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Please see the Editorial Comment by Candice Bolan discussing this article. The treatment of rectal cancer centers around the distinct but related goals of management of distant metastases and manag...

Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. Patients captured in the National Cancer Database (NCDB; 2004–2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1 year, 41%; 3 years, 13%; 5 years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60 years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon–nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND–Dox–TF, CDT) was 10–100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. Significance: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.

Context.— During the past 3 decades, numerous articles in the literature have offered terminology, diagnostic criteria, and consensus recommendations regarding the entity currently referred to by the World Health Organization as sessile serrated lesion. Given the many names and various, variably reproducible diagnostic criteria ascribed to sessile serrated lesion, confusion persists for many pathologists and gastroenterologists regarding the diagnosis. This distinction is important, as sessile serrated lesion can progress to malignancy, unlike its main differential diagnosis, hyperplastic polyp. Research studies have shed light on the characteristic architecture and morphology, immunohistochemical patterns, and molecular alterations of sessile serrated lesion, and multiple consensus meetings around the globe have developed their criteria and nomenclature, often clashing or mixing terms. Objective.— To provide a narrative review from the entity's early description to our current understanding. Data Sources.— The existing scientific and clinical literature, published texts, medical society recommendations, and specialty consensus guidelines. Conclusions.— The current World Health Organization criteria are a distillation of this scientific process, but terminology is still a point of contention worldwide.

Background Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. Methods We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013–2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. Results Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P Conclusion Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.

The role and sequencing of short-course radiation therapy (SCRT) in the preoperative management of locally advanced rectal cancer is unclear. This study of 39 patients compares outcomes between those who had surgery within 14 days after finishing SCRT and those who were delayed. Our data show similar outcomes between these groups, suggesting SCRT is well-tolerated regardless of sequence. BACKGROUND: The role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy. PATIENTS AND METHODS: All patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications. RESULTS: Fifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups. CONCLUSIONS: Though not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence.

Primary epithelioid hemangioendotheliomas of the liver (EHL) are rare tumors with a low incidence. The molecular background of EHL is still under investigation, with WWTR1-CAMPTA1 mutation may function as a tumor marker. Commonly, this tumor is misdiagnosed with angiosarcoma, cholangiocarcinomas, metastatic carcinoma, and hepatocellular carcinoma (sclerosing variant). Characteristic features on imaging modalities such as ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography/computed tomography guide in diagnosis and staging. The “halo sign” and the “lollipop sign” on computed tomography and magnetic resonance imaging are described in the literature. Currently, there are no standardized guidelines for treating EHL with treatment options are broad including: chemotherapy, ablation, surgery and liver transplantation with inconsistent results.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. Prevention Relevance: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.

Aim Complete mesocolic excision (CME) with central vascular ligation (CVL) has been advocated for right colon adenocarcinoma (RC), but the radicality of vascular dissection remains controversial. Our aim is to report outcomes of selective CVL (D3 lymphadenectomy) during minimally invasive CME for RC. Method A prospective database identified patients who were treated for RC between 2009 and 2016. Minimally invasive CME was standard. The radicality of lymphadenectomy was defined as high ligation (HL) versus CVL based on operative reports and videos. Two blinded radiologists independently evaluated the pre- and postoperative CT scans for radiographically abnormal nodes. Results Of 197 patients who underwent CME, HL was performed in 56 (28%) and CVL in 141 (72%). There were no baseline differences in age, sex, body mass index, American Society of Anesthesiologists score or pathological staging, and there were no major intra-operative complications in either group (including no major vascular injuries). The median total number of nodes retrieved was 27 and 31 (P = 0.011) in HL and CVL groups, resepctively, with pathologically positive nodes identified in 33.9% and 39.8% (P = 0.704), respectively. Preoperative imaging identified abnormal cN3 nodes in 1.5% of patients; all of whom underwent CVL. No abnormal cN2 or cN3 nodes remained on postoperative imaging. The 60-day mortality was 0.5%, and major morbidity was 4%. One patient (0.5%) had an anastomotic recurrence after a median follow-up of 22 months. Conclusion With imperfect preoperative clinical nodal staging, and in the absence of randomized data, the low morbidity and oncological outcomes observed support the approach of CME with HL as a minimum standard, with CVL (D3 lymphadenectomy) in selected cases.

