The heterogeneity of cancer-associated fibroblast subpopulations: Their origins, biomarkers, and roles in the tumor microenvironment.

The prognosis for patients with cancers known for a highly activated stromal reaction, including diffuse-type (scirrhous) gastric cancer, consensus molecular subtype 4 (CMS4) colorectal cancer, and pancreatic ductal adenocarcinoma, is extremely poor. To explore the resistance of conventional therapy for those refractory cancers, detailed classification and investigation of the different subsets of cancer-associated fibroblasts (CAFs) involved are needed. Recent studies with a single-cell transcriptomics strategy (single-cell RNA-seq) have demonstrated that CAF subpopulations contain different origins and marker proteins with the capacity to either promote or suppress cancer progression. Through multiple signaling pathways, CAFs can promote tumor growth, metastasis, and angiogenesis with extracellular matrix (ECM) remodeling; they can also interact with tumor-infiltrating immune cells and modulate the antitumor immunological state in the tumor microenvironment (TME). Here, we review the recent literature on the various subpopulations of CAFs to improve our understanding of the cell-cell interactions in the TME and highlight future avenues for CAF-targeted therapy.

[Surgical Technique for Mesorectal Division in the Robotic Anterior Resection for Rectal Cancer].

Since April 2018, robot-assisted rectal resection has been approved as an insurance medical treatment, and robot- assisted rectal resection is rapidly becoming widespread. Even in robot-assisted laparoscopic surgery, mesorectal division is difficult in a narrow pelvic cavity. At the beginning of the operation, Vessel Sealer ExtendTM(price 89,250 yen)was used, but as the procedure became stable, the mesorectal division was started with bipolar forceps and monopolar scissors. The purpose of this study was to investigate the mesorectal division time and postoperative complications associated with changes in the procedure. 36 patients who underwent robot-assisted anterior resection for rectal cancer by the same surgeon from January 2019 to December 2021. We compared mesorectal division time and postoperative complication. Median operation time were 267 minutes, median console time were 132 minutes. There were no complications such as intestinal obstruction or anastomotic leakage. There was no difference in mesorectal division time time between Vessel Sealer groups and Scissors groups(14 min 55 sec vs 16 min 5 sec). The mesorectal division with bipolar forceps and monopolar scissors could be performed without extending the operation time, and could be performed with cost-benefit and safely.

[The Role of Cancer-Associated Fibroblasts in Modulating Tumor Immunity in Colorectal Cancer].

Cancer-associated fibroblasts(CAFs)remodel the extracellular matrix(ECM)and shape the tumor microenvironment (TME), resulting in immune escape and the promotion of tumor metastasis. Using an orthotopic tumor model of colorectal cancers(CRCs)in mice, we demonstrated that the single-cell RNA sequencing of orthotopic rectal tumors identified a subpopulation of CAFs that modulate the immune response. In this review, we report that understanding the role of CAFs in the TME concerning tumor immunity may lead to future avenues for CAF-targeted therapy.

[A Case of Advanced Recurrent Rectal Cancer Successfully Treated by Rechallenge Therapy with an Anti-Epidermal Growth Factor Receptor(EGFR)Drug].

The patient was a 75-year-old man who had undergone potentially curative surgery for Stage Ⅲb rectal cancer followed by resection of liver metastases. Two years after the resection of liver metastases, lung and remnant liver metastases were found. He received chemotherapy for unresectable metastatic tumors. Based on the findings of molecular and pathological examinations(RAS: wild type; BRAF: wild type; MSI: negative; HER2: negative), the following chemotherapy regimens were administered: first-line, FOLFIRI plus panitumumab(PANI); second-line, mFOLFOX6; third-line, trifluridine/tipiracil; fourth- line, regorafenib. After fourth-line treatment, he was judged to have disease progression due to the increase in his lung and liver metastases and the elevation of tumor markers. All standard regimens were refractory, but the Eastern Cooperative Oncology Group performance status was zero and a liquid biopsy for RAS still showed wild type. Therefore, rechallenge therapy with anti-epidermal growth factor receptor(EGFR)drugs, cetuximab(CET)and irinotecan(IRI), was administered 13 months after the final course of FOLFIRI plus PANI treatment. After 4 courses of CET plus IRI, the size of the 2 metastatic tumors markedly decreased and his tumor marker levels normalized.

