Characterization of Pleural Mesothelioma by Hierarchical Clustering Analyses Using Immune Cells within Tumor Microenvironment.

INTRODUCTION: Over the past decade, classifications using immune cell infiltration have been applied to many types of tumors; however, mesotheliomas have been less frequently evaluated. METHODS: In this study, 60 well-characterized pleural mesotheliomas (PMs) were evaluated immunohistochemically for the characteristics of immune cells within tumor microenvironment (TME) using 10 immunohistochemical markers: CD3, CD4, CD8, CD56, CD68, CD163, FOXP3, CD27, PD-1, and TIM-3. For further characterization of PMs, hierarchical clustering analyses using these 10 markers were performed. RESULTS: Among the immune cell markers, CD3 (p < 0.0001), CD4 (p = 0.0016), CD8 (p = 0.00094), CD163+ (p = 0.042), and FOXP3+ (p = 0.025) were significantly associated with an unfavorable clinical outcome. Immune checkpoint receptor expressions on tumor-infiltrating lymphocytes such as PD-1 (p = 0.050), CD27 (p = 0.014), and TIM-3 (p = 0.0098) were also associated with unfavorable survival. Hierarchical clustering analyses identified three groups showing specific characteristics and significant associations with patient survival (p = 0.016): the highest number of immune cells (ICHigh); the lowest number of immune cells, especially CD8+ and CD163+ cells (ICLow); and intermediate number of immune cells (ICInt). ICHigh tumors showed significantly higher expression of PD-L1 (p = 0.00038). Cox proportional hazard model identified ICHigh [hazard ratio (HR) = 2.90] and ICInt (HR = 2.97) as potential risk factors compared with ICLow. Tumor CD47 (HR = 2.36), tumor CD70 (HR = 3.04), and tumor PD-L1 (HR = 3.21) expressions were also identified as potential risk factors for PM patients. CONCLUSION: Our findings indicate immune checkpoint and/or immune cell-targeting therapies against CD70-CD27 and/or CD47-SIRPA axes may be applied for PM patients in combination with PD-L1-PD-1 targeting therapies in accordance with their tumor immune microenvironment characteristics.

Characterization of colorectal cancer by hierarchical clustering analyses of five immune cell markers.

The present study analyzed the expression of five independent immunohistochemical markers, CD4, CD8, CD66b, CD68, and CD163, on immune cells within the colorectal cancer (CRC) tumor microenvironment (TME). Using hierarchical clustering, patients were successfully classified according to significant associations with clinicopathological features and/or survival. Patients with mismatch repair-proficient (pMMR) CRC were categorized into four groups with survival differences (p = 0.0084): CD4Low , CD4High , MΦHigh , and CD8Low . MΦHigh tumors showed significantly higher expression of CD47 (p < 0.0001), a phagocytosis checkpoint molecule. These tumors contained significantly greater numbers of PD-1+ (p < 0.0001), TIM-3+ (p < 0.0001), and SIRPA+ (p < 0.0001) immune cells. Notably, 10% of the patients with pMMR CRC expressed PD-L1 (CD274) on tumor cells with significantly worse survival (p = 0.00064). The Cox proportional hazards model identified MΦ High (hazard ratio [HR] = 2.02, 95%, p = 0.032), CD8Low (HR = 2.45, p = 0.011), and tumor PD-L1 expression (HR = 2.74, p = 0.0061) as potential risk factors. PD-L1-PD-1 and/or CD47-SIRPA axes targeting immune checkpoint therapies might be considered for patients with pMMR CRC according to their tumor cells and tumor immune microenvironment characteristics.

Simultaneous Expression of CD70 and POSTN in Cancer-Associated Fibroblasts Predicts Worse Survival of Colorectal Cancer Patients.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.