Hepatic steatosis can lead to liver cancer, cirrhosis, and portal hypertension. There are two main types, non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease. The detection and quantification of hepatic steatosis with lifestyle changes can slow the evolution from NAFLD to steatohepatitis. Currently, the gold standard for the quantification of fat in the liver is biopsy, has some limitations. Hepatic steatosis is frequently detected during cross sectional imaging. Ultrasound (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) provide noninvasive assessment of liver parenchyma and can detect fat infiltration in the liver. However, the non-invasive quantification of hepatic steatosis by imaging has been challenging. Recent MRI techniques show great promise in the detection and quantification of liver fat. The aim of this article is to review the utilization of non-invasive imaging modalities for the detection and quantification of hepatic steatosis, to evaluate their advantages and limitations.

Objective Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. Design We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). Results Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. Conclusions Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Trial registration number gov Identifier: NCT02052908

Aim There are limited outcome data for lateral pelvic lymph node dissection (LPLND) following neoadjuvant chemoradiotherapy (nCRT), particularly in the West. Our aim was to evaluate the short-term perioperative and oncological outcomes of robotic LPLND at a single cancer centre. Method A retrospective analysis of a prospective database of consecutive patients undergoing robotic LPLND for rectal cancer between November 2012 and February 2020 was performed. The main outcomes were short-term perioperative and oncological outcomes. Major morbidity was defined as Clavien-Dindo grade 3 or above. Results Forty patients underwent robotic LPLND during the study period. The mean age was 54 years (SD ± 15 years) and 13 (31.0%) were female. The median body mass index was 28.6 kg/m2 (IQR 25.5-32.6 kg/m2 ). Neoadjuvant CRT was performed in all patients. Resection of the primary rectal cancer and concurrent LPLND occurred in 36 (90.0%) patients, whilst the remaining 4 (10.0%) patients had subsequent LPLND after prior rectal resection. The median operating time was 420 min (IQR 313-540 min), estimated blood loss was 150 ml (IQR 55-200 ml) and length of hospital stay was 4 days (IQR 3-6 days). The major morbidity rate was 10.0% (n = 4). The median lymph node harvest from the LPLND was 6 (IQR 3-9) and 13 (32.5%) patients had one or more positive LPLNs. The median follow-up was 16 months (IQR 5-33 months), with 1 (2.5%) local central recurrence and 7 (17.5%) patients developing distant disease, resulting in 3 (7.5%) deaths. Conclusion Robotic LPLND for rectal cancer can be performed in Western patients to completely resect extra-mesorectal LPLNs and is associated with acceptable perioperative morbidity.

Background Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, IHC of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on postneoadjuvant therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and posttreatment specimens were compared. In parallel, 2 isogenic cell lines conditioned for MMR functioning and 2 different patient-derived xenografts (PDXs) were exposed to chemotherapy, radiation, or both. We also examined whether establishment of PDXs induced MSI changes in 5 tumors. IHC and MSI were tested after treatment to assess for changes. Results: We identified paired pre- and posttreatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All 3 patients with PCR had microsatellite stable pre- and posttreatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and posttreatment specimens, 1 had equivocal MLH1 staining in the pretreatment and loss in the posttreatment specimen, and 4 had intact pretreatment MSH6 but variable posttreatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions: Our findings show that the expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy. Clin Cancer Res; 23(17); 5246–54. ©2017 AACR.

