Muscarinic receptor agonist-induced ßPix binding to ß-catenin promotes colon neoplasia.

M3 muscarinic receptors (M3R) modulate ß-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, ßPix, binds to ß-catenin in colon cancer cells, augmenting ß-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of ßPix and ß-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of ßPix with ß-catenin. ßPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing ßPix dose-dependently augmented ß-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of ßPix. Expression levels of ß-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from ßPix-deficient conditional knockout mice. Targeting the M3R/ßPix/ß-catenin axis may have therapeutic potential.

Survival outcomes used to validate version 9 of the American Joint Committee on Cancer staging system for appendiceal cancer.

The standard for cancer staging in the United States for all cancer sites, including primary carcinomas of the appendix, is the American Joint Committee on Cancer (AJCC) staging system. AJCC staging criteria undergo periodic revisions, led by a panel of site-specific experts, to maintain contemporary staging definitions through the evaluation of new evidence. Since its last revision, the AJCC has restructured its processes to include prospectively collected data because large data sets have become increasingly robust and available over time. Thus survival analyses using AJCC eighth edition staging criteria were used to inform stage group revisions in the version 9 AJCC staging system, including appendiceal cancer. Although the current AJCC staging definitions were maintained for appendiceal cancer, incorporating survival analysis into the version 9 staging system provided unique insight into the clinical challenges in staging rare malignancies. This article highlights the critical clinical components of the now published version 9 AJCC staging system for appendix cancer, which (1) justified the separation of three different histologies (non-mucinous, mucinous, signet-ring cell) in terms of prognostic variance, (2) demonstrated the clinical implications and challenges in staging heterogeneous and rare tumors, and (3) emphasized the influence of data limitations on survival analysis for low-grade appendiceal mucinous neoplasms.

Outcomes after endoscopic local excision of early-stage gastric adenocarcinoma in the United States.

BACKGROUND AND OBJECTIVES: Local excision (LE) for early-stage gastric cancer has expanded in the United States over recent years, however, national outcomes are unknown. The objective of the study was to evaluate national survival outcomes following LE for early-stage gastric cancer. METHODS: Patients with resectable gastric adenocarcinoma between 2010 and 2016 were identified from the National Cancer Database then classified by LE curability into eCuraA (high) and eCuraC (low) according to Japanese Gastric Cancer Association guidelines. Demographics, clinical/provider descriptors, and perioperative/survival outcomes were extracted. Propensity-weighted cox proportional hazards regression assessed factors associated with overall survival. RESULTS: Patients were stratified into eCuraA (N = 1167) and eCuraC (N = 13,905) subgroups. Postoperative 30-day mortality (0% vs 2.8%, p < 0.001) and readmission (2.3% vs 7.8%, p = 0.005) favored LE. Local excision was not associated with survival on propensity-weighted analyses. However, among eCuraC patients, LE was associated with higher likelihood of positive margins (27.1% vs 7.0%, p < 0.001), which was the strongest predictor of poor survival (HR 2.0, p < 0.001). CONCLUSIONS: Although early morbidity is low, oncologic outcomes following LE are compromised for eCuraC patients. These findings support careful patient selection and treatment centralization in the early adoption phase of LE for gastric cancer.

Increasing utilization of endoscopic local excision for early-stage gastric cancers in the United States.

BACKGROUND: The Japanese Gastric Cancer Association provided updated criteria for endoscopic local excision of early-stage gastric cancer in 2018. The purpose of this study was to evaluate utilization patterns for endoscopic local excision in the United States for resectable gastric adenocarcinoma. METHODS: Patients with resectable gastric adenocarcinoma were identified from the National Cancer Database between 2010 and 2017. Patients were classified into strict appropriate criteria, expanded criteria, and inappropriate based on the Japanese Gastric Cancer Association guidelines. Factors associated with endoscopic local excision were identified using univariate and logistic multivariate regression. RESULTS: Within the National Cancer Database, 46,334 patients were stratified into strict appropriate criteria (n = 1,405), expanded criteria (n = 727), and inappropriate (n = 43,675). Annual cases of local excision increased by 76.9% over the study period, from 273 in 2010 to 483 in 2017. Among patients who underwent local excision, 10.1% were classified as strict appropriate criteria, 1.6% were classified as expanded criteria, and 84.5% were classified as inappropriate. Among inappropriate patients, factors associated with endoscopic local excision were: more recent year of diagnosis, increasing age, female sex, tumor located in the cardia, smaller size, low-grade, absence of lymphovascular invasion, and treatment at an academic facility. CONCLUSION: The use of endoscopic local excision for gastric cancer has nearly doubled since 2010. However, most patients do not satisfy consensus criteria for endoscopic therapy.