[A Case of Intractable Pyogenic Spondylitis Due to Suture Failure and MRSA Infection Secondary to Surgery for Ascending Colon Cancer].

A 79-year-old man diagnosed with ascending colon cancer underwent laparoscopic right hemicolectomy(Stage Ⅱ). Postoperatively, suture failure occurred on Day 5 and was alleviated with conservative therapy. However, on Day 23, he was diagnosed with MRSA-induced sepsis with a body temperature of 39 °C. After administration of vancomycin, his general conditions stabilized, although intermittent low-grade fever and a high C-reactive protein(CRP)level persisted. Although the source of the infection could not be easily identified, he was diagnosed with suppurative spondylitis after lumbar MRI examination on Day 43. The CRP level was normalized with long-term administration of antibiotics and the symptoms were gradually improved with rehabilitation. The patient was discharged after approximately 4 months and could walk without assistance 8 months postoperatively. In this case, purulent spondylitis may have occurred via hematogenous infection due to the suture failure after surgery for ascending colon cancer. Purulent spondylitis is a relatively rare disease. However, it may lead to the patient requiring long-term treatment and cause serious sequelae. Therefore, it is important to keep this disease in mind when treating patients with postoperative fever of unknown origin or aggravating lower back pain.

[Impact of Sarcopenia on Patients with Advanced Gastric Cancer Who Underwent Surgery].

This study aimed to investigate the short- and long-term outcomes in patients with sarcopenia who underwent surgery for advanced gastric cancer. We included 76 patients with pStage Ⅱ or Ⅲ gastric cancer who underwent gastrectomy between January 2017 and June 2021. Patients with pT3N0 cancer were excluded. Using the Asian Working Group for Sarcopenia( AWGS)2019 criteria, the patients were divided into the sarcopenia group(S group)and the non-sarcopenia group (NS group). The surgical outcomes, effects on postoperative adjuvant chemotherapy, and prognosis of the 2 groups were evaluated and compared. No significant differences were observed in the operative time, blood loss, postoperative hospital stays, or incidence of postoperative complications with a grade higher than Clavien-Dindo Grade Ⅱ. The number of patients who received postoperative adjuvant chemotherapy was 5(26.3%)in the S group and 38(66.7%)in the NS group which was significantly lower in the S group(p=0.003). The 3-year overall survival rate was 45.7% in the S group and 71.0% in the NS group(p=0.302). There was no significant difference but survival rate was lower in the S group. The results suggest that postoperative adjuvant chemotherapy is not always available for patients with advanced gastric cancer, and that may worsen the prognosis.

[A Case of Advanced Gastric Cancer-Recurrence of Skin Metastasis Nine Years after Surgery and Rectal Stenosis Due to Peritoneal Dissemination Ten Years Later].

A 70-year-old man previously underwent laparoscopic total gastrectomy for gastric cancer in 2010 and pathological diagnoses were pT4a, pN3, M0, pStage ⅢC. The postoperative adjuvant chemotherapy was interrupted due to nausea, but the patient had no apparent recurrence within 5 years after gastrectomy. In 2019, a swelling appeared from the left inguinal region to the scrotum, and MRI scan showed subcutaneous edematous changes in the same region. Biopsy showed adenocarcinoma and we diagnosed a recurrence of gastric cancer with skin metastasis. In November 2020, the patient complained of defecation disorder, and CT scan showed a circumferential wall thickening with contrast effect in the rectum. Although colonoscopy revealed rectal stenosis, biopsy specimen showed no malignant findings. We suspected rectal stenosis due to peritoneal dissemination of gastric cancer and performed a colostomy. Intraoperative findings showed that the rectal wall was remarkably thickened with serosal erythema. Adenocarcinoma cells were found from the cytology of ascites. The patient was treated with nab-paclitaxel plus ramucirumab, then treated with nivolumab after failure of first-line therapy.

[Short- and Long-Term Surgical Outcomes for Patients with Colorectal Cancer Aged 80 Years or Older].