IntroductionAcellular intra-abdominal mucin is associated with a favourable prognosis in pseudomyxoma peritonei. There are no current guidelines on how many blocks are needed to classify the mucin as acellular with confidence.MethodsSpecimens from cytoreductive surgery for mucinous appendiceal neoplasia, in which acellular mucin was found on initial histopathological examination, were prospectively identified. Additional tissue blocks were then taken to include either all residual visible intra-abdominal mucin or a maximum of 30 blocks. We also sent a questionnaire to pathologists in other centres.ResultsTwelve patients were identified. In two cases, neoplastic epithelial cells were found on taking additional blocks. The questionnaire results suggested considerable variation in block-taking practice.ConclusionTaking additional tissue identified neoplastic cells in 2 of 12 cases. We recommend that sampling additional material should be considered when only acellular mucin is found on initial histology. Further work to determine the optimum sampling protocol is indicated.

Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

Low-grade appendiceal mucinous neoplasm of uncertain malignant potential are poorly understood lesions characterized by extraluminal mucin or fibrosis with neoplastic cells confined to the appendiceal lumen. The purpose of this study is to investigate the clinical and pathologic parameters of these lesions to optimize our understanding and management of these tumors. Subjects with these tumors were identified from the appendiceal tumor databases at the University of Texas MD Anderson Cancer Center. Univariate and multivariate Cox proportional hazards regression analyses assessed relationships between clinicopathologic variables [including age, gender, margin status and serum levels of the tumor markers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA19-9] disease-free survival, postrecurrence survival and overall survival. Ninety-eight subjects with this disease were identified. Most patients did not experience disease recurrence after initial appendectomy. At last follow-up, 25 (26 %) had disease recurrence or died. Of the 20 patients who had disease recurrence, 5 (25 %) died, and 15 (75 %) were alive. Disease-free survival was significantly reduced with positive margin status (p = 0.02) and elevated serum levels of CEA (p

Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

4012 Background: Identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) other than for N1c designation. The aim of this study was to determine the prognostic impact, beyond AJCC N1c designation, of TD among primary CRC patients. Methods: Patients with stage 1 to 3 primary CRC diagnosed between 2010 and 2015 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Cancer specific survival (CSS) stratified by TDs and nodal status was calculated, and Kaplan-Meier method and multivariable COX proportional hazards regression analyses were performed. Results: A total of 74,494 patients with primary CRC were identified. Mean age was 66.4 (SD+/-13.2) years, 36,988 (49.7%) were female and 40,651 (54.6%) were right-sided. TDs were present in 4,481 patients (6.0%) and 26,603 (35.7%) had lymph node metastases. The presence of TDs were significantly associated with adverse tumor characteristics including advanced pathological stage, nodal and metastasis status, higher grade and perineural invasion. Incorporating TDs into each nodal status was independently associated with worse CSS and supported reclassification of nodal status to incorporate TDs following multivariable regression analysis as outlined in the table. Following multivariable regression analysis, the proposed AJCC nodal reclassification incorporating TDs, in combination with tumor stage was a strong predictor of CSS, and also represents a new summary staging. Conclusions: TDs are an independent predictor of worse outcome in CRC. The presence of TDs have distinctly different CSS and these data support modification of the current N classification. This study proposes a reclassification of the AJCC system for CRC to incorporate TDs and informs an updated node and summary stage. [Table: see text]

Background: Improving the quality of health care is a national priority, and providing patient-centered care is one of the 6 key areas for quality improvement. In the setting of patients with young-onset colorectal cancer (CRC), appropriate genetic workup and testing for potential underlying inherited CRC syndromes is fundamental to patient-centered care. Lynch syndrome (LS) is the most common of these inherited syndromes, and current recommendations from the NCCN and other professional societies advocate universal screening for LS among young patients with CRC. However, practical implementation of these guidelines often falls short. Methods: We conducted a prospective quality improvement intervention trial to optimize universal screening for LS in young (age