Outcomes of complex abdominal wall reconstruction at the time of CRS and HIPEC.

INTRODUCTION: Cytoreduction Surgery with Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is a treatment option for patients with peritoneal metastatic cancer. This procedure has been shown to improve survival, however, patients are often left with abdominal wall and soft tissue defects requiring further surgical correction. We aim to assess the safety and clinical outcomes of abdominal reconstruction performed concurrent with CRS/HIPEC. METHODS: We conducted a retrospective chart review on patients with peritoneal metastases who received CRS/HIPEC therapy and abdominal wall reconstruction at tertiary center from 2012 to 2018. Records were evaluated for the patient characteristics, oncologic history, operative details, and postoperative course. Complications were graded with the Clavien-Dindo classification. RESULTS: Five patients aged 29-54 years old met the inclusion criteria. The most common type of cancer within this cohort was colorectal cancer. To close the abdomen, four patients underwent component release, biologic mesh placement, and primary fascial closure. The last patient was closed with adjacent tissue transfer. Two patients experienced Grade I complications: deep vein thrombosis and leukocytosis (both self-resolved). Three patients experienced Grade II complications: atrial fibrillation, anemia, and a wound infection which required readmission. No patients experienced grades III, IV or V complications. The follow up period was a median of 5.3 months [r: 2.6-21.9 months]. CONCLUSION: The patients benefitted therapeutically from combined abdominal reconstruction and CRS/HIPEC with minimal complications and good long-term survival. We advocate for the coupling of these procedures as the benefits outweigh the risks, and allows wound closure at the time of surgery.

The impact of stage, grade, and mucinous histology on the efficacy of systemic chemotherapy in adenocarcinomas of the appendix: Analysis of the National Cancer Data Base.

BACKGROUND: Adenocarcinomas of the appendix represent a heterogeneous disease depending on the presence of mucinous histology, histologic grade, and stage. In the current study, the authors sought to explore the interplay of these factors with systemic chemotherapy in a large population data set. METHODS: Patients in the National Cancer Data Base (NCDB) who were diagnosed with mucinous, nonmucinous, and signet ring cell-type appendiceal neoplasms from 1985 through 2006 were selected. Multivariable Cox proportional hazards regression models were developed. RESULTS: A total of 11,871 patients met the inclusion criteria for the current study: 50.3% had mucinous neoplasms, 40.5% had nonmucinous neoplasms, and 9.2% had signet ring cell-type neoplasms. The 5-year overall survival (OS) stratified by grade was similar among patients with American Joint Committee on Cancer stage I to stage III disease but not for those with stage IV disease. The median OS for patients with stage IV mucinous and nonmucinous tumors was 6.4 years and 2.3 years, respectively, for those with well differentiated histology (P<.0001) and was 1.5 years and 0.8 years, respectively, for those with poorly differentiated histology (P<.0001). In multivariable modeling for stage I to III disease, adjuvant chemotherapy improved OS for both mucinous and nonmucinous histologies, with hazard ratios (HRs) of 0.78 (95% confidence interval [95% CI], 0.68-0.89 [P = .0002]) and 0.83 (95% CI, 0.74-0.94 [P = .002]), respectively. For patients with stage IV disease, systemic chemotherapy significantly improved OS for those with nonmucinous (HR, 0.72; 95% CI, 0.64-0.82 [P<.0001]) but not mucinous (HR, 0.95; 95% CI, 0.86-1.04 [P = .2) histologies, although this was grade-dependent. The median OS for chemotherapy versus no chemotherapy was 6.4 years versus 6.5 years (P value not significant) for patients with mucinous, well-differentiated tumors and 1.6 years versus 1.0 years (P = .0007) for patients with mucinous, poorly differentiated tumors. CONCLUSIONS: Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for patients with stage IV disease, the benefit of systemic chemotherapy varied by tumor histology and grade, with patients with well-differentiated, mucinous, appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy. Cancer 2016;122:213-221. © 2015 American Cancer Society.

Tumour antigen targeted monoclonal antibodies incorporating a novel multimerisation domain significantly enhance antibody dependent cellular cytotoxicity against colon cancer.

