcinoma at the National Cancer Centre Singapore was retrospectively analyzed. RESULTS: Thirty-two (6%) patients received three or more lines of chemotherapy. The median age and ECOG performance status were 59 years (36-82) and 1 (0-2), respectively. Majority of patients (88%) had tumor located in the stomach and 13 patients (41%) had diffuse histology or poorly cohesive or signet ring cells. Four (12%) patients had HER2-positive disease. Prior therapy was platinum (100%), fluoropyrimidine (97%), taxane (63%), irinotecan (28%), anthracycline (13%) and ramucirumab (3%). Third-line therapy consisted of 24 (75%) monotherapy, 6 (19%) doublet, 1 (3%) triplet chemotherapy and 1 (3%) clinical trial. Monotherapy irinotecan (44%) was most common, followed by docetaxel (19%) and paclitaxel (9%). Of 22 patients evaluable for response, there was 1 (5%) partial response, 9 (41%) stable disease. Median overall survival was 18.3 weeks (4.3-65.1). Of 30 patients evaluable for toxicities, 17 (57%) experienced at least one grade 3 or 4 toxicities. CONCLUSION: The benefit of using non-cross resistant second-line regimens as third-line chemotherapy was small with moderate toxicity. Newer agents such as nivolumab or TAS-102 or clinical trial may be preferred.

Systematic review of current prognostication systems for pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms are a heterogenous group of rare tumors whose natural history remains poorly defined. Accurate prognostication of pancreatic neuroendocrine neoplasms is essential for guiding clinical decisions. This paper aims to summarize all the commonly utilized and recently proposed prognostication systems for pancreatic neuroendocrine neoplasms published in the literature to date. METHODS: A systematic review of Pubmed, Scopus, and Embase databases, of the period from January 1, 2000-November 29, 2016, was conducted to identify all published articles reporting on prognostication systems of pancreatic neuroendocrine neoplasms. RESULTS: A total of 23 articles were included in our review, and a total of 25 classification systems were identified. There were 2 modifications of the World Health Organization 2004 criteria, 4 modifications of the World Health Organization 2010 criteria, 2 modifications of the American Joint Committee on Cancer 2010 staging system, 3 modifications of the European Neuroendocrine Tumor Society 2006 tumor, node, metastasis staging system, 7 novel categorial classification systems, and 2 novel proposed continuous classifications. The most commonly included variables included age, size of tumor, presence of distant and lymph node metastases, Ki-67 index, and mitotic count. CONCLUSION: Numerous prognostication systems have been proposed for pancreatic neuroendocrine neoplasms, of which the most commonly used systems presently include the World Health Organization 2010 criteria and the two tumor, node, metastasis staging systems by the European Neuroendocrine Tumor Society and the American Joint Commission on Cancer. However, prognostication systems for pancreatic neuroendocrine neoplasms continue to evolve with time as more prognostication factors are identified. More validation and comparative studies are needed to identify the most effective prognostication system.

Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma.

INTRODUCTION: Advanced hepatocellular carcinoma (HCC) has a dismal prognosis and is notoriously chemo-resistant. We conducted a Phase II prospective study to evaluate the activity and tolerability of gemcitabine and cisplatin in chemo-naïve advanced hepatocellular carcinoma. The trial considered a "no further interest" response rate of 10% and a target response rate of 30%. Utilising a Simon's minimax two-stage design with a type I error of 0.05 and power of 80%, 25 subjects would be required. Fifteen patients would be needed in stage 1 and if fewer than 2 responses were observed, the trial would be stopped and lack of efficacy claimed. MATERIALS AND METHODS: Patients with advanced HCC, diagnosed based on histology or by World Health Organization (WHO) criteria, were administered gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on day 1 and day 8 of a 21-day schedule. Assessment of response based on computer tomography was performed after every 2 cycles of chemotherapy. RESULTS: The trial was stopped early due to a lack of efficacy. A total of 15 patients were accrued. Twelve patients were hepatitis B positive and the other 3 patients were negative for both hepatitis B and C. Only 1 patient had a history of prior heavy alcohol use. Two patients had Child C liver cirrhosis, 5 patients had Child B cirrhosis, and the remaining 8 patients had Child A cirrhosis. This regime was well tolerated and there was only 1 patient who experienced grade IV toxicities. Only 5 of 15 patients experienced grade III toxicities (nausea and emesis, 1 patient; anemia, 1 patient; thrombocytopenia, 1 patient; and neutropaenia, 2 patients). Only 1 patient experienced a partial response to the combination of gemcitabine and cisplatin. A further 3 patients experienced stable disease and 11 patients progressed on chemotherapy. The median time to progression was 6 weeks. The progression-free curve showed a sharp descent in the initial part of the study, suggesting that many patients had disease progression after enrollment. The median overall survival was 18 weeks. CONCLUSION: The progression-free survival and overall survival in our study were extremely short. Based on the results of our phase 2 study, we are unable to recommend further studies utilising gemcitabine and cisplatin combination in patients with advanced HCC.

Validation and comparison between current prognostication systems for pancreatic neuroendocrine neoplasms: A single-institution experience with 176 patients.

BACKGROUND: This article aims to validate and compare the performance of 6 prognostication systems-the World Health Organization 2010 grading criteria, the European Neuroendocrine Tumour Society and the American Joint Committee for Cancer staging systems, the Memorial Sloan Kettering Cancer Center staging and grading systems, as well as the Bilimoria criteria in a cohort of patients with pancreatic neuroendocrine neoplasms at a single institution. METHODS: A retrospective review of 176 patients with histologically proven pancreatic neuroendocrine neoplasm was performed. The prognostic ability of the various prognostication systems for pancreatic neuroendocrine neoplasm was assessed by analyzing the homogeneity, discriminatory ability, monotonicity of gradient, and Akaike information criteria. RESULTS: The 5-year overall survival for the 176 patients was 69% and 5-year recurrence-free survival in 119 patients who underwent curative resection was 78%. Comparison between the 6 prognostication systems demonstrated that the World Health Organization 2010 system had the lowest Akaike information criteria score and was hence the best prognostication system in predicting overall survival and recurrence-free survival rates in our cohort of patients. The European Neuroendocrine Tumour Society was superior to the American Joint Committee for Cancer in prognosticating overall survival rates for pancreatic neuroendocrine neoplasms, as there was a statistically significant difference in overall survival across the different stages when stratified by the European Neuroendocrine Tumour Society, while the use of the American Joint Committee for Cancer was limited to distinguishing between patients in stages I and II versus stages III and IV only. CONCLUSION: All 6 prognostication systems were useful in the prognostication of pancreatic neuroendocrine neoplasm. The World Health Organization 2010 grading system was the best prognostication system in predicting both overall survival in our entire cohort of patients and recurrence-free survival in the subset of patients who underwent curative resection.