Impact of comprehensive geriatric assessment on treatment strategies and complications in older adults with colorectal cancer considering surgery.

BACKGROUND AND OBJECTIVES: This study aimed to assess the effectiveness of Comprehensive Geriatric Assessment (CGA) in customizing care for elderly cancer patients, specifically focusing on colorectal cancer. The research compared treatment strategies and outcomes in older adults considered for surgery before and after the initiation of a Geriatric Oncology Service (GOS). METHODS: Conducting a comparative study, two cohorts of consecutive colorectal cancer patients aged 75 or older were examined: the control group (n = 156) and the GOS group (n = 158). Upon the treating surgeon's GOS consultation request, a geriatrician and an oncologist performed CGA, guiding treatment decisions and perioperative interventions. Postoperative complications were compared using propensity score matching (PSM). RESULTS: In the GOS group, 91% (n = 116) underwent CGA consultations, influencing decisions to forego surgery in 12 patients. After PSM for surgical cases (controls n = 146, GOS n = 146), each group comprised 128 patients. Perioperative physical therapy and pharmacist referrals were more frequent in the GOS group. The GOS group exhibited a significantly lower incidence of postoperative complications (22%) compared to the control group (33%) (p = 0.0496). CONCLUSION: Patients undergoing colorectal surgery post-GOS implementation experienced a notable reduction in postoperative complications, highlighting the positive impact of personalized geriatric assessment on surgical outcomes in the elderly.

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α.

BACKGROUND: Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. OBJECTIVE: We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. METHODS: LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. RESULTS: Gene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-ß-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. CONCLUSIONS: There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.

The evolution of surgical treatment for gastrointestinal cancers.

INTRODUCTION: According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. MATERIALS AND METHODS, AND RESULTS: Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. CONCLUSION: We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival.

Prognostic Significance of Postoperative Complications After Curative Resection for Patients With Esophageal Squamous Cell Carcinoma.

OBJECTIVE: The objective of this study was to elucidate the impact of postoperative complications on long-term survival after curative resection for esophageal squamous cell carcinoma. BACKGROUND: The relation between postoperative complications and long-term survival after curative surgery for esophageal squamous cell carcinoma is controversial; thus, this issue should be resolved with a large-scale, well-designed study. METHODS: Clinicopathological features and survival of 580 consecutive patients who received curative resection for esophageal squamous cell carcinoma were investigated according to the development of postoperative pulmonary complications and anastomotic leakage. RESULTS: The 5-year survival rates of patients with pStage 0, I, and II disease with postoperative complications (n = 116) were significantly poorer than those of patients without postoperative complications (n = 288) (overall 69.6% vs 46.9%, P < 0.0001; disease-specific; 76.7% vs 58.9%, P < 0.0022), whereas no differences were found in patients with pStage III and IV disease (n = 176). In the univariate and multivariate analyses for disease-specific survival, pT3, pT4, pN positivity, and development of postoperative complications were significant prognostic factors in all patients. Also, when the analysis was limited to the pStage 0, I, and II patients, development of postoperative complications, and pT3, pT4, and pN positivity, were found to be independent poor prognostic factors in multivariate analyses (hazard ratio: 1.56, 95% confidence interval, 1.01-2.41, P = 0.0476). CONCLUSIONS: The development of postoperative complications is an independent disease-specific poor prognostic factor after curative resection for patients with less-advanced esophageal squamous cell carcinoma.

Clinicopathological Features of Cervical Esophageal Cancer: Retrospective Analysis of 63 Consecutive Patients Who Underwent Surgical Resection.

OBJECTIVE: The objectives of this retrospective study were to elucidate the clinicopathological features and recent surgical results of cervical esophageal cancer. SUMMARY BACKGROUND DATA: Cervical esophageal cancer has been reported to have a dismal prognosis. Accurate knowledge of the clinical characteristics of cervical esophageal cancer is warranted to establish appropriate therapeutic strategies. METHODS: The clinicopathological features and treatment results of 63 consecutive patients with cervical esophageal cancer (Ce group) who underwent surgical resection from 1980 to 2013 were analyzed and compared with 977 patients with thoracic or abdominal esophageal cancer (T/A group) who underwent surgical resection during that time. RESULTS: Among the patients who received curative resection, the 5-year overall and disease-specific survival rates of the Ce patients were significantly better than those of the T/A patients (overall: 77.3% vs 46.5%, respectively, P = 0.0067; disease-specific: 81.9% vs 55.8%, respectively, P = 0.0135). Although total pharyngo-laryngo-esophagectomy procedures were less frequently performed in the recent period, the rate of curative surgical procedures was markedly higher in the recent period (2000-1013) than that in the early period (1980-1999) (44.4% vs 88.9%, P = 0.0001). The 5-year overall survival rate in the recent period (71.5%) was significantly better than that in the early period (40.7%, P = 0.0342). CONCLUSIONS: Curative resection for cervical esophageal cancer contributes to favorable outcomes compared with other esophageal cancers. Recent surgical results for cervical esophageal cancer have improved, and include an increased rate of curative resection and decreased rate of extensive surgery.