Tumour antigen targeted antibodies (mAbs) can induce natural killer (NK) cells to kill tumours through antibody dependent cellular cytotoxicity (ADCC) upon engagement of NK cell expressed FcγRIIIa. FcγRIIIa polymorphisms partially dictate the potency of the ADCC response. The high affinity FcγRIIIa-158-valine (V) polymorphism is associated with more potent ADCC response than the low affinity FcγRIIIa-158-phenylalanine (F) polymorphism. Because approximately 45% of patients are homozygous for the FcγRIIIa-158-F polymorphism (FF genotype), their ability to mount ADCC is impaired. We investigated whether a novel mAb capable of binding multiple antigen specific targets and engaging multiple low affinity FcγRIIIa receptors could further enhance ADCC against colon cancer in vitro. Specifically, we generated a novel anti-epidermal growth factor receptor (EGFR) antibody (termed a stradobody) consisting of an unmodified Fab sequence and two Immunoglobulin G, subclass 1 (IgG1) Fc domains separated by an isoleucine zipper domain and the 12 amino-acid IgG2 hinge. The stradobody framework induced multimerisation and was associated with increased binding to the EGFR and FcγRIIIa. From a functional perspective, when compared to an unmodified anti-EGFR mAb with a sequence identical to cetuximab (a commercially available anti-EGFR mAb), stradobodies significantly enhanced ADCC. These effects were observed using both KRAS wild type HT29 and KRAS mutant SW480 colon cancer cells as targets, and by NK cells obtained from healthy donors and a cohort of patients with colon cancer. These data suggest that high avidity cross-linking of multiple tumour surface antigens and multiple NK cell associated FcγRIIIa molecules can enhance ADCC and partially overcome impaired ADCC by FF genotype individuals in vitro.

Surgical intensive care unit admission variables predict subsequent readmission.

Intensive care unit (ICU) readmissions are associated with increased resource use. Defining predictors may improve resource use. Surgical ICU patients requiring readmission will have different characteristics than those who do not. We conducted a retrospective cohort study of a prospectively maintained database. The Acute Physiology and Chronic Health Evaluation (APACHE) IV quality database identified patients admitted January 1 through December 31, 2011. Patients were divided into groups: NREA = patients admitted to the ICU, discharged, and not readmitted versus REA = patients admitted to the ICU, discharged, and readmitted. Comparisons were made at index admission, not readmission. Categorical variables were compared by Fisher's exact testing and continuous variables by t test. Multivariate logistic regression identified independent predictors of readmission. There were 765 admissions. Seventy-seven patients required readmission 94 times (12.8% rate). Sixty-two patients died on initial ICU admission. Admission severity of illness was significantly higher (APACHE III score: 69.54 ± 21.11 vs 54.88 ± 23.48) in the REA group. Discharge acute physiology scores were equal between groups (47.0 ± 39.2 vs 44.2 ± 34.0, P = nonsignificant). In multivariate analysis, REA patients were more likely admitted to emergency surgery (odds ratio, 1.9; 95% confidence interval, 1.01 ± 3.5) more likely to have a history of immunosuppression (2.7, 1.4 ± 5.3) or higher Acute Physiology Score (1.02; 1.0 ± 1.03) than NREA. Patients who require ICU readmission have a different admission profile than those who do not "bounce back." Understanding these differences may allow for quality improvement projects such as instituting different discharge criteria for different patient populations.

Assessment of neoadjuvant chemotherapy on operative parameters and outcome in patients with peritoneal dissemination from high-grade appendiceal cancer.

BACKGROUND: High-grade appendiceal adenocarcinoma is a rare malignancy with propensity for peritoneal metastases (PM). The impact of neoadjuvant chemotherapy on operative cytoreduction (CRS) and intraperitoneal chemotherapy (HIPEC) and patient survival was reviewed. METHODS: A total of 45 patients with PM from high-grade appendiceal adenocarcinoma were identified from a prospective database. All patients had laparotomy with intent to undergo CRS and HIPEC. Operative parameters, complications, and survival outcomes were analyzed. RESULTS: Of the 45 patients (male: 27, female: 18; median age: 55 years), 26 received neoadjuvant chemotherapy ± bevacizumab. Of the 26, 15 (58 %) had a response based on improvement in imaging, biomarkers, or both and 9 (34 %) had stable disease. The median peritoneal cancer index (PCI) was 27. Also, 30 (67 %) had a completeness of cytoreduction score (CCR) of ≤1 and 37 (82 %) received HIPEC. There were no differences in PCI, CCR score, operative blood loss, or major organ resection between those who received or did not receive neoadjuvant chemotherapy. Operative time was significantly shorter in those who did not receive neoadjuvant chemotherapy. Major complications and length of hospital stay were similar between the groups. The median actuarial overall survival calculated from the date of initial therapeutic intervention was not different in those treated with or without neoadjuvant therapy. CONCLUSIONS: Neoadjuvant chemotherapy has marked clinical activity in patients with PM from high-grade appendiceal adenocarcinoma and does not adversely affect operative outcomes. These data support conducting a prospective clinical trial to define the role of neoadjuvant chemotherapy in this clinical setting.

