International classification of abdominal wall planes (ICAP) to describe mesh insertion for ventral hernia repair.

BACKGROUND: Nomenclature for mesh insertion during ventral hernia repair is inconsistent and confusing. Several terms, including 'inlay', 'sublay' and 'underlay', can refer to the same anatomical planes in the indexed literature. This frustrates comparisons of surgical practice and may invalidate meta-analyses comparing surgical outcomes. The aim of this study was to establish an international classification of abdominal wall planes. METHODS: A Delphi study was conducted involving 20 internationally recognized abdominal wall surgeons. Different terms describing anterior abdominal wall planes were identified via literature review and expert consensus. The initial list comprised 59 possible terms. Panellists completed a questionnaire that suggested a list of options for individual abdominal wall planes. Consensus on a term was predefined as occurring if selected by at least 80 per cent of panellists. Terms scoring less than 20 per cent were removed. RESULTS: Voting started August 2018 and was completed by January 2019. In round 1, 43 terms (73 per cent) were selected by less than 20 per cent of panellists and 37 new terms were suggested, leaving 53 terms for round 2. Four planes reached consensus in round 2, with the terms 'onlay', 'inlay', 'preperitoneal' and 'intraperitoneal'. Thirty-five terms (66 per cent) were selected by less than 20 per cent of panellists and were removed. After round 3, consensus was achieved for 'anterectus', 'interoblique', 'retro-oblique' and 'retromuscular'. Default consensus was achieved for the 'retrorectus' and 'transversalis fascial' planes. CONCLUSION: Consensus concerning abdominal wall planes was agreed by 20 internationally recognized surgeons. Adoption should improve communication and comparison among surgeons and research studies.

ANTECEDENTES: La nomenclatura de la inserción de una malla para la reparación de una hernia incisional ventral (ventral hernia, VH) es inconsistente y confusa. En la literatura indexada se usan varios términos, tales como 'inlay', 'sublay', y 'underlay' que pueden referirse a los mismos planos anatómicos. Este hecho frustra las comparaciones de técnicas quirúrgicas e invalida los metaanálisis que comparan resultados quirúrgicos en función del plano de inserción de la malla. En consecuencia, el objetivo de este estudio fue establecer una clasificación internacional de los planos de la pared abdominal (International Classification of Abdominal Wall Planes, ICAP). MÉTODOS: Se realizó un estudio Delphi, en el que participaron 20 cirujanos de pared abdominal reconocidos internacionalmente. Se identificaron diferentes términos que describían los planos de la pared abdominal anterior mediante la revisión de la literatura y el consenso de expertos. La lista inicial incluía 59 términos posibles. Los panelistas completaron un cuestionario que sugería una lista de opciones para los planos individuales de la pared abdominal. El consenso sobre un término fue predefinido cuando dicho término había sido seleccionado por ≥ 80% de panelistas. Se eliminaron los términos con una puntuación < 20%. RESULTADOS: La votación comenzó en agosto de 2018 y se completó en enero de 2019. Durante la Ronda 1, 43 (73%) términos fueron seleccionados por < 20% de los panelistas y se sugirieron 37 términos nuevos, dejando 53 términos para la Ronda 2. Cuatro planos alcanzaron un consenso en la Ronda 2 con los términos 'onlay', 'inlay', 'pre-peritoneal' e 'intra-peritoneal'. Treinta y cinco (66%) términos fueron seleccionados por < 20% de los panelistas y fueron eliminados. Después de la Ronda 3, se logró un consenso para 'anterectus' (ante-recto), 'interoblique' (inter-oblicuo), 'retrooblique' (retro-oblicuo) y 'retromuscular'. Se alcanzó un consenso por defecto para los planos 'retrorectus' (retro-recto) y 'transversalis fascial' (fascial transverso). CONCLUSIÓN: La ICAP ha sido desarrollada por el consenso de 20 cirujanos reconocidos internacionalmente. Su implementación debería mejorar la comunicación y la comparación entre cirujanos y estudios de investigación.

Precision GERD management for the 21st century.

The highly heterogeneous nature of gastroesophageal reflux disease (GERD), together with the multiplicity of available diagnostic and therapeutic options (lifestyle, pharmacologic, endoscopic and surgical) available today call for a new approach that funnels the multidimensionality of the disease into precise and effective algorithms - reviewed herein- aimed at improving clinical outcomes.

Whole greater than the parts: integrated esophageal centers (IEC) and advanced training in esophageal diseases.