ContextThe prognosis of appendiceal goblet cell carcinoid tumors (GCTs) is believed to be intermediate between appendiceal adenocarcinomas and conventional carcinoid tumors. However, GCTs can have mixed morphologic patterns, with variable amount of adenocarcinoma.ObjectiveTo evaluate the behavior of GCTs and related entities with variable components of adenocarcinoma.DesignWe classified 74 cases of appendiceal tumors into 3 groups: group 1, GCTs or GCTs with less than 25% adenocarcinoma; group 2, GCTs with 25% to 50% adenocarcinoma; group 3, GCTs with more than 50% adenocarcinoma; and a comparison group of 68 adenocarcinomas without a GCT component (group 4). Well-differentiated mucinous adenocarcinomas were excluded. Clinicopathologic features and follow-up were obtained from computerized medical records and the US Social Security Death Index.ResultsOf the 142 tumors studied, 23 tumors (16%) were classified as group 1; 27 (19%) as group 2; 24 (17%) as group 3; and 68 (48%) as group 4. Staging and survival differed significantly among these groups. Among 140 patients (99%) with available staging data, stages II, III, and IV were present in 87%, 4%, and 4% of patients in group 1 patients; 67%, 7%, and 22% of patients in group 2; 29%, 4%, and 67% of patients in group 3; and 19%, 6%, and 75% of patients in group 4, respectively (P = .01). Mean (SD) overall survival was 83.8 (34.6), 60.6 (30.3), 45.6 (39.7), and 33.6 (27.6) months for groups 1, 2, 3, and 4, respectively (P = .01). By multivariate analysis, only stage and tumor category were independent predictors of overall survival.ConclusionOur data highlight the importance of subclassifying the proportion of adenocarcinoma in appendiceal tumors with GCT morphology because that finding reflects disease stage and affects survival.

Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death. Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes. Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011). In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms. From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists’ interpretations. Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P = 0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P = 0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18–0.78) and with well-differentiated histologic grade (40% vs 24%; P = 0.002; OR, 0.47; 95% CI, 0.29–0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9–37.2%), a specificity of 99.3% (95% CI, 96–100%), a PPV of 99.1% (95% CI, 94.9–100%), and an NPV of 37.4% (95% CI, 32.4–42.6%). This case–control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention.

Inflammatory and reactive conditions are known to mimic dysplasia or malignancy in the gastrointestinal tract. Epithelial atypia that closely mimics low-grade dysplasia (LGD) or high-grade dysplasia (HGD) can sometimes be seen in ischemic bowel. To study this phenomenon, we evaluated surgical resections for ischemic enteritis (n = 65) and ischemic colitis (n = 99) that included sections of viable epithelium adjacent to necrosis. Viable epithelium was classified as normal, obviously reactive, LGD-like atypia or high-grade dysplasia (HGD)-like atypia. Cases with available paraffin blocks were characterized immunohistochemically with antibodies to p16, p53, and MIB-1. Fourteen dysplastic lesions in chronic ulcerative colitis served as controls. Dysplasia-like atypia was found in 13 small bowel resections (20%) and 15 colectomies (15%), most common near re-epithelializing erosions. Two colectomies had extensive dysplasia-like atypia, whereas the other 26 demonstrated focal or several foci of atypia. Nine cases contained HGD-like atypia, 15 contained LGD-like atypia, and 4 showed both HGD- and LGD-like atypia. Features indicating subacute-to-chronic ischemia were more frequent in LGD-like atypia (13/15, 87%) than HGD-like atypia (2/9, 22%; P = .003). Dysplasia-like atypia showed overexpression of p16 (73%), p53 (50%), and MIB-1 (92%), but these markers did not reliably distinguish dysplasia-like atypia from true dysplasia in chronic ulcerative colitis (P = .45 for p16, P = .51 for p53, P = .08 for MIB-1). These results underscore the frequency of dysplasia-like atypia in ischemic bowel, which can occasionally be an extensive and worrisome finding. Distinction from true dysplasia requires recognizing the context of the epithelial atypia because cell cycle markers were not helpful in classifying individual cases.