Palliative surgical oncology.

Palliative surgical oncology is a relatively new concept, but builds on a long tradition in surgery. As the field of palliative medicine grows and becomes its own specialty, surgeons have been receiving some specialized training in palliative care; devising specific palliative surgical procedures; and reevaluating the ethics of their interactions with patients, especially for the selection of palliative surgical procedures. This is leading to a new form of surgical practice in which the emphasis is on relief of present or anticipated symptoms, even if the interventions do not prolong a patient's life span.

Is there a role for palliative gastrectomy in patients with stage IV gastric cancer?

Patients with metastatic gastric cancer are currently not considered operative candidates and are most often offered systemic therapy. Palliative resection of the primary tumor has been considered irrelevant to the outcome and has been recommended only for palliation of symptoms. We have examined the role of palliative gastrectomy and its impact on survival in patients with stage IV gastric cancer at initial diagnosis between 1990 and 2000. A total of 105 patients with stage IV disease were identified during this period; 81 of them (77.1%) had no resection, and 24 (22.9%) underwent palliative gastric resection. Mean survival in those without resection who received chemotherapy (with or without radiation) treatment was 5.9 months (95% confidence interval 4.2-7.6). For those with resection and adjuvant therapy, mean survival time was 16.3 months (95% confidence interval 4.3-28.8 months). Kaplan-Meier survival analysis showed significantly better survival in those with resection and adjuvant therapy (log-rank test, P = 0.01). Mortality and morbidity rates associated with palliative resection were 8.7% and 33.3%, respectively, which did not differ statistically from the 3.7% and 25.3% in patients who underwent curative gastrectomy during same period of time. However, the length of hospitalization (22 versus 16 days) was significantly higher compared with those without stage IV disease. These data suggest that palliative resection combined with adjuvant therapy may improve survival in a selected group of patients with stage IV gastric cancer. Palliative gastrectomy plus systemic therapy should be compared with systemic therapy alone in a randomized trial.

Radiofrequency ablation of primary and metastatic hepatic malignancies.

Radiofrequency interstitial tissue ablation is a local ablative therapy in which tumors are destroyed in situ by thermal coagulation and protein denaturation through frictional heating produced by tissue ionic agitation from high-frequency alternating current. This technology can be used to destroy primary and metastatic hepatic lesions generally considered nonresectable or nonoperable, thus providing patients with these tumors, who have few treatment options, a relatively safe and effective alternative with the potential for improved chance of survival. Knowledge of the broad spectrum of potential complications associated with radiofrequency ablation (RFA) is essential for prevention, early detection, and proper management. Combining RFA with other modalities such as surgical resection or hepatic artery infusional chemotherapy is feasible, has increased the pool of operable patients, and may improve treatment efficacy and clinical outcome in properly selected patients. The approach to perform RFA percutaneously, laparoscopically, or during laparatomy should take into consideration tumor characteristics, imaging and technical limitations, and the role of other treatment modalities. Therefore, patients considered for RFA should be evaluated within the context of a multidisciplinary approach to insure proper patient selection and coordination of adjunct therapy.

Ovarian neoplasms in patients with colorectal cancer: understanding the role of prophylactic oophorectomy.

Although the role of prophylactic oophorectomy is currently under debate and not well defined, it is of increasing and considerable relevance, especially in premenopausal women, particularly those with identifiable hereditary cancer syndromes. Patients with colorectal cancer with ovarian metastases are often symptomatic, require surgery, and have poor survival. Prophylactic oophorectomy abolishes the increased risk of primary ovarian cancer in these patients, resects synchronous metastases, and prevents development of metachronous ovarian metastases. Prophylactic oophorectomy trials, mostly conducted in postmenopausal women, have not shown survival advantage. In patients with ovarian metastases of colorectal cancer, maximal cytoreductive surgery followed by adjuvant therapy employing newer chemotherapeutic agents, whole abdominal irradiation with chemosensitization, or hyperthermic intraperitoneal chemotherapy may improve outcomes in selected patients.