An integrated esophageal center (IEC) is a multidisciplinary team with expertise, skill, range, and facilities necessary to achieve optimal outcomes in patients with esophageal diseases efficiently and expeditiously. Within IEC, patients presenting with esophageal symptoms undergo a detailed clinical, functional and structural evaluation of their esophagus prior to implementation of tailored medical, endoscopic or surgical therapy. Serving as a core, the IEC clinical practice also supports research and innovation in esophageal diseases as well as public and physician education. Referrals to the unit may be primary, either from primary care or self-initiated, or secondary from other specialty practices, to reassess patients who have previously failed therapies and to manage complex or complicated cases. The fundamental goals of the IEC are to provide value for patients with esophageal diseases, streamlining complex diagnostic investigations and expediting therapies aiming at reducing costs while improving clinical outcomes, and to accelerate knowledge generation through robust interaction and cross-training across disciplines. The organization of the IEC goes beyond traditional academic and clinical silos and involves a director and administrative team coordinating faculty and fellows from both medical and surgical disciplines and supported by other clinical lines, such as radiology, pathology, etc., while it interfaces with physicians, the public, basic, translational and clinical research groups, and related industry partners.

Molecular mechanisms of activation and regulation of ANO1-Encoded Ca2+-Activated Cl- channels.

Ca2+-activated Cl- channels (CaCCs) perform a multitude of functions including the control of cell excitability, regulation of cell volume and ionic homeostasis, exocrine and endocrine secretion, fertilization, amplification of olfactory sensory function, and control of smooth muscle cell contractility. CaCCs are the translated products of two members (ANO1 and ANO2, also known as TMEM16A and TMEM16B) of the Anoctamin family of genes comprising ten paralogs. This review focuses on recent progress in understanding the molecular mechanisms involved in the regulation of ANO1 by cytoplasmic Ca2+, post-translational modifications, and how the channel protein interacts with membrane lipids and protein partners. After first reviewing the basic properties of native CaCCs, we then present a brief historical perspective highlighting controversies about their molecular identity in native cells. This is followed by a summary of the fundamental biophysical and structural properties of ANO1. We specifically address whether the channel is directly activated by internal Ca2+ or indirectly through the intervention of the Ca2+-binding protein Calmodulin (CaM), and the structural domains responsible for Ca2+- and voltage-dependent gating. We then review the regulation of ANO1 by internal ATP, Calmodulin-dependent protein kinase II-(CaMKII)-mediated phosphorylation and phosphatase activity, membrane lipids such as the phospholipid phosphatidyl-(4,5)-bisphosphate (PIP2), free fatty acids and cholesterol, and the cytoskeleton. The article ends with a survey of physical and functional interactions of ANO1 with other membrane proteins such as CLCA1/2, inositol trisphosphate and ryanodine receptors in the endoplasmic reticulum, several members of the TRP channel family, and the ancillary Κ+ channel ß subunits KCNE1/5.

Anti-reflux procedures: complications, radiologic findings, and surgical and gastroenterologic perspectives.

This article provides an overview of the current surgical anti-reflux procedures and their imaging findings, as well as the surgical complications. Accurate and timely clinical assessment requires an engaged radiologist fluoroscopist who understands the perspectives of their interdisciplinary colleagues, including the surgeon and gastroenterologist. The complex pathophysiology calls for an interdisciplinary approach, and the radiologist needs to tailor their evaluation to answer the specific questions posed by their clinical colleagues and by the presenting symptomatology.

Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine.

The phenomenon of alkylation tolerance has been observed in cells that are deficient in some component of the DNA mismatch repair (MMR) system. An alkylation-induced cell cycle arrest had been reported previously in one MMR-proficient cell line, whereas a MMR-defective clone derived from this line escapes from this arrest. We examined human cancer cell lines to determine if the cell cycle arrest were dependent upon the MMR system. Growth characteristics and cell cycle analysis after MNNG treatment were ascertained in seven MMR-deficient and proficient cell lines, with and without confirmed mutations in hMLH1 or hMSH2 by an in vitro transcription/translation assay. MMR-proficient cells underwent growth arrest in the G2 phase of the cell cycle after the first S phase, whereas MMR-deficient cells escaped an initial G2 delay and resumed a normal growth pattern. In the HCT116 line corrected for defective MMR by chromosome 3 transfer, the G2 phase arrest lasted more than five days. In another MMR-proficient colon cancer cell line, SW480, cell death occurred five days after MNNG treatment. A competent MMR system appears to be necessary for G2 arrest or cell death after alkylation damage, and this cell cycle checkpoint may allow the cell to repair damaged DNA, or prevent the replication of mutated DNA by prohibiting clonal expansion.

Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint.

