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Laparoscopic colorectal surgery (LCRS) requires a small laparotomy at the umbilicus. The wound is small and inconspicuous, but if the patient develops an umbilical incisional hernia (UIH), the wound is visible and the patient suffers from symptoms of discomfort. However, the incidence of UIH after LCRS and its risk factors are not well understood. The purpose of this study was to investigate the risk factors for UIH after LCRS for colorectal cancer.This was a single-centre retrospective study of 135 patients with colorectal cancer, conducted at our hospital from April 2013 to March 2019. The diagnosis of UIH was based on computed tomography and physical examination findings. Preoperative patient data such as enlargement of the umbilical orifice (EUO), subcutaneous fat thickness (SFT) and intraperitoneal thickness (IPT) were collected and analysed using univariate and multivariate analyses for the presence of risk factors for UIH.A total of 135 patients who underwent LCRS were analysed. The incidence of UIH was 20.7%. Univariate analysis revealed significantly high body mass index (BMI) ≥ 25 (P = 0.032), EUO (P 0.001), SFT ≥18 mm (P = 0.011), and IPT ≥61 mm (P 0.01) in the UIH group. Multivariate analysis revealed significant differences in EUO (P 0.001), SFT ≥18 mm (P = 0.046) and IPT ≥61 mm (P = 0.022).EUO was the most important risk factor for UIH, followed by IPT and SFT. These findings are predictive indicators of the development of UIH after LCRS and can be assessed objectively and easily with preoperative computed tomography.

Supplementary Figure 2 from Hyaluronan Deficiency in Tumor Stroma Impairs Macrophage Trafficking and Tumor Neovascularization

Supplementary Figure 3 from Hyaluronan Deficiency in Tumor Stroma Impairs Macrophage Trafficking and Tumor Neovascularization

Supplementary Figure 1 from Hyaluronan Deficiency in Tumor Stroma Impairs Macrophage Trafficking and Tumor Neovascularization

Supplementary Methods, Figure Legends 1-3 from Hyaluronan Deficiency in Tumor Stroma Impairs Macrophage Trafficking and Tumor Neovascularization

Radical surgical procedures for malignant diseases of the pelvis result in a large pelvic defect that requires soft tissue reconstruction. The mesentery can be used for pelvic floor reconstruction when debridement with intestinal resection is required. A 75-year-old woman was diagnosed with sacral necrosis, infection and sepsis after carbon ion radiotherapy for sacral chordoma. She underwent sacral debridement three times, which resulted in a large pelvic defect of 14 × 13 cm. Surgery was performed to completely resect the necrotic tissue. We performed extended debridement of sacrum and adjacent tissue around the rectum and anus. Since it was impossible to preserve the anus, laparoscopic left hemicolectomy, abdominosacral resection, and left-sided mesocolic leaf repair for the pelvic defect, and reconstructed the pelvis and buttocks using a gluteal thigh flap were performed. Indocyanine green fluorescent (ICG) imaging was used to detect the margin of the pelvic floor and necrotic tissue and the blood flow of the left-sided mesocolic leaf flap. Left-sided mesocolic leaf reconstruction is useful for large pelvic defects. ICG imaging enabled the detection of the resection margins and the blood flow of the mesocolic leaf.

Background; Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method; Here, we describe four cases of HDGC in a single Japanese family. Results; The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in three relatives, which revealed abnormal small pale mucosal patches, small ulcerative lesion, and no abnormal findings, respectively. Random and targeted biopsies were compatible with the pathological diagnosis of HDGC. They underwent total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection. Conclusion; In the management of HDGC, multidisciplinary and family-oriented approaches are critical, including genetic analysis of CDH1 variants in the proband, presymptomatic diagnosis of at-risk relatives through careful genetic counseling, and random biopsy-based surgery or prophylactic total gastrectomy.

Background: Tumor budding (TB) is a poor prognostic factor in colorectal adenocarcinoma (CA), but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in TB and its association with TB in CA. Methods: The clinicopathological and prognostic significance of IL6 in TB was examined using a tissue microarray consisting of 36 patient samples of TB in CA. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results: IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. In the IL6-positive group in cancer stroma, TB grade was higher than in the IL6-negative group (P=0.0161). The IL6-positive group significantly exhibited the epithelial–mesenchymal transition (EMT) phenotype compared with the IL6-negative group in cancer stroma (P=0.0301). There was no significant difference in overall survival between CA cases in the IL6-positive and -negative groups in cancer stroma. Conclusions: TB may be affected by IL6 expression, and IL6expression in cancer stroma at TB may be an important prognostic marker.