Molecular genetics and management strategies in hereditary cancer syndromes.

The origin, characteristics, and lifetime risk for the following five types of hereditary cancer (HCS) syndromes are briefly described in this review: hereditary breast and ovarian cancer (HBOC) syndrome, familial adenomatous polyposis (FAP), and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, hereditary diffuse gastric cancer (HDGC) syndrome, and medullary thyroid carcinoma (MTC). Most are caused by mutations in tumor suppressor genes. In HCS, a single copy of the mutated tumor suppressor gene is inherited, and mutation of the second wild type allele of the gene is required for tumorigenesis. Patients with HCS have a higher than normal risk of a second malignancy. Management strategies to address increased cancer risk in HCS include genetic counseling and testing, targeted surveillance, chemoprevention, and prophylactic surgery. Genetic testing for high-risk family members is strongly recommended. Available data indicate surgical prophylaxis is more successful than surveillance in reducing cancer risk in carriers of BRCA, CDH1, APC, and RET mutation.

Dual induction of the Epo-Egr-TNF-alpha- plasmid in hypoxic human colon adenocarcinoma produces tumor growth delay.

Gene therapy is a modality for the treatment of solid tumors that involves the introduction of a suicide gene into the tumor cells. Genetic radiotherapy involves the placement of a radiation-sensitive promoter upstream from a suicide gene. Because of their irregular vasculature some solid tumors are chronically hypoxic and hence are resistant to conventional treatment with chemotherapy and ionizing radiation (IR). The purpose of this study was to demonstrate that regional tumor hypoxia could be exploited to improve local tumor control. The cDNA coding the erythropoietin hypoxia-responsive element (EPO) was placed upstream from the Egr-TNF-alpha construct. WIDR human colon adenocarcinoma cells were injected into the right hind limb of nude mice and treated with Epo-Egr-TNF-alpha plasmid with or without IR. Tumor volumes were measured by calipers and tumor necrosis factor (TNF)-alpha content of the tumor was determined by enzyme-linked immunosorbent assay. Treatment with the combined regimen of Epo-Egr-TNF-alpha plasmid + IR resulted in significant tumor growth delay. Tumor TNF-alpha content was increased by 30 per cent in the combined treatment group compared with each treatment alone. Regional tumor hypoxia can be exploited successfully to induce tumor growth delay, enhance local control, and enhance the therapeutic ratio.

Intraoperative parasympathetic nerve stimulation with tumescence monitoring during total mesorectal excision for rectal cancer.

BACKGROUND: Unilateral or bilateral division of the parasympathetic nerves during resection of rectal cancer may result in sexual erectile dysfunction. The purposes of this project were twofold: to determine the ability to demonstrate penile tumescence in response to parasympathetic nerve stimulation after rectal cancer resection and to correlate the nerve stimulation response with clinical sexual function 6 months after operation. STUDY DESIGN: In 21 consecutive male patients with normal erectile function undergoing total mesorectal excision, cavernous nerve identification and integrity before and after pelvic dissection were assessed intraoperatively, both visually by an experienced surgeon and by using the CaverMap nerve stimulator. The minimal effective current necessary to produce a 2% increase in penile tumescence was recorded for both the left- and right-sided nerves, primarily the largest nerve trunk, S3. Postclearance stimulation data were then correlated with sexual function outcomes, specifically erection and orgasm at 6 months after surgery. RESULTS: The operating surgeon's visual assessment of the pelvic autonomic nerve's integrity after pelvic dissection was deemed intact in 20 of the 21 patients (95.2%). Of the 20 patients who were evaluated with CaverMap after completion of total mesorectal excision, 17 (85%) had tumescence response after nerve stimulation on either side, and 3 patients (15%) had unilateral response only. Of the 19 patients evaluated for sexual function 6 months after surgery, 18 (94.7%) had normal function, including the 3 patients with only unilateral nerve stimulation tumescence response. CONCLUSIONS: Intraoperative mapping of the parasympathetic nerve trunks with the CaverMap nerve stimulator may be a valuable aid to less experienced pelvic surgeons and may help in autonomic nerve preservation during total mesorectal excision clearance.