The human colon tumor cell line HCT116 is deficient in wild-type hMLH1, is defective in mismatch repair (MMR), exhibits microsatellite instability, and is tolerant to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Transferring a normal copy of hMLH1 on chromosome 3 into the cell line restores MMR activity, stabilizes microsatellite loci, and increases the sensitivity of the cell to MNNG. Previous studies in other cell lines tolerant to alkylating agents such as MNNG or N-methylnitrosourea have shown cross-tolerance to 6-thioguanine (6TG), leading to a hypothesis that tolerance to MNNG or 6TG may be the result of MMR deficiency. To test this hypothesis, we studied the effects of 6TG on the MNNG-tolerant, MMR-deficient HCT116 cell line and its MNNG-sensitive, MMR-proficient, MNNG-tolerant, and MMR-deficient derivatives. Continuous exposure to low doses of 6TG (0.31-1.25 micrograms/ml) had no apparent effect on colony-forming ability (CFA) in MNNG-tolerant, MMR-deficient cells, whereas MNNG-sensitive, MMR-proficient cells exhibited a dose-dependent decrease in CFA. Growth kinetics and cell cycle analysis revealed that the growth of 6TG-treated HCT116 + chr3 cells was arrested at G2 after exposure to low dose of 6TG. In contrast, the same exposure to 6TG did not induce G2 arrest but rather a G1 delay in HCT116 and HCT116 + chr2. To obtain further evidence for the role of MMR on 6TG and MNNG toxicity, we isolated an MNNG-resistant revertant clone, M2, from the MNNG-sensitive, MMR-proficient HCT116 + chr3 cell line and characterized the MMR activity, hMLH1 status, and 6TG response. The results showed that M2 cells lost MMR activity as well as the previously introduced normal hMLH1 gene. Restoration of the CFA of M2 and an absence of G2 arrest were observed after treatment with low doses of 6TG. These results suggest that the mismatch repair system interacts with the G2 checkpoint in response to 6TG or MNNG-induced DNA lesions. The results further suggest that any agent that induces DNA mispairs will cause G2 arrest in MMR-proficient cells but not in MMR-deficient cells.

Patient satisfaction, chronic pain, and quality of life after elective incisional hernia repair: effects of recurrence and repair technique.

PURPOSE: To determine the effects of repair technique and hernia recurrence on patient-reported outcomes after incisional hernia repair. METHODS: This cohort study included patients from sixteen Veteran's Affairs Medical Centers across the United States who underwent elective incisional hernia repair between 1997 and 2002. Technical details and outcomes (repair type and recurrence status) were determined by physician chart review. Patient satisfaction, chronic pain (McGill pain scale and visual analogue scale), and health-related quality of life (Short Form 36) were evaluated with a mailed survey at a median of five years after repair. Multivariable regression modeling was performed to evaluate the effect of repair type and recurrence status on patient-reported outcomes. RESULTS: Of 854 patients alive at the time of survey mailing, 371 responded (43.4%). Patients with active recurrence were more likely to be dissatisfied with their results (odds ratio (OR) 6.2, P < 0.0001), to have chronic sensory hernia site pain (OR 3.2, P = 0.01), to report disturbance from pain (OR 2.1, P = 0.04), and to have significantly worse quality of life on the Physical Function, General Health, and Physical Component Score domains. Repair technique with permanent mesh versus suture had no independent effect on patient satisfaction, chronic pain, or QOL. CONCLUSIONS: Recurrence has a substantial negative effect on patient-reported outcomes after incisional hernia repair, whereas the repair technique has no independent effect.

Open suture versus mesh repair of primary incisional hernias: a cost-utility analysis.

BACKGROUND: Despite 100,000 ventral hernia repairs (VHR) being performed annually, no gold standard for the technique exists. Mesh has been shown to decrease recurrence rates, yet, concerns of increased complications and costs prevent its systematic use. We examined the cost-effectiveness of open suture (OS) versus open mesh (OM) in primary VHR. METHODS: A decision analysis model from the payer's perspective comparing OS to OM was constructed for calculating the total costs and cost-effectiveness. Probabilities for complications and outcomes were derived from the literature. The costs represented institutional fixed costs. The outcome measure of effectiveness was recurrence. One-way sensitivity analysis and a probabilistic analysis using Monte Carlo simulation were performed. RESULTS: OS was associated with a total cost of $16,355 (+/-6,041) per repair, while OM was $16,947 (+/-7,252). At 3-year follow-up, OM was the more effective treatment with 73.8% being recurrence-free, compared with 56.3% in the OS group. The incremental cost to prevent one recurrence by the placement of mesh was $1,878. OM became the less effective treatment strategy when the infection rate exceeded 35%. At a willingness to pay level of $5,500, OM was the more cost-effective treatment strategy. CONCLUSION: In subjects without contraindication to mesh placement, OM repair is the more effective surgical treatment for VHR, with a lower risk of recurrence at a small cost to the payer.