The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers.

Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.

Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.

Clinicopathological characteristics of esophageal squamous cell carcinoma in patients younger than 50 years.

PURPOSE: This study clarifies age differences in clinicopathologic characteristics and risk factor exposure of patients who have undergone esophagectomy for esophageal cancer (EC). METHODS: Clinical results of esophagectomy were compared between 22 patients younger than 50 years of age (Group I) and 327 patients older than 50 years of age (Group II) with esophageal squamous cell carcinoma. RESULTS: The two groups did not significantly differ in clinicopathological characteristics, including prognosis. Postoperative pulmonary complication incidence rates were 4.2 % (Group I) and 14.4 % (Group II). In Group I, the incidence of multiple ECs was 36.4 %, and association with head and neck cancer was 31.8 %, which were significantly higher than in Group II (13.4 %, p = 0.021; and 9.2 %, p = 0.015, respectively). Furthermore, the patients in Group I with multiple cancers were almost all heavy smokers and/or users of alcohol. CONCLUSIONS: These results suggest that multiple upper aerodigestive tract cancers are associated with heavy exposure to risk factors in patients younger than 50 years of age.

Recent advances in multidisciplinary approach for rectal cancer.

Surgery is a major treatment option for rectal cancer, and total mesorectal excision has been demonstrated to be advantageous in terms of oncological outcome and thus has been the standard surgical approach. Radiotherapy before or after radical surgery is the optimal treatment to control local recurrence of advanced rectal cancer. To date, in many countries, the combination of neoadjuvant concurrent chemotherapy and radiotherapy is considered the standard therapy. A more recent interest in neoadjuvant therapy has been the use of oxaliplatin or targeted agents for neoadjuvant chemoradiotherapy. However, despite many trials of oxaliplatin and targeted agents, 5-FU-based concurrent chemoradiotherapy has remained the only standard treatment option. Postoperative adjuvant chemotherapy with neoadjuvant chemoradiotherapy or induction chemotherapy with neoadjuvant chemoradiotherapy may further improve patient survival, as some clinical studies recently indicated. In Japan, neoadjuvant therapy is not the standard treatment method, because surgery with lateral lymph node dissection is usually performed and this type of surgery may reduce recurrence rate as does radiation therapy. The phase III study to evaluate the oncological effect of the Japanese standard operation (mesorectal excision, ME) with lateral lymph node dissection in comparison with ME alone for clinical stage II and III lower rectal cancer is currently ongoing.

Non-cirrhotic portal-systemic encephalopathy caused by enlargement of a splenorenal shunt after pancreaticoduodenectomy for locally advanced duodenal cancer: report of a case.

We report a case of portal-systemic encephalopathy occurring secondary to a splenorenal shunt, 2 years after a pancreaticoduodenectomy for locally advanced duodenal carcinoma. A 55-year-old woman was brought to our hospital with a decreased level of consciousness. Laboratory testing revealed an elevated serum ammonia level (221 µg/dl) and normal liver function. Retrospective review of a series of contrast-enhanced computed tomography scans of the abdomen identified a splenorenal shunt, which had gradually enlarged over the past 2 years (Fig. 1). The decreased level of consciousness was thought to be due to portal-systemic encephalopathy secondary to the splenorenal shunt. We performed balloon-occluded retrograde transvenous obliteration to occlude the splenorenal shunt, following which her serum ammonia level returned to normal (28 µg/dl) and an alert level of consciousness was maintained.

Gender differences in prognosis after esophagectomy for esophageal cancer.