The cisplatin-induced acute kidney injury is a novel risk factor for postoperative complications in patients with esophageal cancer: a retrospective cohort study.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is common during preoperative chemotherapy for esophageal cancer. The purpose of this study was to investigate the association between AKI after preoperative chemotherapy and postoperative complications in patients with esophageal cancer. METHODS: In this retrospective cohort study, we included patients who had received preoperative chemotherapy with cisplatin and underwent surgical resection for esophageal cancer under general anesthesia from January 2017 to February 2022 at an education hospital. A predictor was stage 2 or higher cisplatin-induced AKI (c-AKI) defined by the KDIGO criteria within 10 days after chemotherapy. Outcomes were postoperative complications and length of hospital stays. Associations between c-AKI and outcomes including postoperative complications and length of hospital stays were examined with logistic regression models. RESULTS: Among 101 subjects, 22 developed c-AKI with full recovery of the estimated glomerular filtration (eGFR) before surgery. Demographics were not significantly different between patients with and without c-AKI. Patients with c-AKI had significantly longer hospital stays than those without c-AKI [mean (95% confidence interval (95%CI)) 27.6 days (23.3-31.9) and 43.8 days (26.5-61.2), respectively, mean difference (95%CI) 16.2 days (4.4-28.1)]. Those with c-AKI had higher C-reactive protein (CRP) levels and prolonged weight gain after surgery and before the events of interest despite having comparable eGFR trajectories after surgery. c-AKI was significantly associated with anastomotic leakage and postoperative pneumonia [odds ratios (95%CI) 4.14 (1.30-13.18) and 3.87 (1.35-11.0), respectively]. Propensity score adjustment and inverse probability weighing yielded similar results. Mediation analysis showed that a higher incidence of anastomotic leakage in patients with c-AKI was primarily mediated by CRP levels (mediation percentage 48%). CONCLUSION: c-AKI after preoperative chemotherapy in esophageal cancer patients was significantly associated with the development of postoperative complications and led to a resultant longer hospital stay. Increased vascular permeability and tissue edema due to prolonged inflammation might explain the mechanisms for the higher incidence of postoperative complications.

Impact of the indocyanine green fluorescence method for anastomotic blood flow in robotic distal gastrectomy.

PURPOSE: To evaluate the blood flow at the site of delta-shaped anastomosis during robotic distal gastrectomy and determine surgical outcomes and risk factors for ischemia at the anastomotic site from the perspective of clinical characteristics, surgical outcomes and perigastric vascular anatomy. METHODS: We included 55 patients who underwent robotic distal gastrectomy with a blood flow evaluation in the duodenal walls using intravenous indocyanine green injection with the da Vinci Xi-equipped Firefly system. Additional resection was performed in patients with a poor blood flow. Clinical characteristics, surgical outcomes and perigastric vascular anatomy were compared between the 45 patients with sufficient blood flow (group S) and the 10 patients with insufficient blood flow (group I). Vascular anatomy was assessed by preoperative contrast-enhanced computed tomography according to Hiatt's classification. RESULTS: The patient characteristics and surgical outcomes were not significantly different. No patient developed anastomotic complications requiring intervention; more patients in group I had aberrant branching of the left hepatic artery than those in group S (p = 0.047). CONCLUSIONS: An indocyanine green-based blood flow evaluation might be an effective method of preventing anastomotic complications of delta-shaped anastomosis. Anatomical branching variations of the left hepatic artery might be a risk factor for impaired vascular perfusion of the anastomotic site.

Near infrared ray-guided surgery using Firefly technology of the daVinci Xi system and intraoperative upper gastrointestinal endoscopy for subtotal gastrectomy and surgery for cancer of the gastroesophageal junction.