Carbonic anhydrase II gene expression in isolated canine gastric parietal cells.

The participation of carbonic anhydrase (CA II) in the gastric acid secretory process has been the subject of considerable controversy. We utilized a cDNA probe for CA II to measure CA II gene expression in canine gastric parietal cells that had been stimulated with the three principal acid secretagogues, carbachol, gastrin, and histamine. Hybridization to dot blots of total parietal cell RNA showed a significant increase in specific CA II mRNA content within minutes of secretagogue addition: carbachol stimulation led to an increase of 52 +/- 8.9%, reaching a maximum within 20 min; gastrin stimulation led to an increase within 60 min of 104 +/- 10.6%; stimulation with histamine was followed within 20 min by an increase of 30 +/- 7.2%. We also measured transcription rates for the CA II gene in cells stimulated by each agent and found an increase within 15 min. Our results show that CA II gene expression is regulated by agents that stimulate the parietal cell to secrete acid and that the accumulation of CA II mRNA subsequent to the initial interaction of stimulant appears to result from new transcription of the CA II gene. These data suggest the participation of CA II in the acid secretory response of the parietal cell to secretagogues.

Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer.

BACKGROUND & AIMS: Allelic loss of a portion of chromosome 18q and lack of expression of deleted in colorectal cancer (DCC) protein has been reported as an adverse prognostic indicator for stage II (i.e., Dukes' B2) colorectal cancer. Our aim was to assess whether the DCC gene locus was responsible. METHODS: We amplified five DNA microsatellite markers located on chromosome 18q21 surrounding or within the DCC gene locus, including a DCC intragenic (TA)n microsatellite, from DNA microdissected and isolated from paraffin-embedded, formalin-fixed specimens of 70 patients with stage II colorectal cancer. Epidemiological and survival data were blinded from the microsatellite analysis to avoid bias. RESULTS: The average follow-up time was 63.3 months for all patients. Eleven patients died of colorectal cancer by the end of the study. Loss of heterozygosity of 18q21 was present in 30 of 70 (43%) tumors. After adjustment for all other evaluated factors, 18q21 allelic loss was not a predictor of survival (hazard ratio, 1.17; 95% confidence interval, 0.27-5.10; P = 0.84). CONCLUSIONS: Loss of heterozygosity of 18q21 does not seem to predict a survival disadvantage in stage II colorectal cancer in our patient population, and its proposed use as a prognosticator of survival or chemotherapy stratification marker for stage II tumors is not substantiated.

Developing a free supportive care program for cancer patients within an integrative medicine clinic.

The cancer patient's journey not only includes a threat to one's life, but the need to face many medical and emotional challenges. The free Cancer Supportive Care Program (CSCP) within the Center for Integrative Medicine Clinic at Stanford University Hospital and Clinics has been identified as a successful model for helping patients to deal with these challenges. Its programs include informational lectures, support groups, chair massages, exercise, alternative modality classes, a Life Tapes Project, an informational website, and a bimonthly newsletter available free to anybody touched by cancer. Now in its third year, this program benefits from a blending of leadership resources, availability of space, institutional agreement on patient need and funds from private and corporate donations. By presenting the basic premises of the Cancer Supportive Care program and outlining specifics about the program, institutions in various national and international demographic regions may implement similar programs according to their resources and the needs of patients. It is our hope that the CSCP can become a model for the development of similar programs in various parts of the United States and abroad.

In vitro transcription/translation assay for the screening of hMLH1 and hMSH2 mutations in familial colon cancer.

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) has been linked recently to a defect in repairing mismatched nucleotides in DNA. The aim of this study was to screen for germline mutations that result in prematurely truncated proteins in two of the mismatch repair genes identified at this time, hMLH1 and hMSH2, in a consecutive series of patients belonging to familial aggregations of colorectal cancer. METHODS: Nineteen individuals with colorectal cancer from 19 families were consecutively referred because of a strong positive family history of colorectal cancer. Premature truncation mutations in hMLH1 and hMSH2 were sought from lymphocyte RNA by using an in vitro transcription/translation (IVTT) assay. RESULTS: Protein truncating mutations in the hMLH1 or hMSH2 genes were found in 50% of families with HNPCC (6 of 12) but were not observed in any of the remaining familial aggregations that did not fulfill the standard criteria for HNPCC. In some of the IVTT-positive samples, the mutations were characterized by genomic sequencing. CONCLUSIONS: IVTT may be a practical method to accomplish primary screening of germline mutations in DNA mismatch pair genes in HNPCC; however, a broader approach is necessary to obtain a more complete picture of the mutational spectrum in HNPCC and other familial aggregations of colorectal cancer.