PURPOSE: The purpose of this study was to clarify the gender differences in the prognosis, as well as mortality and morbidity, of patients who have undergone esophagectomy for esophageal cancer. METHODS: The clinical results of esophagectomy were compared between 975 male and 156 female patients with esophageal cancer. RESULTS: The male to female ratios of cervical and thoracic esophageal cancer were 1.87 and 7.38, respectively (P < 0.01). The incidence of preoperative comorbidities was 32.4 and 17.4 %, respectively, and the rates of both tobacco and alcohol abuse were significantly lower in the females than in the males. The mortality rate was lower in the females (3.8 %) than in the males (5.7 %), although the differences were not significant. The overall survival was significantly better in the female than in the male patients (P = 0.039). The 5- and 10-year overall survival rates were 32.6 and 20.5 % in the males and 39.5 and 32.5 % in the females, respectively. A multivariate analysis revealed gender to be an independent prognostic factor. However, no significant differences were recognized in disease-specific survival. CONCLUSIONS: These results suggest that the prognosis of females with esophageal cancer is better than that of males after esophagectomy, most likely due to multiple clinical factors, such as a more favorable lifestyle and general status.

Multimodal treatment strategy for clinical T3 thoracic esophageal cancer.

PURPOSE: Our goal was to create a multimodal treatment strategy for patients with locally advanced esophageal cancer (EC). METHODS: A retrospective review identified a total of 193 patients with clinical T3 thoracic EC were categorized into 3 groups: 81 who had surgery only (group I); 102 who had planned neoadjuvant chemoradiotherapy (NACRT; group II); and 10 who had salvage esophagectomy after definitive chemoradiotherapy (dCRT; group III). RESULTS: Postoperative complications developed in 27, 45, and 80 % of patients in group I, group II, and group III, respectively. NACRT and dCRT were independent risk factors associated with postoperative complications; the odds ratios for group II and group III, compared with group I, were 2.1 and 8.8, respectively. The respective mortality rates were 4, 2, and 20 % (group I vs. group III, p < 0.05; group II vs. group III, p < 0.01). The 5-year survival rate was 25.2 % in group I and 41.6 % in group II. The 5-year survival rate in group II patients with markedly effective NACRT (89.2 %) was significantly better than in patients with ineffective/slightly effective (11.8 %; p < 0.0001) and moderately effective treatment (51 %; p < 0.05). Four patients who had noncurative surgery died within 4 months after salvage esophagectomy, whereas four of six patients were still alive after curative surgery. CONCLUSIONS: A pathological complete response to NACRT is critical for improving survival in patients with clinical T3 thoracic EC. Salvage surgery should be considered only in carefully selected patients with locally advanced EC.

Clinical results of preoperative CDDP/5-FU chemotherapy followed by surgery for patients with clinical stage II/III thoracic esophageal cancer.

PURPOSE: The purpose of this study was to clarify the outcomes of preoperative CDDP/5-FU chemotherapy (FP therapy) followed by surgery for patients with clinical Stage II/III thoracic esophageal cancer. METHODS: Seventeen patients with clinical Stage II/III thoracic esophageal cancer who underwent FP therapy followed by esophagectomy were investigated with regard to the perioperative clinical results and postoperative outcomes. RESULTS: Grade 3 or 4 adverse effects associated with FP therapy were recognized in 2 of the 17 (11.8%) cases, and 16 patients completed 2 cycles of FP therapy (94.1%). Complications after surgery occurred in 7 cases (41.2%). There were 7 patients with postoperative recurrences (41.2%), 6 of whom had clinical Stage III disease. Similarly, 4 out of the 5 patients who died of cancer had clinical Stage III disease. All recurrences and cancer-related deaths were recognized in histological effectiveness of Grade 0/1 cases. CONCLUSIONS: Preoperative FP therapy was found to be safe for patients with clinical Stage II/III thoracic esophageal cancer. However, the treatment seemed to be less beneficial for Stage III patients than for Stage II patients, thus suggesting that a more powerful preoperative treatment may be necessary for clinical Stage III patients.

CD73+ Epithelial Progenitor Cells That Contribute to Homeostasis and Renewal Are Depleted in Eosinophilic Esophagitis.