BACKGROUND: In gastrectomies, especially subtotal gastrectomies and operations on the gastroesophageal junction, identifying the exact location of the tumor and establishing the appropriate resection line is very important. Accurate resection lines have a major impact on the preservation of organ function and curability. Preservation of as much as possible of the remaining stomach, including the fornix, may be an important surgical goal for maintaining an adequate postoperative quality of life. In adenocarcinoma of the gastroesophageal junction, the height of the esophageal dissection may affect reconstruction of the transhiatal approach. METHODS: We perform a new technique, near infrared ray-guided surgery, for the accurate localization of a tumor using the Firefly technology of the daVinci Xi system and intra-operative upper gastrointestinal endoscopy. We used this new technique for cases of upper gastric cancer or adenocarcinoma of the gastroesophageal junction. In this retrospective study, we examined to determine the extent (mm) of the tumor invasion of the esophagus, visualization of near infrared ray contained within endoscopic light, and distance from the proximal margin of the tumor to the surgical cut line on rapid histopathology and in the permanent preparation, including the operative videos and extracted specimens. RESULTS: We performed near infrared ray-guided surgery for 12 patients with gastric cancer or adenocarcinoma of the gastroesophageal junction, and the near infrared ray was clearly seen as green light with Firefly mode in all the patients. Near infrared ray-guided surgery was useful for obtaining localization of the tumor. In addition, it was possible to resect organ with adequate margins from tumor. Rapid intraoperative histopathological examinations confirmed that the resected specimens had negative margins. None of the patients required additional resection. CONCLUSIONS: We believe that because near infrared ray-guided surgery can provide an accurate resection line, it will be useful for the resection of upper gastric cancer and adenocarcinoma of the gastroesophageal junction. It will also provide patients with a good postoperative quality of life after surgery.

Diagnosis of recurrent laryngeal nerve paralysis following esophagectomy by evaluating movement of the vocal cords and arytenoid cartilages using ultrasonography.

Advancements in thoracoscopic surgery have provided us with a deeper anatomical understanding of recurrent laryngeal nerve paralysis (RLNP), which is likely to occur after lymph node dissection. Taking a novel approach to researching the diagnosis of RLNP, we evaluated movement of the vocal cords and arytenoid cartilages using ultrasonography in patients who underwent thoracoscopic esophagectomy. RLNP occurred in six of the 24 patient cohort. The rate of hoarseness and difficulty in discharging sputum was significantly higher in the paralyzed group than in the non-paralyzed group. The diagnostic accuracy of RLNP by ultrasonography had a sensitivity of 83.3% (5/6), a specificity of 88.8% (16/18), a false positive rate of 5.6% (1/18), and a false negative rate of 0% (0/6). Although it is not completely accurate, our findings indicate that ultrasonography is quite effective for diagnosing RLNP, more so in combination with clinical symptoms. Ultrasonography may also be effective for identifying patients who are amenable to laryngoscopy for diagnosing RLNP, or for evaluating the recovery status of nerve paralysis.

Impact of endoscopic resection on the choice of surgical procedure in patients with additional laparoscopic gastrectomy.

BACKGROUND: Additional surgery is recommended for patients with noncurative resection after endoscopic submucosal dissection (ESD) for early gastric cancer. Additional resection requires the excision of an area larger than that of the resected mucosa in ESD, which is larger than the lesion, with convergence of the gastric mucosa due to scarring. Thus, the selection of the surgical procedure for lesion removal in specific areas can be affected by ESD. This study therefore aimed to evaluate the impact of ESD on the selection of additional gastrectomy in patients with early gastric cancer in the boundary area between the upper third and middle third of the stomach (UM boundary region). METHODS: Between January 2013 and June 2018, laparoscopic gastrectomy was performed in 89 patients with cT1N0M0 gastric cancer located only in the UM boundary region. The patients' backgrounds and surgical and pathological results were retrospectively investigated. The predictive factors for performing laparoscopic distal gastrectomy (LDG) were evaluated by multivariate analysis. RESULTS: Among 89 patients, 23 patients underwent ESD before surgery. LDG was significantly less often performed in the ESD-surgery group than in the surgery-only group (34.8% vs. 72.7%; p = 0.003). Preoperative ESD was an independent negative predictor of LDG (odds ratio = 0.266; p = 0.025). CONCLUSIONS: Preoperative ESD has an impact on the selection of the type of additional gastrectomy, including reducing the conduct of LDG for early gastric cancer in the UM boundary region.

Effect of azygos arch preservation during thoracoscopic esophagectomy on facilitation of postoperative refilling.