This study aimed to assess short-term and long-term outcomes and to identify the factors that affect outcomes for patients with colorectal cancer aged 80 years or older. Two hundred patients with colorectal cancer who were underwent resection of the primary tumor between January 2013 and December 2018 were enrolled. Short-term outcomes of elderly patients with poor PS and of those who take antithrombotic agents and of those who were underwent open surgery were poor. Long-term outcomes of elderly patients with high GNRI and of those who were underwent D3 lymph nodes dissection were better. Laparoscopic surgery with D3 lymph nodes dissection for elderly patients who were more than 80 years old should be useful to improve short- and long-term outcomes. GNRI might be a prognostic predictive factor for patients with colorectal cancer aged 80 years or older.

[Prognostic Analysis of Colorectal Cancer Patients by the Controlling Nutritional Status(CONUT)Score].

We examined the controlling nutritional status(CONUT)score and the long-term prognosis of colorectal cancer surgery cases. We retrospectively examined the prognosis of colorectal cancer patients who underwent surgery between January 2013 and December 2015. We targeted 449 patients who were able to calculate the CONUT score. A total of 266 patients (59.2%)had normal nutritional status(1 or less)and 183 patients(40.8%)had mildly poor or worse nutritional status (2 or more). The CONUT score was calculated through preoperative blood tests. The relationship between the CONUT score and overall survival was examined in the low and high groups. Overall survival was significantly shorter in the high group but relapse-free survival did not differ significantly between the 2 groups. There was no difference in cancer-specific survival between the 2 groups, but the survival time due to death from other diseases was significantly shorter in the high group. The CONUT score obtained from preoperative blood sampling suggested that the overall survival time was short in the malnourished group, and that it could be used as an index of prognosis due to death from other diseases.

[Short-Term Clinical Outcome of Robotic Surgery for Advanced Rectal Cancer after Neoadjuvant Therapy].

We examined 14 cases who underwent robotic rectal resection with neoadjuvant chemotherapy(NAC)or neoadjuvant chemoradiation therapy(NACRT)for local advanced rectal cancer in our hospital from 2018 June to 2020 December. Two patients underwent NACRT, 12 patients underwent NAC. Sex was 10 males and 4 females. The median age was 66. The surgical procedure was ISR 2 cases, LAR 8 cases, APR 4 cases. The median operation time was 397 minutes and the median blood loss was 73 mL. The histological response grade were Grade 3: 1 case, 2: 7 cases, 1b: 3 cases, and 1a: 3 cases. Surgical margin was negative in all cases. Postoperative complications(≥Clavien-Dindo Grade Ⅲ)required reoperation due to intestinal obstruction in 1 case. Urinary dysfunction was nothing in all cases. Although long-term results such as prognosis and function preservation need to be examined, short-term results of robot-assisted rectal resection after NAC or NACRT were generally good.

[A Case of Robot Assisted Low Anterior Resection for a Patient with Persistent Descending Mesocolon].

Persistent descending mesocolon(PDM)is caused by absence of fusion of the descending colon to the retroperitoneum. A 67-year-old man with bloody stools was diagnosed with rectal cancer on colonoscopy. A computed tomography showed a medial displacement of his descending colon. The preoperative clinical diagnosis was rectal cancer with PDM, and robot assisted low anterior resection was performed. We found that the left-sided colon was shifted to the midline and adhered the cecum and the mesentery of small intestine. Robot assisted surgery enables surgery with the precise adhesiotomy in a stable field. PDM is a relatively rare anatomic abnormality. Character of PDM is adhesion between the left-sided colon and other organs and radially branch from the inferior mesenteric artery. It is important to understand the anatomical characteristics of PDM and to improve on existing surgical procedures to ensure safe robot assisted surgery these patients.

[Clinical Significance of Preoperative Chemotherapy for Advanced Colorectal Cancer].

We examined 22 cases who underwent preoperative chemotherapy in our hospital from 2013 April to 2018 December. Seven patients were treated as neoadjuvant chemotherapy(NAC). Out of 15 patients with unresectable diseases before chemotherapy, 6 patients were able to R0 resection after chemotherapy(conversion). Although only one patients was underwent RM1 resection, the other patients were underwent RM0 resection. The median overall survival was 42 months in NAC group, 28 months in conversion group, and 17 months in palliative resection group, respectively. Recurrence was observed in 1 patient in NAC group, however, all patients had recurrent disease in conversion group. In this study, although further examination should be done according to the clinical significance of preoperative chemotherapy, preoperative chemotherapy may be carried out without severe adverse event and severe postoperative complication.