BACKGROUND & AIMS: Although basal cell hyperplasia is a histologic hallmark of eosinophilic esophagitis (EoE), little is known about the capabilities of epithelial renewal and differentiation in the EoE inflammatory milieu. In murine esophageal epithelium, there are self-renewing and slowly proliferating basal stem-like cells characterized by concurrent expression of CD73 (5'-nucleotidase ecto) and CD104 (integrin ß4). Here, we investigated CD73+CD104+ cells within the basal population of human esophageal epithelium and clarified the biological significance of these cells in the EoE epithelium. METHODS: We performed flow cytometry on esophageal biopsy samples from EoE and non-EoE patients to determine the quantity of CD73+CD104+ cells in the epithelium. Simulating the EoE milieu we stimulated primary patient-derived and immortalized cell line-derived esophageal organoids with interleukin (IL)4 and IL13 and analyzed by flow cytometry, immunohistochemistry, and quantitative reverse-transcription polymerase chain reaction. We performed single-cell RNA sequencing on primary organoids in the setting of IL13 stimulation and evaluated the CD73+CD104+ population. We performed fluorescent-activated cell sorting to purify CD73+CD104+ and CD73- CD104+ populations and seeded these groups in organoid culture to evaluate the organoid formation rate and organoid size. We used RNA interference to knock down CD73 in esophageal organoids to evaluate organoid formation rates and size. We evaluated the effects of signal transducer and activator of transcription 6 (STAT6) signaling inhibition by RNA interference, a STAT6 inhibitor, AS1517499, as well as the proton pump inhibitor omeprazole. RESULTS: EoE patients showed decreased epithelial CD73+CD104+ cell content. IL4 and IL13 stimulation depleted this population in 3-dimensional organoids with a recapitulation of basal cell hyperplasia as corroborated by single-cell RNA sequencing of the organoids, which suggests depletion of CD73+CD104+ cells. The CD73+CD104+ population had enhanced organoid formation compared with the CD73-CD104+ population. Similarly, knock-down of CD73 resulted in decreased organoid formation rate. Genetic and pharmacologic inhibition of STAT6 prevented T helper 2 cytokine-induced depletion of CD73+CD104+ cells. Lastly, omeprazole treatment prevented the effects of IL4 and IL13 on the CD73+CD104+ population. CONCLUSIONS: This study addressed the role of CD73+CD104+ cells in epithelial renewal and homeostasis in the context of EoE. The depletion of the CD73+CD104+ self-renewal population by helper T cell 2 cytokines in EoE milieu may be perpetuating epithelial injury. Future therapies targeting epithelial restitution in EoE could decrease the need for immune modulation and steroid therapy.

Recent developments in cancer research: Expectations for a new remedy.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Resection and reconstruction of pancreatic artery aneurysms caused by the compression of the celiac trunk by the median arcuate ligament: a report of two cases.

BACKGROUND: Some patients with the compression of the celiac trunk by the median arcuate ligament (MAL) suffer pancreatic artery aneurysms (PAAs) due to excessive blood flow from the superior mesenteric artery. These aneurysms are in peril because they are prone to rupture irrespective of size. Here, we present two cases of resection and reconstruction of PAAs caused by the compression of the celiac trunk by the MAL. CASE PRESENTATION: Patient 1 was a 44-year-old man who was first diagnosed to have a visceral artery aneurysm with a diameter of 4 cm accidentally found by ultrasound examination at a regular medical check-up. Contrast-enhanced CT revealed the compression of the celiac trunk by the MAL and a PAA originating from the first jejunal artery. First, laparoscopic excision of the MAL followed by a stent placement into the celiac trunk was performed. Although the stent was patent, the PAA still grew. The patient underwent resection and reconstruction of the PAA. Reconstruction of the pancreatic arterial arcade was needed because clamping of the inferior pancreaticoduodenal artery (IPDA) resulted in disappearance of the hepatic arterial blood flow. The follow-up CT 2 years and 9 months after the operation revealed no recurrence of aneurysms and the patent anastomosis. Patient 2 was a 68-year-old man who presented with an epigastric pain. Contrast-enhanced CT revealed the compression of the celiac trunk by the MAL and a PAA approximately 6 cm in diameter originating from the IPDA. The PAA was surrounded by a relatively low-intensity area, suggesting impending rupture of the PAA. The patient underwent resection and reconstruction of the PAA under an emergency situation. Reconstruction of the pancreatic arterial arcade was needed because clamping of the inflow IPDA resulted in disappearance of the hepatic blood flow. The follow-up CT 1 year and 8 months after the operation revealed no recurrence of aneurysms and the patent anastomosis. CONCLUSIONS: Although long-term follow-up is needed, resection and reconstruction is one of the therapeutic choices for PAAs caused by the compression of the celiac trunk by the MAL in order to prevent catastrophic aneurysm rupture.

Validating the efficacy of interval appendectomy for acute appendicitis: representative three cases with different etiologies.