PURPOSE: In esophageal cancer surgery, the significance of preserving the azygos arch during thoracoscopic esophagectomy remains unknown. To determine the significance, we examined the difference in postoperative courses between patients who underwent an azygos arch-preserving technique and patients whose azygos arch had been dissected. METHODS: We retrospectively analyzed 119 patients with esophageal cancer who underwent thoracoscopic esophagectomy from January 2017 to December 2019. Statistical tests, including univariate or multivariate analyses and propensity score-matched analysis, were performed focusing on changes in fluid balance caused by the preservation of the azygos arch. RESULTS: The azygos arch was preserved in 65 patients and dissected in 54 patients. Urine output on postoperative day 2 was higher, and the IN-OUT balance on postoperative day 2 or accumulated IN-OUT balance up to postoperative day 2 tended to be lower in the azygos arch-preserving group than in the dissected group. The azygos arch-preserving technique did not affect the number of dissected mediastinal lymph nodes. CONCLUSION: The azygos arch-preserving technique during thoracoscopic esophagectomy facilitated postoperative refilling and avoided postoperative fluid excess. This technique might be a novel minimally invasive option for an otherwise highly invasive esophageal cancer surgery.

[A Case of Esophagogastric Junction(EGJ)Cancer for Which Pathological Complete Response(pCR)Was Obtained by Multidisciplinary Treatment].

We report the case of a 68-year-old male with EGJ cancer, who was treated with palliative radiotherapy for persistent bleeding, and for whom, pCR was ultimately obtained by chemotherapy. Chemotherapy was planned to treat the EGJ cancer with intramural metastasis of the esophagus, but anemia due to persistent bleeding from the tumor was noted. Even with frequent blood transfusions, the anemia was difficult to control. Palliative radiotherapy was performed at 30 Gy/10 Fr for hemostasis, followed by chemotherapy. After approximately 9 months of chemotherapy, reduction of the primary tumor, a metastatic lymph node, and disappearance of the intramural metastasis of the esophagus were noted, and conversion surgery was performed. In the final histopathological examination, pCR was obtained. Radiotherapy for persistent bleeding from advanced gastric cancer is a minimally invasive treatment, and therefore could be an effective treatment to enable chemother- apy without any loss of compliance.

[A Case Report of Esophageal Cancer Accompanied with Esophago-Bronchial Fistula Which Treated Using Multimodal Therapy Including Esophageal Bypass Surgery].

We report the case of a patient with esophageal cancer accompanied by esophago-bronchial fistula and pneumonia, who experienced improved quality of life following multimodal therapy that included esophageal bypass surgery. A 56-year-old man was diagnosed with advanced esophageal cancer with an esophago-bronchial fistula on computed tomography scan. He underwent esophageal bypass surgery followed by definitive chemoradiotherapy. He started eating 12 days after the surgery and was discharged home after the completion of chemoradiotherapy. On follow-up, the primary lesion was found to be significantly decreased in size and the esophago-bronchial fistula was closed. Although the patient ultimately died owing to distant metastases, he enjoyed a prolonged period of survival following surgery. Multimodal therapy including esophageal bypass surgery is an useful strategy for treating patients with critical conditions such as esophago-bronchial fistula induced by esophageal cancer.

Laparoscopic pancreas-preserving duodenectomy: Minimally invasive surgery for superficial nonampullary duodenal epithelial tumors.

No consensus exists regarding the optimal treatment for superficial nonampullary duodenal epithelial tumors. Herein, we describe a laparoscopic pancreas-preserving duodenectomy for the treatment of a 30-mm adenoma located in the third portion of the duodenum. The adenoma was located on the pancreatic side, further hindering safe endoscopic resection. Via laparoscopy, the jejunum was transected first. After releasing the third portion of the duodenum from the retroperitoneal space, the jejunum was pulled to the right side of the superior mesenteric artery and separated from the pancreas. Under endoscopic guidance, the duodenum was then transected and duodenojejunostomy performed intracorporeally. Laparoscopic pancreas-preserving duodenectomy can be considered minimally invasive, achieving tumor radicality while preserving organs and causing minimal destruction to the abdominal wall. In conclusion, although technically demanding, laparoscopic pancreas-preserving duodenectomy is a valuable treatment option for superficial nonampullary duodenal epithelial tumors.

Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers.

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.

Robotic distal gastrectomy plus spleen-preserving distal pancreatectomy: optimal resection for simultaneous gastric cancer and intraductal papillary mucinous neoplasm of the pancreatic body.

BACKGROUND: Organ-preserving surgery has recently gained increasing attention. However, performing the surgery for duplicated gastric and distal pancreatic tumors is difficult because of procedural complexity and concerns of remnant gastric necrosis. We present the first case of simultaneous robotic distal gastrectomy plus spleen-preserving distal pancreatectomy in a patient with overlapping gastric cancer and intraductal papillary mucinous neoplasm. CASE PRESENTATION: A 78-year-old man was diagnosed with gastric cancer in the middle stomach and intraductal papillary mucinous neoplasm of the pancreatic body. Radical cure surgery was performed using the da Vinci Xi robotic system. Conventional distal gastrectomy was initially completed using near-infrared ray guidance when transecting the stomach. After dividing the pancreas, the parenchyma of the distal pancreas was detached from the splenic artery and vein; multiple branches from these splenic vessels were dissected. Indocyanine green imaging confirmed sufficient blood flow in the splenic vessels and perfusion of the remnant stomach. Ultimately, gastrointestinal reconstruction was performed, and the postoperative course was uneventful. CONCLUSIONS: The robotic distal gastrectomy plus spleen-preserving distal pancreatectomy procedure was safely performed. Compared to the total gastrectomy plus distal pancreatectomy with splenectomy procedure, this technique may improve the quality of dietary life, reduce weight loss, and prevent complications associated with splenectomy.

Laparoscopic gastrectomy for gastric cancer with two left gastric arteries: Safe and adequate lymphadenectomy in a rare arterial abnormality.

Clinical studies have established the safety and advantages of laparoscopic surgery for gastric cancer; therefore, laparoscopic gastrectomy (LG) in clinical practice is increasing. We report the case of a 77-year-old patient with gastric cancer who was referred to our center for LG. Esophagogastroduodenoscopy revealed a type 3 tumor identified as adenocarcinoma on biopsy. Three-dimensional computed tomography-angiography revealed two left gastric arteries (LGAs) branching from the celiac trunk. By laparoscopically performing the outermost layer-oriented lymphadenectomy (OML-OL), the two LGAs were detected and appropriately divided. Subtotal gastrectomy was completed, and the patient had an uneventful postoperative course. The OML-OL was appropriate for LG in this situation. This case demonstrates the necessity of preoperative three-dimensional computed tomography-angiography with 1-mm slices and the importance of performing OML-OL.

Severe esophageal stricture after perforation and necrotizing esophagitis: unusual presentation of a duodenal gastrinoma.

Gastrinomas are pancreatic or duodenal endocrine tumors that secrete excess gastrin, which causes gastroesophageal reflux disease, peptic ulcers, and chronic diarrhea. Due to the rarity of the disease, nonspecific symptoms, and the outstanding effect of proton pump inhibitors, diagnosing gastrinomas is difficult. Here, we present the case of a 58-year-old woman who had a duodenal gastrinoma that caused rare but critical events, including esophageal perforation, necrotizing esophagitis, and severe esophageal stricture. She presented with a non-malignant severe lower esophageal stricture, which was resistant to endoscopic dilatation. During esophagectomy, a duodenal mass was excised and diagnosed as gastrinoma. This was considered the main cause of all events. Gastrinomas are rarely encountered in clinical practice, but early diagnosis is necessary to avoid serious conditions. Therefore, whenever we encounter a patient with gastroesophageal reflux disease requiring long-term treatment or is refractory, we must not forget to screen for gastrinomas.

Robotic gastrectomy for remnant gastric cancer after pancreaticoduodenectomy.