BACKGROUND Adhesive small bowel obstruction (ASBO) is one of the major causes of postoperative morbidity. Non-surgical management is generally applied to non-strangulated ASBO. Several factors have been reported to affect the response to non-surgical management in patients with ASBO. However, the association between sex differences and non-strangulated ASBO remains unclear. This study aimed to elucidate the effect of sex differences in non-strangulated postoperative ASBO. METHODS We divided 139 patients with a first episode of non-strangulated postoperative ASBO into two groups: male group (n = 83) and female group (n = 56). Clinical features and prognosis were compared between the two groups. RESULTS Female patients had lower proportions of oesophageal/gastric malignancies (P = 0.044) and colorectal malignancies (P = 0.030) and a higher proportion of uterine/ovarian malignancies (P

Introduction: Patients with unresectable or recurrent gastric cancer who have an objective response (OR) to nivolumab monotherapy are expected to have a good long-term prognosis. However, the OR rate for nivolumab treatment is low at 11%, and there is a need for biomarkers to predict the treatment response. This study aimed to analyze the significance of systemic inflammation-related variables and clinicopathologic characteristics as predictive markers of response to nivolumab monotherapy in patients with advanced gastric cancer. Methods: In this retrospective cohort study, we enrolled 71 consecutive patients who received nivolumab monotherapy for unresectable or recurrent gastric cancer. Receiver operating characteristic curve analysis was performed to determine the cutoff values of systemic inflammation-related variables, predictors of treatment response, and other prognostic factors related to nivolumab therapy. We focused on systemic inflammation-related variables measured before nivolumab induction and 2 weeks after its first administration and performed multivariate analysis to assess whether they could be used as prognostic factors. Results: Multivariate analysis revealed that a lymphocyte-to-monocyte ratio (LMR) of ≤3.28 after 2 weeks of initial nivolumab treatment (2wLMR) is a statistically significant predictor of treatment response (p = 0.012). The progression-free survival (PFS) rate of patients with liver metastasis was significantly worse than that of the other patients (1-year PFS: 0.0 vs. 24.4%, respectively; p = 0.005). The overall survival (OS) of patients with a low 2wLMR was significantly longer than that in patients with a high 2wLMR (1-year OS: 37.4 vs. 18.9%, respectively; p = 0.022). Conclusions: Thus, the 2wLMR could be a useful biomarker to predict response to nivolumab treatment and the prognosis of unresectable and recurrent gastric cancer.

Intestinal injuries in seat belt syndrome are relatively uncommon but can be potentially lethal due to accompanying peritonitis and hemorrhaging. It can be difficult to identify the exact injury sites of the intestine as multiple areas are often damaged and massive intraperitoneal hemorrhaging may make it challenging to determine causal bleeding points of mesenteric injuries. This study aimed to clarify the incidence and distribution of intestinal injuries in seat belt syndrome.We retrospectively reviewed the clinical records of 25 patients who underwent laparotomy for suspected intestinal injuries due to seat belt syndrome during a frontal impact. The incidence and distribution of the sites of intestinal injuries, as well as associated injuries, were investigated. Intestinal injuries were divided into bowel and mesenteric injuries. Additionally, bowel injuries were classified into two types: perforation and non-perforation (seromuscular tears/intramural hematomas). Regarding the injured sites, the small intestine was divided into the following three parts: (1) the ligament of Treitz (100-cm distal from the ligament [proximal jejunum]), (2) the ileocecal valve (100-cm proximal from the valve [distal ileum]), and (3) the intermediate area between those two regions (jejunoileal junction).In total, there were 64 major injuries among 25 patients requiring surgical intervention: 34 bowel injuries (20 perforations and 14 non-perforations) and 30 mesenteric injuries. Significantly more bowel perforations occurred in the small intestine (1 [interquartile range (IQR), 0-1]) than in the large intestine (0 [IQR, 0-0]) (In patients with seat belt syndrome, the small intestine was more vulnerable to perforation and mesenteric injury than the large intestine. Additionally, for mesenteric injuries, the jejunoileal junction was more likely to be damaged than the proximal jejunum.