BACKGROUND: Appendectomy for acute appendicitis (AA) is considered one of the most common emergency surgeries. However, emergency appendectomy accompanied with complex lesions such as extensive abscess formation is not recommended in most cases. Therefore, non-operative management followed by interval appendectomy (IA) for AA has been tried. Herein, we present three AA cases with specific etiology that underwent interval appendectomy. CASE PRESENTATION: Case 1: A 68-year-old man was diagnosed AA with intestinal malrotation and intra-abdominal abscesses. He initially treated with conservative therapy and underwent laparoscopic IA after detailed preoperative examination. Case 2: A 22-year-old man had been under treatment for pancolitis-type ulcerative colitis (UC), also bothered by right-lower abdominal pain several times a year. The appendix always appeared swollen on every CT taken during symptoms. He underwent laparoscopic IA; pathological finding revealed typical UC histological features in the resected appendix. After the surgery, he never suffered from terrible right lower abdominal pain. Case 3: A 69-year-old woman complaining a right lower abdominal pain had undergone CT examination, which revealed AA with appendiceal mass, irregular wall thickness of the cecum, and mediastinal and para-aortic lymph node swelling. The operation was carried out after conservative therapy. The pathological diagnosis revealed BRAF mutated colorectal carcinoma. She had received systematic chemotherapy after the surgery, and all metastatic lesions have completely disappeared. CONCLUSION: Interval appendectomy provided us with much clearer anatomical information and precise therapeutic strategies, avoiding technical and general operative complications, and also induced fast recovery and short length of hospital stay. Interval appendectomy is a reasonable procedure and could be recommended in case of AA with some different etiology.

Primary anorectal malignant melanoma with laparoscopic abdominoperineal resection: a case study and review of the relevant literature.

ARMM is a disease with a poor prognosis. ARMM is often diagnosed at an advanced stage, and the 5-year survival rate of ARMM is < 20%. Although the number of case reports on ARMM is gradually increasing, the optimal treatment strategy for ARMM remains controversial. We report the case of an 81-year-old woman who had experienced bloody stool for 6 months before her diagnosis and who had been initially diagnosed with hemorrhoids. The pathological diagnosis of a biopsy specimen was malignant melanoma. Other examinations showed no evidence of lymph node or distant metastasis. Based on these results, laparoscopic abdominoperineal resection was performed. Three months later on her first follow-up examination, distant metastasis to the lung and liver was detected. Immunotherapy using Nivolumab was initiated to treat the recurrent disease. We reviewed the characteristics of a total of 1834 ARMM patients described in previous reports on ARMM for which the full text was available on PubMed. We experienced a case of ARMM. The prognosis of ARMM is still poor, regardless of the surgical procedure. Previous studies and our case report suggest that systemic therapy, such as immunotherapy using an anti-PD-1 ligand may be more important than reinforcement of local control for improving the prognosis of ARMM patients.

Modeling Epithelial Homeostasis and Reactive Epithelial Changes in Human and Murine Three-Dimensional Esophageal Organoids.

The homeostatic proliferation-differentiation gradient in the esophageal epithelium is perturbed under inflammatory disease conditions such as gastroesophageal reflux disease and eosinophilic esophagitis. Herein we describe the protocols for rapid generation (<14 days) and characterization of single-cell-derived, three-dimensional (3D) esophageal organoids from human subjects and mice with normal esophageal mucosa or inflammatory disease conditions. While 3D organoids recapitulate normal epithelial renewal, proliferation, and differentiation, non-cell autonomous reactive epithelial changes under inflammatory conditions are evaluated in the absence of the inflammatory milieu. Reactive epithelial changes are reconstituted upon exposure to exogenous recombinant cytokines. These changes are modulated pharmacologically or genetically ex vivo. Molecular, structural, and functional changes are characterized by morphology, flow cytometry, biochemistry, and gene expression analyses. Esophageal 3D organoids can be translated for the development of personalized medicine in assessment of individual cytokine sensitivity and molecularly targeted therapeutics in esophagitis patients © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Generation of esophageal organoids from biopsy or murine esophageal epithelial sheets Basic Protocol 2: Propagation and cryopreservation of esophageal organoids Basic Protocol 3: Harvesting of esophageal organoids for RNA isolation, immunohistochemistry, and evaluation of 3D architecture Basic Protocol 4: Modeling of reactive epithelium in esophageal organoids.

Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells.

Background & Aims: Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas. Methods: We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo. Results: Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment. Conclusions: The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.