The utility of robotic surgery for remnant gastric cancer remains unclear. We report a case of a robotic gastrectomy for remnant gastric cancer after pancreaticoduodenectomy and Child reconstruction with Braun enteroenterostomy. Adhesiolysis, lymphadenectomy, and gastrectomy were robotically performed. Indocyanine green fluorescence imaging confirmed the tissue perfusion of the reconstructive tract. The patient's postoperative course was uneventful. Robotic surgery facilitates safety for gastrectomy after pancreaticoduodenectomy because of its precise manipulation; its advantages can be further exploited by maximizing usage of the assistant's forceps. Indocyanine green fluorescence imaging capability of the da Vinci Xi Surgical System allows timely evaluation of tissue perfusion at the site of interest, leading to a more reliable procedure.

Simultaneous robotic distal gastrectomy and distal pancreatectomy: Avoiding total gastrectomy using indocyanine green fluorescence imaging.

Remnant gastric ischemia is the most significant complication in distal pancreatectomy (DP) after distal gastrectomy (DG). Some studies have reported the safety of asynchronous DP in patients who underwent DG. We report a case of simultaneous robotic DG and DP. A 78-year-old man was diagnosed with gastric and pancreatic cancer. We preoperatively confirmed the absence of anomalies in the left inferior phrenic artery. Robotic simultaneous DG and DP was performed; subtotal resection of the stomach was carried out, enabling the left inferior phrenic artery to maintain perfusion of the remnant stomach, even after ligation of the splenic artery. The remnant stomach was preserved as scheduled, and indocyanine green fluorescence imaging confirmed sufficient remnant stomach tissue perfusion. Robotic surgery using the da Vinci surgical system (with a fluorescence imaging system and technology enabling surgical precision) is suitable for this surgical procedure because it considers tumor radicality and allows for function preservation.

Benefits of laparoscopic trans-hiatal approach with Heller-Dor surgery in a case of mid-esophageal diverticulum.

Compared to the more common epiphrenic diverticula, those located at the central section of the esophagus are quite rare. Minimally invasive approaches for mid-esophageal diverticula have lacked standardization. Certain mid-esophageal diverticula, like epiphrenic diverticula, have been attributed to esophageal motility disorders. Thus, we believe that surgery for esophageal diverticula requires preoperative evaluation of esophageal function, with additional surgery being performed in case of abnormalities. The laparoscopic trans-hiatal approach has been a common technique for managing epiphrenic diverticula but can also be used for mid-esophageal diverticula located far from the esophagogastric junction provided that the port location is carefully considered. Laparoscopic surgery is also preferable given that it is a minimally invasive procedure and allows for diverticulum resection and Heller myotomy and Dor surgery to prevent reflux in the same field of view. Hence, laparoscopic surgery may be a beneficial alternative to the traditional thoracic or thoracoabdominal techniques.

Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

The effect of the cyclooxygenase-2 (COX-2) inhibitor etodolac on the mechanical allodynia induced by paclitaxel was investigated in mice and compared with the effects of the nonselective COX inhibitors indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib, the calcium channel α(2)δ subunit inhibitor pregabalin, the sodium channel blocker mexiletine, and the serotonin-norepinephrine reuptake inhibitor duloxetine. The decrease in the paw-withdrawal threshold induced by paclitaxel was reversed by oral administration of etodolac at 10 mg/kg but was not affected by indomethacin, diclofenac, or celecoxib. The antiallodynic effect of etodolac gradually increased during repeated administration, and after 2 weeks the paw-withdrawal threshold at the preadministration point was significantly increased. Pregabalin, duloxetine, and mexiletine also showed an antiallodynic effect in this model. Whereas pregabalin had a preadministration effect similar to that of etodolac during repeated administration, mexiletine or duloxetine had no such effect. There was almost no difference in the distribution of etodolac and diclofenac in nervous tissue, indicating that COX inhibition is unlikely to be involved in the antiallodynic effect of etodolac. Etodolac did not show a neuroprotective effect against morphological transformations such as the axonal degeneration induced by paclitaxel. Instead, etodolac probably acts at the level of functional changes accompanying paclitaxel treatment, such as alterations in the activation state of components of the pain transmission pathway. Our findings suggest that etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway and that it might be useful for the treatment of paclitaxel-induced peripheral neuropathy.