The influence of air temperature on adhesive small bowel obstruction (ASBO) is unknown. This study aimed to investigate the relationship between air temperature and postoperative ASBO.Overall, 312 patients with postoperative ASBO were included. They were categorized into two groups: the surgery group (n = 83) comprising patients who needed surgery, and the non-surgery group (n = 229) comprising patients who responded to conservative treatment. The associations between patients' characteristics and weather variables on days of symptom onset with the need for surgical management were investigated. Weather variables included the daily mean barometric pressure, daily mean air temperature, day-to-day differences, daily variances, and diurnal variation in the air temperature. Day-to-day differences in weather variables were calculated as the daily mean variables on the day of symptom onset minus those on the previous day. The daily variances in weather variables were defined as the absolute value of day-to-day differences.Compared to the non-surgery group, the surgery group had older patients (75 vs. 70 years, p = 0.009), a higher proportion of female patients (44.6% vs. 32.3%, p = 0.046), increased incidence of closed-loop sign (50.6% vs. 0.9%, p0.001), a lower proportion of feces sign (18.1% vs. 31.3%, p = 0.024), and a prolonged hospital stay (11 vs. 22 days, p0.001). The number distribution of patients in the surgery group in day-to-day differences in air temperature was different from that of the non-surgery group; the former has several peaks whereas the latter has almost one peak. Daily variance in mean air temperature on the day of symptom onset was higher in the surgery group than in the non-surgery group (2.3 vs. 1.3℃, p0.001). Multiple logistic regression analysis revealed that increased daily variance in air temperature on the onset day was associated with the need for surgical management (odds ratio 1.254, p = 0.002) and closed-loop obstruction (odds ratio 1.235, p = 0.017). Regarding seasonal variations, the risk of the need for surgery and closed-loop obstruction in each ASBO patient was the highest in spring, followed by that in summer, autumn, and winter. Consistently, the daily variance in mean air temperature in spring was higher than that in summer, autumn, and winter (p0.0001, p0.0001, and p = 0.0047, respectively). The risk of the need for surgery and closed-loop obstruction in each ASBO patient was the highest in spring, followed by that in summer, autumn, and winter. Consistently, daily variance in mean air temperature was higher in spring than that in summer, autumn, and winter (p0.0001, p0.0001, and p = 0.0047, respectively).Increased daily variance in mean air temperature on the day of onset is associated with the need for surgical management and closed-loop obstruction. Spring is characterized by the highest daily variance in mean air temperature among the four seasons, and is associated with high proportions of the need for surgery and closed-loop obstruction. These results can be clinically useful in terms of hospital resource reallocation and staffing, and can help clarify the pathogenesis of ASBO.

Whether seasonal and meteorological factors affect the incidence of adhesive small bowel obstruction (ASBO) remains unclear. This study aimed to clarify the impacts of seasonal and meteorological factors on the occurrence of ASBO.Clinical data of patients with ASBO were acquired from 42 national university hospitals in Japan, using a national inpatient database, between April 2012 and March 2020. Meteorological data were obtained from the Japan Meteorological Agency. The number of monthly admissions of patients with ASBO was compared between each of the 12 months. Daily weather variables were investigated to clarify their association with ASBO patient admissions on a total of 119 802 days (Formula for calculation: study period [2922 days] ×41 cities).Overall, 4985 patients with ASBO were admitted. The number of admissions in June was smaller than that in October, November, and December (39 vs 63.5,The incidence of ASBO is susceptible to barometric pressure and humidity and varies monthly. These results can contribute to the prevention, early detection, and immediate and appropriate management of ASBO.