3592 Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age

Background. Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR). Patients and Methods. We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics. Results. Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS. Conclusion. In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

Intrabiliary growth by metastatic colorectal carcinoma (CRC) is an unusual finding that can clinically mimic cholangiocarcinoma. We evaluated prevalence of intrabiliary growth by retrospective review of 1596 diagnostic reports and by prospective evaluation of 223 hepatectomies. Positive cases were scored for extent of intrabiliary growth (major vs. minor duct involvement), architectural pattern (colonization of biliary epithelium and/or intrabiliary tumor plugs), and secondary sclerosing cholangitis in non-neoplastic parenchyma. By retrospective review, we identified intrabiliary growth in 41 (3.6%) of 1144 metastatic CRCs but only 3 (0.7%) of 452 noncolorectal tumors (P

BACKGROUND The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer. METHODS The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and

Solid pseudo-papillary tumors are rare pancreatic tumors, which occur in females and are typically indolent neoplasms. However, atypical, aggressive variants can occur with locally advanced disease or metastases. They have characteristic imaging features, which vary according to size. This article provides a current update on the molecular biology, histopathology, clinico-radiological features, and management of these tumors.

Though histological grade is known to have a major prognostic impact in metastatic mucinous appendiceal adenocarcinomas, the prognostic impact of grade in localized disease, and the validity of the American Joint Committee on Cancer AJCC Staging Manual 7th edition's decision to combine moderately and poorly differentiated mucinous adenocarcinomas into a single mucinous high-grade category, is not known.Patients with adenocarcinoma of the appendix diagnosed between 1988 and 2007 were identified from the SEER database. Cancer-specific survival (CSS) stratified by histological subtype, stage, and grade was calculated, and Cox proportional hazards regression analyses were performed.We analyzed a total of 2469 appendiceal adenocarcinomas, of which 1375 had mucinous histology and 860 had nonmucinous histology. Though overall CSS was similar for mucinous and nonmucinous subtypes, differences in stage distribution and stage-stratified CSS were seen. Female sex, stage IV disease, and well-differentiated histology were more common for mucinous adenocarcinomas. Histological grade had a strong prognostic impact, especially in patients with stage IV mucinous adenocarcinoma. The adjusted hazard ratios for stage IV moderately and poorly differentiated histological grade were 1.63 [95% confidence interval (CI): 1.14-2.34] and 4.94 (95% CI: 3.32-7.35) for mucinous histology, in comparison with 1.44 (95% CI: 0.82-2.52) and 1.90 (95% CI: 0.95-3.80) for nonmucinous histology, respectively.The strong prognostic impact of histological grade for mucinous adenocarcinomas is primarily restricted to stage IV disease. Stage IV moderately and poorly differentiated mucinous adenocarcinomas have distinctly different CSS and these data do not support the combination of these 2 histological grades in the recent AJCC Staging Manual 7th edition.

Hereditary colorectal adenocarcinomas only represent a small proportion of all colorectal cancers and, of those, only a fraction have distinct clinical or pathologic features and a mutation of a gene associated with a hereditary syndrome. These hereditary conditions include hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MUTYH -associated polyposis, Peutz–Jeghers syndrome, and juvenile polyposis syndrome. Histopathologic features in patients with colorectal lesions (polyps, adenocarcinoma) that suggest the presence of a hereditary condition include the number and type of polyps, the morphologic features of the colorectal carcinoma, and the presence of extracolonic lesions or tumors. In addition, immunohistochemical stains can assist in identifying patients with hereditary nonpolyposis colorectal cancer.

IMPORTANCE: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. OBJECTIVE: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. MAIN OUTCOMES AND MEASURES: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. RESULTS: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). CONCLUSIONS AND RELEVANCE: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.