[A Case Report with R0 Resection for Locally Advanced Appendiceal Cancer Invading to the Right External Iliac Vessels].

A 46-year-old man presented with right lower quadrant pain. Enhanced CT revealed a 30 mm sized irregular shaped mass originating from the appendix and invading the abdominal wall. We performed the laparoscopic appendectomy. Finally, the pathologic finding revealed a local advanced appendiceal carcinoma. From the intraoperative findings, the residual tumor was existed around the right external iliac vessels and abdominal wall. The patient was treated with chemotherapy for 13 months. Although the residual tumor encased the right external iliac vessels, the abdominal wall, and psoas major muscle, there were no signs of distant metastasis. We performed ileocecal resection with D3 lymph node dissection. The right external iliac vessels, abdominal wall, and psoas major muscle were resected simultaneously, and reconstructed by femoral- femoral bypass. As a result, R0 resection was achieved pathologically.

[A 3mm Gastric Neuroendocrine Tumor That Metastasized to a Lymph Node].

A 46-year-old man underwent a medical check-up and gastrointestinal endoscopy, which revealed a brown lesion at the greater curvature of the gastric body. Biopsy was performed, and a gastric neuroendocrine tumor(NET)was diagnosed. The serum levels of gastrin and other tumor markers were not elevated. The preoperative diagnosis was Rindi type Ⅲ gastric NET, and laparoscopic distal gastrectomy with D1 plus lymph node dissection was performed. Histological examination showed that the resected specimen was positive for chromogranin A, CD56, and synaptophysin, which was consistent with the findings of NET. Even though the tumor diameter was only 3 mm, a metastatic #4d lymph node was found. This case suggests that Rindi type Ⅲ gastric NET has high malignant potential, and gastrectomy with lymph node dissection is necessary, regardless of tumor size.

[A Case of Appendiceal Adenocarcinoma with Vesico-Appendiceal Fistula Treated by Additional Laparoscopic Excision].

A 40-year-old woman was admitted to our hospital with the chief complaint of miction pain. MRI showed fundal wall thickening of the bladder in contact with the appendix. Under cystoscopy, redness of the mucous membrane was found in the posterior wall of the bladder. Therefore, laparo-appendectomy with partial cystectomy was performed. Microscopically, adenocarcinoma cells were observed in the lumen of the appendix, invading the wall of the urinary bladder at the fundus of the appendix. We performed laparo-ileocecal resection for a regional lymphadenectomy. Thus, the patient was diagnosed with adenocarcinoma of the appendix[V, type 3, 16×7 mm, tub2, pT4b(SI, urinary bladder), int, INF b, ly0, v0, pN0, cM0, pStage Ⅱ]. The patient has been receiving adjuvant chemotherapy using capecitabine for 6 months. There was no evidence of recurrence after 9 months of follow-up.

[A Case of Ductal Carcinoma In Situ in Sclerosing Adenosis].

A 67-year-old female was referred to our hospital because she was pointed out mass in her right breast by her previous doctor. Core needle biopsy examination was performed at that time which revealed invasive ductal carcinoma. There'reno palpable masses in her breast or any superficial lymph nodes on her visiting our hospital. Breast ultrasonography images showed multiple nodules in C area of right breast. Breast enhanced MRI image revealed multiple enhanced nodules which showed rapid arising and plateau or slowly decreasing pattern in time intensity curve. CT scan and bone scintigraphy revealed no distant metastasis. Based on these findings, the case was diagnosed as right breast cancer, cT1N0M0, Stage I . For this case, we performed right mastectomy and sentinel lymph node biopsy. The pathological findings was ductal carcinoma in situ (DCIS)accompanied by sclerosing adenosis. Though we didn't perform adjuvant chemotherapy, she has been alive without recurrence for 6 years. Because it's difficult to make correct diagnosis with small specimen collected by core needle biopsy, we should take DCIS in sclerosing adenosis into consideration to prevent overdiagnosis.

[Prognostic Analysis of Breast Cancer Patients Who Underwent Neoadjuvant Chemotherapy Using QOL-ACD].

