Surgical Options for End-Stage Achalasia.

PURPOSE OF REVIEW: Achalasia is one of the most commonly described primary esophageal motility disorders worldwide, but there is significant controversy regarding ideal management of end-stage disease. This article reviews the definition of end-stage achalasia and summarizes past and present surgical treatment. RECENT FINDINGS: Myotomy of the lower esophageal sphincter remains the mainstay of treatment of achalasia, even in advanced disease. Esophagectomy may have benefit as a primary treatment modality in end-stage achalasia with sigmoid esophagus, but international guidelines recommend consideration of laparoscopic or endoscopic approaches initially in most patients. Novel peroral esophageal plication techniques may provide alternative treatment options in patients with significant esophageal dilation that fail myotomy or esophagectomy. SUMMARY: End-stage achalasia is characterized by progressive tortuosity and dilation of the esophagus as a failure of primary peristalsis. Up to 20% of patients with achalasia will progress to end-stage disease. In most cases, laparoscopic or endoscopic myotomy is recommended as initial approach to surgical management.

Abnormal response after multiple rapid swallow provocation is not predictive of post-operative dysphagia following a tailored fundoplication approach.

INTRODUCTION: The aim was to evaluate the clinical significance of multiple rapid swallows (MRS) during high-resolution manometry (HRM) prior to fundoplication. Despite pre-operative HRM, up to 38% of patients report post-fundoplication dysphagia. Suggestion that MRS improves prediction of dysphagia after fundoplication has not been investigated when using a tailored approach. We hypothesize response to MRS is predictive of dysphagia after tailored fundoplication. METHODS: A retrospective cohort study was performed on patients undergoing HRM with MRS provocation 5/2019-7/2021 at a single institution. Patients who underwent subsequent index laparoscopic fundoplication, without peptic stricture or achalasia, were included. After performing standard 10-swallow HRM, MRS provocation was performed. Patient-reported dysphagia frequency scores were collected at initial consultation and post-operative follow-up. At least weekly symptoms were considered clinically significant. Normal MRS response was defined as adequate deglutitive inhibition and MRS contractile response. Fundoplications were tailored based on standard HRM values. RESULTS: HRM was performed in 1201 patients, 220 met inclusion criteria. Clinically significant pre-operative dysphagia was reported by 85 (38.6%). Patients undergoing partial fundoplication (n = 123, 55.9%) had lower mean distal contractile integer, distal esophageal contraction amplitude, and percent peristalsis (p < 0.005). Post-operatively, 120 (54.5%) were without dysphagia, 59 (26.8%) had improved dysphagia, 26 (11.8%) had unchanged dysphagia, and 15 (6.8%) reported new dysphagia. There was no statistical difference in early or late dysphagia outcome between tailored fundoplication groups (p = 0.69). On univariate and multivariate analysis, neither MRS response, nor standard HRM metrics were significantly associated with post-operative dysphagia. Younger age (OR 0.96, 95% CI 0.94-0.986, p = 0.042) and the presence of pre-operative dysphagia (OR 2.54, 95% CI 1.17-5.65, p = 0.015) were significant predictors of post-operative dysphagia. CONCLUSION: The risk of clinically significant dysphagia post-fundoplication is low when using a tailored approach based on standard HRM metrics. Additional data provided by MRS does not add to surgical decision-making using the investigated approach.

Diaphragmatic relaxing incisions for complex hiatal reconstruction: longer-term follow-up confirms safety, efficacy and rare complications.