298 Background: Appendiceal adenocarcinomas (AAs) are orphan tumors. Little is known about their molecular profile limiting understanding of their biology and development of novel targeted therapies. The purpose of this study was to delineate the molecular landscape of AAs. Methods: We performed a retrospective review of AAs patients (pts) who were evaluated at MD Anderson Cancer Center between October 2012 and April 2017 and underwent next-generation sequencing (NGS) with internal or external assays (at least 45 genes) using either tumor tissue specimens or peripheral blood for circulating cell-free DNA (cfDNA). The primary outcome was to assess the prevalence of genomic alterations (GAs) in AAs. We then performed comparative exploratory analyses of GAs using TCGA colorectal cancer (CRC) sequencing. Results: A total of 78 patients were identified of which 57 (73%) and 18 (23%) underwent tissue based and ctDNA based sequencing, respectively (3 cases had both). At least 1 GA was found in 61 (78%) of AA specimens, with a mean (SD) of 2.8 (1.6) GAs per case. Of these 44 (72%) had ≥ 2 GAs and 31 (51%) had ≥ 3 GAs. The most frequent GAs were KRAS (38 [62%]), TP53 (22 [36%]), GNAS (17 [28%]), SMAD4 (11 [18%]), PIK3CA (10 [16%]), APC (9 [15%]), ATM (8 [13%]), BRAF (5 [8%]), KIT (5 [8%]), NRAS (3 [5%]) and MET (3 [5%]). GNAS mutations frequently co-occurred with KRAS mutations (42% v 5%, OR 14.3, P < 0.001). No GA was associated with grade, mucinous histology or overall survival (OS). Besides these mutations, we also found unusual cases with targetable mutations such as ALK, EGFR, MET, IDH1 and ERBB2. In our comparative analyses, mutations in KRAS (p = 0.009), TP53 (p = 0.020), GNAS (p < 0.001) and APC (p < 0.001) genes were significantly different from CRC whereas there was no difference in prevalence of PIK3CA, SMAD4 and ATM genes. Conclusions: To date, our analysis of one of the largest cohorts of AAs, demonstrate a majority of AAs harbor at least 1 GAs. Although treatment paradigms in AAs are extrapolated from CRC, the molecular profile of these tumors differs significantly. Molecular characterization of these rare tumors is a necessary first step towards discovery of opportunities for use of targeted therapies in these patients.

650 Background: Peritoneal mesothelioma (PeM) is an orphan disease with approximately 300-400 cases diagnosed in the United States each year. Due to its rarity, data on its presentation and prognostic factors is limited. The purpose of this study was to investigate the clinicopathological profile and outcome of Malignant PeM (MPeM). Methods: We retrospectively reviewed 128 PeM patients (pts) seen at UTMDACC (2011 - 2017) comprised of 111 MPeM and 17 variants (VPeM) [9 well-differentiated papillary and 8 multicystic]. Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age at diagnosis was 57 yrs. with a higher proportion of women (61%). The mOS for MPeM was significantly shorter than VPeM (HR 3.7, 95% CI: 1.6 – 8.4, P = 0.002). Among pts with MPeM, median age at diagnosis was 56 yrs. and 58% were women. Only 22% had prior exposure to asbestos. Epithelioid subtype was seen in 94 (85%) pts. Calretinin and WT-1 IHC were positive in 98% and 96% of cases. BerEP4 and MOC-31 IHC were negative in 90% and 84% of cases. After median follow-up of 31 months (m), the mOS for MPeM cohort was 78 m. In univariate analysis, age, prior asbestos exposure, ECOG PS, histologic subtype, CA125, neutrophil-lymphocyte ratio (NLR) and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses, age ≥ 65 years (HR 4.5, 95% CI: 1.3 - 15.2, P = 0.02), prior asbestos exposure (HR 4.1, 95% CI: 1.1 – 15.6, P = 0.04), poor PS (ECOG 2/3) (HR 8.9, 95% CI: 1.7 – 47.7, P = 0.01), elevated CA125 ( > 3X upper limit of normal) (HR 4.5, 95% CI: 1.3 – 15.5, P = 0.02), and high NLR (HR 3.8, 95% CI: 1.1 – 12.6, P = 0.03) were found to be independently associated with poor OS. A total of 50 (45%) pts underwent CRS and among these the completion of cytoreduction score (CCS) was strongly associated with OS (mOS: 201 m, 53 m and 36 m for CCS 0, 1, 2/3, respectively, P = 0.005). Conclusions: MPeM is associated with poor survival outcomes. Prognostic factors include age, history of asbestos exposure, CA-125 level, NLR, and PS. CRS with CCS 0 results in favorable survival. Further understanding of molecular genetics is warranted to improve prognostication and outcomes.