We investigated into association of quality of life(QOL)and prognosis of breast cancer patients who underwent neoadjuvant chemotherapy(NAC). We retrospectively studied 228 patients with breast cancer who were performed NAC during a period between 2007 and 2015. TheQ OL score was measured with"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs(QOL-ACD)". We evaluate association between QOL score with antitumor effect and prognosis. Changes in the QOL score between before and after NAC were compared as well. We divided 2 groups by QOL-ACD scoreinto high and low groups. Therapeautic effect of NAC on 75 patients were pathological complete response(pCR). QOL-ACD score was not significantly associated with pCR rate in both high and low groups(p=0.199). High group was significantly associated with higher survival rate in both of disease free survival(p=0.009, logrank)and overall survival(p=0.040, logrank). QOLACD score decreased after NAC in both of pCR and non-pCR patients. In conclusion, QOL evaluation using QOL-ACD could be an indicator of breast cancer patients' prognosis who underwent NAC.

Cachexia and efficiency of trifluridine/thymidine phosphorylase inhibitor + bevacizumab in metastatic colorectal cancer.

In later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) + bevacizumab (Bmab) therapy as a later-line treatment for mCRC, and assessed the impact of cancer cachexia on chemotherapeutic efficacy using CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group, although there were no marked differences in tumor factors, such as the number of metastatic organs or gene mutations, between the two groups. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI + Bmab therapy.

Blood viscometer applying electromagnetically spinning method.

Viscosity is an important parameter which affects hemodynamics during extracorporeal circulation and long-term cardiac support. In this study, we have aimed to develop a novel viscometer with which we can easily measure blood viscosity by applying the electromagnetically spinning (EMS) method. In the EMS method, we can rotate an aluminum ball 2 mm in diameter indirectly in a test tube with 0.3 ml sample of a liquid by utilizing the moment caused by the Lorentz force as well as separate the test tube from the viscometer body. First, we calibrated the EMS viscometer by means of liquid samples with known viscosities and computational fluid dynamics. Then, when we measured the viscosity of 9.4 mPa s silicone oil in order to evaluate the performance of the EMS viscometer, the mean viscosity was found to be 9.55 ± 0.10 mPa s at available shear rates from 10 to 240 s(-1). Finally, we measured the viscosity of bovine blood. We prepared four blood samples whose hematocrit levels were adjusted to 23, 45, 50, and 70% and a plasma sample without hemocyte components. As a result, the measurements of blood viscosities showed obedience to Casson's equation. We found that the viscosity was approximately constant in Newtonian silicone oil, whereas the viscosity decreased with increasing shear rate in non-Newtonian bovine blood. These results suggest that the EMS viscometer will be useful to measure blood viscosity at the clinical site.

Comparison of Short-Term Surgical Outcomes of Two Types of Robotic Gastrectomy for Gastric Cancer: Ultrasonic Shears Method Versus the Maryland Bipolar Forceps Method.

BACKGROUND: This study investigated the impact and short-term surgical outcomes of two different main energy devices for robotic gastrectomy for gastric cancer. The outcomes of robotic gastrectomy with ultrasonic shears and those of robotic gastrectomy with conventional forceps were compared. METHODS: We retrospectively evaluated 171 patients who underwent robotic distal gastrectomy or total gastrectomy for gastric cancer. We classified patients into the ultrasonic shears (US) and Maryland bipolar (MB) forceps groups according to the main energy device used for robotic gastrectomy. RESULTS: We extracted 58 patients from the US group and 58 patients from the MB forceps groups using propensity score matching. The total console time (310 min [interquartile range (IQR), 253-369 min] and 332 min, [IQR, 294-429 min]; p = 0.022) and the console time to gastrectomy (222 min [IQR, 177-266 min] and 247 min [IQR, 208-321 min]; p = 0.004) were significantly shorter in the US group than in the MB forceps group. Less blood loss occurred in the US group than in the MB forceps group (20 mL [IQR, 10-40 mL] and 30 mL [IQR, 16-80 mL]; p = 0.014). The postoperative complication rate and postoperative hospital stay length were similar between groups. A multivariate multiple linear regression analysis demonstrated that the use of an ultrasonically activated device was one an independent factor that reduced the operative time of robotic gastrectomy. CONCLUSION: Using ultrasonic shears as the main energy device may contribute to better surgical outcomes after robotic gastrectomy for gastric cancer.