BACKGROUND: Tension is an important factor in hernia repairs. Relaxing incisions to reduce tension are common with ventral hernia repairs, and techniques for relaxing incisions also exist for the hiatus. The aim of this study was to update our original experience with a diaphragm relaxing incision (DRI) in a larger group of patients with longer follow-up. METHODS: A retrospective chart review was performed to identify all patients who had a DRI between August 2016 and September 2021 during hiatal hernia repair. All DRI defects were repaired with permanent mesh remote from the esophagus. Objective follow-up was with chest x-ray, upper GI series (UGI) or both. RESULTS: Seventy-three patients had a total of 79 DRI (right in 63, left in 4, and bilateral in 6 patients), during a primary (n = 52) or redo (n = 21) hiatal hernia repair. Concomitant Collis gastroplasty was used in 38 patients (52%). A single intra-operative complication occurred where the right crus tore during a right DRI. At a median of 15 months, 78% of patients had objective follow-up. There was one hernia through a repaired right DRI (1.2%). No patient had evidence of diaphragm paralysis and there were no mesh infections. The 1-year hernia recurrence rate in these patients was 3.9%. CONCLUSIONS: A DRI can be done safely with minimal risk of intra- or post-operative complications. There was a low rate of herniation through the defect when repaired with permanent mesh. No patient developed a mesh infection despite concomitant Collis gastroplasty in 52% of patients, and there was no evidence of diaphragm paralysis on imaging studies. Further, the low rate of hiatal hernia recurrence suggests efficacy of a DRI to reduce crural closure tension. These excellent outcomes should encourage use of a DRI in patients with a difficult hiatus during hernia repair.

Tropomyosins induce neuritogenesis and determine neurite branching patterns in B35 neuroblastoma cells.

BACKGROUND: The actin cytoskeleton is critically involved in the regulation of neurite outgrowth. RESULTS: The actin cytoskeleton-associated protein tropomyosin induces neurite outgrowth in B35 neuroblastoma cells and regulates neurite branching in an isoform-dependent manner. CONCLUSIONS: Our data indicate that tropomyosins are key regulators of the actin cytoskeleton during neurite outgrowth. SIGNIFICANCE: Revealing the molecular machinery that regulates the actin cytoskeleton during neurite outgrowth may provide new therapeutic strategies to promote neurite regeneration after nerve injury. SUMMARY: The formation of a branched network of neurites between communicating neurons is required for all higher functions in the nervous system. The dynamics of the actin cytoskeleton is fundamental to morphological changes in cell shape and the establishment of these branched networks. The actin-associated proteins tropomyosins have previously been shown to impact on different aspects of neurite formation. Here we demonstrate that an increased expression of tropomyosins is sufficient to induce the formation of neurites in B35 neuroblastoma cells. Furthermore, our data highlight the functional diversity of different tropomyosin isoforms during neuritogenesis. Tropomyosins differentially impact on the expression levels of the actin filament bundling protein fascin and increase the formation of filopodia along the length of neurites. Our data suggest that tropomyosins are central regulators of actin filament populations which drive distinct aspects of neuronal morphogenesis.

Missed Opportunities: the Timing and Frequency of Screening Colonoscopy in Patients That Develop Esophageal Adenocarcinoma.

INTRODUCTION: Screening colonoscopy (SC) is widely accepted and has been shown to decrease the rate of colorectal cancer death. Guidelines and acceptance of screening for Barrett's esophagus (BE) are less established despite the fact that esophageal adenocarcinoma (EA) remains the fastest increasing cancer in the USA. The aim of this study was to assess the timing and frequency of SC in patients ultimately found to have EA and to evaluate the presence of symptoms and risk factors that might have prompted an esophagogastroduodenoscopy (EGD) and potentially earlier diagnosis of the EA. METHODS: A retrospective chart review was performed to identify all patients who were referred to a single center with esophageal cancer between July 2016 and November 2022. Patients with any histology other than adenocarcinoma were excluded. RESULTS: There were 221 patients referred with EA. Of these, a SC had been done prior to the diagnosis of EA in 108 patients (49%): 96 men and 12 women. A total of 203 SC had been done (range 1-7 per patient), and 47% of patients had more than 1 SC. The median interval from the last SC to the diagnosis of EA was 2.9 years. At the time of SC, gastroesophageal reflux disease (GERD) symptoms or chronic acid suppression medication use was reported by 81% of patients, and 80% had an American Society of Gastrointestinal Endoscopy (ASGE) indication for a screening EGD. Only 19 patients (18%) that had a SC had an EGD at any time prior to the diagnosis of EA, and in these patients, 74% had erosive esophagitis or BE. The EA in most patients was stage III or IV and associated with lymph node metastases. CONCLUSIONS: Nearly one-half of patients ultimately diagnosed with EA had one or more SCs, and most of these patients had GERD symptoms, were using acid suppression medications or had an ASGE indication for a screening EGD. Despite this, only 18% had an EGD prior to the EA diagnosis. The addition of an EGD at the time of SC in these patients may have allowed the detection of BE or EA at an early, endoscopically curable stage and represents a missed opportunity to intervene in the natural history of this disease.