773 Background: Histological grade is a key prognostic factor in appendiceal adenocarcinomas (AAs) and has been incorporated in classification of stage IV AAs (IVA – Grade 1: Well; IVB – Grade 2/3: Moderately/Poorly differentiated) in AJCC Cancer Staging (8th edition). The purpose of the study was to corroborate the prognostic impact of this staging classifier. Methods: We performed a retrospective review of 98 AA patients (pts) at UTMDACC (2013 - 2017). Kaplan-Meier method was used to estimate median overall survival (mOS), compared with log-rank tests with emphasis on stage and grade. Results: The cohort included 18, 8, 14, 47 and 11 cases of stage II, III, IVA, IVB and IVC AAs. Histologically, 75 were mucinous (21 non mucinous) and 19, 35 and 42 were grade 1, 2 and 3 respectively. Median age of cohort was 54 years. Median follow-up was 46 months (m). The mOS of stage II, III, IVA, IVB and IVC was 136, 106, 140, 48, 23 m, respectively (P < 0.0001). The mOS of grade 1, 2 and 3 was 160, 75 and 33 m, respectively (P < 0.0001). In univariate analysis (restricted to stage IV pts), grade, AJCC stage, and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses (restricted to stage IV pts), only AJCC stage (HR 3.9, 95% CI: 1.5 - 10.6, P = 0.005) and CRS (HR 3.4, 95% CI: 1.4 – 8.3, P = 0.009) were found to be independently associated with poor OS. In subgroup of mucinous AAs, mOS of grade 3 (32 m) was significantly shorter than grade 2 (54 m) (P = 0.02). In non-mucinous AAs, mOS of grade 3 and grade 2 pts was 38 and 29 m, respectively (P = 0.97). Conclusions: AJCC staging classification has a strong prognostic value in AAs. Beyond the well differentiated AAs which are regarded as a distinct entity in stage IV disease, moderate and poor differentiation also has strong and dissimilar prognostic impact which appears to be dependent on mucinous or non-mucinous subtype in stage IV AAs. Further efforts are needed to incorporate the complex interplay of all grades and mucinous characteristics within the staging system for better prognostication and management.

The analysis of MUTYH-associated polyposis cases of the EPIPOLIP cohort confirms the importance of including serrated polyps in the diagnostic work-up of patients with oligopolyposis, suggests a role for screening polyps for the somatic c.34G>T KRAS mutation, and allows the implementation of a genetic testing strategy based on population data. Clin Cancer Res; 20(5); 1061–3. ©2014 AACR.

Several critical issues need to be considered in interpreting the results of the single-center observational study of the FOLFOX regimen in appendiceal pseudomyxoma peritonei (PMP) reported by Pietrantonio et al. [1]. Clinical behavior of mucinous appendiceal neoplasms is variable and highly dependent on histological grade [2]. Currently, multiple histopathological grading systems exist [3–5]. Although the authors’ eligibility criteria describe inclusion of borderline mucinous tumors and well-differentiated appendiceal adenocarcinomas, the grading is reported as either low (n = 12) or high (n = 8). Because no reference grading system is provided, the meaning of high and low grade is unclear. According to the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, 7th edition, high-grade mucinous appendiceal adenocarcinomas are defined as moderate to poorly differentiated tumors [6], and that is inconsistent with the inclusion criteria. Eligible patients were either unresectable (n = 6) or had relapsed following initial cytoreductive surgery (CRS; n = 14). It was reported that 2 of the 6 initially unresectable cases underwent cytoreductive surgery, but the rate of repeat CRS in the 14 patients who had initially relapsed following a complete CRS was not reported. Because repeated CRS in appendiceal PMP represents a proven approach [7, 8] the rate of a second CRS should be reported. Because both PFS and overall survival times are not censored at the time of a second CRS, the reported time-to-event analyses may best reflect an anticancer approach of chemotherapy followed by repeated CRS [9]. Low-grade mucinous appendiceal neoplasms are known to have an indolent disease course; therefore, the presence of 7 cases with >20% growth at 3 months (progressive disease) is highly unusual for this disease type. Furthermore, the >30% shrinkage seen in 4 of these patients is unusual in the context of a median of 8 cycles (∼4 months) and a maximum of 12 (∼6 months). As a center that has conducted extensive research in appendiceal neoplasms, we disagree with the statement that a “decrease in the amount of mucus was invariably observed” and feel that the magnitude of radiographic change reported over a 3- to 6-month period for low-grade mucinous appendiceal neoplasms is not an accurate reflection of the disease biology under study. Prior reports documenting radiographic responses have all included more aggressive and higher grade appendiceal neoplasms and are not reflective of the population in this report [10, 11]. In part, we believe that the findings reported reflect the intrinsic challenges of both separating mucinous from more serous peritoneal accumulations and measuring geographically shaped mucinous implants that shift between scans. This latter point is amplified by the limitation of measuring only two peritoneal areas, as per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Prospective controlled studies are needed to clarify the role of chemotherapy in PMP. A clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01946854","term_id":"NCT01946854"}}NCT01946854) for unresectable low-grade mucinous appendiceal adenocarcinomas with PMP is ongoing at MD Anderson. In that trial, patients are randomized to either 6 months of chemotherapy followed by 6 months of observation or 6 months of observation followed by 6 months of chemotherapy. Within this study, a modified peritoneal RECIST measurement in which five locations are measured is being investigated. Because each patient serves as his or her own control, we hope this study will better clarify the true rate of radiographic change for this biologically unique tumor type.

Intramural gastric masses arise in the wall of the stomach (generally within the submucosa or muscularis propria), often with intact overlying mucosa. These tumors are typically mesenchymal in origin and have overlapping radiologic appearances. A combination of features such as location, attenuation, enhancement, and growth pattern may suggest one diagnosis over another. Gastrointestinal stromal tumors (GISTs) account for the majority of intramural tumors and can vary widely in appearance, from small intraluminal lesions to exophytic masses that protrude into the peritoneal cavity, commonly with areas of hemorrhage or necrosis. A well-circumscribed mass measuring −70 to −120 HU is a lipoma. Leiomyomas usually manifest as low-attenuation masses at the gastric cardia. Homogeneous attenuation is a noteworthy characteristic of schwannomas, particularly for larger lesions that might otherwise be mistaken for GISTs. A hypervascular mass in the antrum is a common manifestation of glomus tumors. Hemangiomas are also hypervascular but often manifest in childhood. Inflammatory fibroid polyps usually arise as a polypoid mass in the antrum. Inflammatory myofibroblastic tumors are infiltrative neoplasms with a propensity for local recurrence. Plexiform fibromyxomas are rare, usually antral tumors. Carcinoid tumors are epithelial in origin, but often submucosal in location, and therefore should be distinguished from other intramural lesions. Multiple carcinoid tumors are associated with hypergastrinemia, either in the setting of chronic atrophic gastritis or Zollinger-Ellison syndrome. Sporadic solitary carcinoid tumors not associated with hypergastrinemia have a higher rate of metastasis. Histopathologic analysis, including immunohistochemistry, is usually required for diagnosis of intramural masses. © RSNA, 2013

Aims Oesophageal hyperkeratosis is rarely described. In contrast to hyperkeratosis of orolaryngeal mucosa, where its risk factors and association with squamous neoplasia are well-studied, the prevalence and clinicopathological features of oesophageal hyperkeratosis are unknown. Methods and results We reviewed prospectively 1845 oesophageal biopsies and found hyperkeratosis in 37 (2.0%). Among 98 patients studied, hyperkeratosis occurred in two distinct settings: group 1 [within Barrett's oesophagus (BO)/adenocarcinoma, n = 61, 62%] and group 2 (outside BO/adenocarcinoma, n = 37, 38%). In contrast to group 1, hyperkeratosis in group 2 was more often multifocal (>3 foci in 51% versus 16%, P = 0.0001), involved mid-oesophagus (51% versus 2%, P

3605Background: Response to nCRT is a key prognostic indicator for rectal cancer and may be influenced by the systemic inflammatory response. The purpose of this study was to determine the relation...

Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS).A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010.One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01).Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.