Tropomyosin isoform 3 promotes the formation of filopodia by regulating the recruitment of actin-binding proteins to actin filaments.

Tropomyosins are believed to function in part by stabilizing actin filaments. However, accumulating evidence suggests that fundamental differences in function exist between tropomyosin isoforms, which contributes to the formation of functionally distinct filament populations. We investigated the functions of the high-molecular-weight isoform Tm3 and examined the molecular properties of Tm3-containing actin filament populations. Overexpression of the Tm3 isoform specifically induced the formation of filopodia and changes in actin solubility. We observed alterations in actin-binding protein recruitment to filaments, co-incident with changes in expression levels, which can account for this functional outcome. Tm3-associated filaments recruit active actin depolymerizing factor and are bundled into filopodia by fascin, which is both up-regulated and preferentially associated with Tm3-containing filaments in the Tm3 overexpressing cells. This study provides further insight into the isoform-specific roles of different tropomyosin isoforms. We conclude that variation in the tropomyosin isoform composition of microfilaments provides a mechanism to generate functionally distinct filament populations.

Cell elasticity is regulated by the tropomyosin isoform composition of the actin cytoskeleton.

The actin cytoskeleton is the primary polymer system within cells responsible for regulating cellular stiffness. While various actin binding proteins regulate the organization and dynamics of the actin cytoskeleton, the proteins responsible for regulating the mechanical properties of cells are still not fully understood. In the present study, we have addressed the significance of the actin associated protein, tropomyosin (Tpm), in influencing the mechanical properties of cells. Tpms belong to a multi-gene family that form a co-polymer with actin filaments and differentially regulate actin filament stability, function and organization. Tpm isoform expression is highly regulated and together with the ability to sort to specific intracellular sites, result in the generation of distinct Tpm isoform-containing actin filament populations. Nanomechanical measurements conducted with an Atomic Force Microscope using indentation in Peak Force Tapping in indentation/ramping mode, demonstrated that Tpm impacts on cell stiffness and the observed effect occurred in a Tpm isoform-specific manner. Quantitative analysis of the cellular filamentous actin (F-actin) pool conducted both biochemically and with the use of a linear detection algorithm to evaluate actin structures revealed that an altered F-actin pool does not absolutely predict changes in cell stiffness. Inhibition of non-muscle myosin II revealed that intracellular tension generated by myosin II is required for the observed increase in cell stiffness. Lastly, we show that the observed increase in cell stiffness is partially recapitulated in vivo as detected in epididymal fat pads isolated from a Tpm3.1 transgenic mouse line. Together these data are consistent with a role for Tpm in regulating cell stiffness via the generation of specific populations of Tpm isoform-containing actin filaments.

A novel class of anticancer compounds targets the actin cytoskeleton in tumor cells.

The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers.

The actin cytoskeleton as a sensor and mediator of apoptosis.

Apoptosis is an important biological process required for the removal of unwanted or damaged cells. Mounting evidence implicates the actin cytoskeleton as both a sensor and mediator of apoptosis. Studies also suggest that actin binding proteins (ABPs) significantly contribute to apoptosis and that actin dynamics play a key role in regulating apoptosis signaling. Changes in the organization of the actin cytoskeleton has been attributed to the process of malignant transformation and it is hypothesized that remodeling of the actin cytoskeleton may enable tumor cells to evade normal apoptotic signaling. This review aims to illuminate the role of the actin cytoskeleton in apoptosis by systematically analyzing how actin and ABPs regulate different apoptosis pathways and to also highlight the potential for developing novel compounds that target tumor-specific actin filaments.