Introduction. Acute mesenteric ischemia is a life-threatening complication after cardiovascular surgery with a mortality rate of 52.9–81.3%. However, few studies have evaluated the predictors of clinical outcome after treatment for acute mesenteric ischemia following cardiovascular surgery. Therefore, this study aimed to elucidate prognostic factors in patients who underwent laparotomy for acute mesenteric ischemia after cardiovascular surgery. Methods. We retrospectively analyzed 29 patients (20 men and 9 women; median age, 71.0 years) who underwent laparotomy for acute mesenteric ischemia after cardiovascular surgery between January 2010 and August 2020. These patients were classified into the survivor group (comprising patients who were discharged or referred to another hospital, n = 16) and the nonsurvivor group (comprising those who experienced in-hospital mortality, n = 13). We compared clinical parameters between the groups to identify the predictors of outcomes. Results. More patients in the nonsurvivor group underwent emergency cardiovascular surgery (62.5% vs. 100%, p = 0.017) and received hemodialysis (12.5% vs. 61.5%, p = 0.008) at the onset of acute mesenteric ischemia than those in the survivor group. The prelaparotomy serum creatinine level was higher in the nonsurvivor group than in the survivor group (1.27 vs. 2.33 mg/dL, p = 0.004). Logistic regression analysis revealed an association between preoperative serum creatinine level and in-hospital mortality (odds ratio 5.047, p = 0.046), and Cox regression analysis demonstrated a relationship between serum creatinine level and in-hospital mortality (hazard ratio 1.610, p = 0.009). The area under the curve (receiver operating characteristic analysis) for the serum creatinine level was 0.813. Furthermore, the optimal cutoff value of the serum creatinine level was 1.59 mg/dL with a sensitivity and specificity of 0.846 and 0.687, respectively, in predicting in-hospital mortality. Conclusions. The elevated serum creatinine level was associated with a poor clinical outcome after surgery for acute mesenteric ischemia following cardiovascular surgery.

Background Neurofibromatosis type 1 is an autosomal dominant inherited disease associated with multiple skin neurofibromas or other neurogenic tumors, such as nodular plexiform neurinoma or cerebrospinal tumor. Gastrointestinal stromal tumors are often complicated in patients with neurofibromatosis type 1, although involvement of the appendix is rare, and there have been few reports of appendiceal ganglioneuroma. Case presentation The patient was a 29-year-old man diagnosed with neurofibromatosis type 1 based on physical findings and his family history. During the follow-up of neurofibromatosis, computed tomography was performed to detect neurological tumors, such as neurofibromas in the brain, spinal cord, and gastrointestinal tract. Computed tomography showed a markedly thickened appendix wall, and an appendiceal tumor was suspected. Laparoscopic appendectomy was performed, and a 50 × 35 mm appendiceal submucosal tumor was resected with a negative resection margin. At histopathological examination, the tumor was diagnosed as ganglioneuroma; it showed short spindle-shaped cells and ganglion cells diffusely infiltrated into the proper muscle layer and fibrous tissue that grew around nerve cells. The patient was discharged on the 5th postoperative day without postoperative complications and was doing well at 13 months following the operation. Conclusions Gastrointestinal stromal tumor and neurofibroma are the most common gastrointestinal tumors associated with neurofibromatosis type 1, but ganglioneuroma of the appendix is rare. Appendiceal neurogenic tumors should be considered in patients with neurofibromatosis type 1, and surgical resection is necessary because of the risk of malignancy.

Background: Ras homolog family member A (RhoA), a member of the Rho family of small GTPases, and Vav1, a guanine nucleotide exchange factor for Rho family GTPases, have been reported to activate pathways related to the actin cytoskeleton and regulation of cell shape, attachment, and motility. The interaction between these molecules in lymphoma is involved in malignant signaling, but its function in epithelial malignancy is unknown. Here, we investigated the malignant signal of mutant RhoA in gastric cancer and demonstrated the potential of RhoA G17E/Vav1 as a therapeutic target for diffuse gastric cancer. Methods: The RhoA mutants R5W, G17E, and Y42C were retrovirally transduced into the gastric cancer cell line MKN74. The stably transduced cells were used for morphology, proliferation, and migration/invasion assays in vitro. MKN74 cells stably transduced with ectopic wild-type RhoA and mutant RhoA (G17E) were used in a peritoneal xenograft assay. Results: The RhoA mutations G17E and Y42C induced morphological changes in MKN74. G17E induced Vav1 expression at the mRNA and protein levels and promoted the migration and invasion of MKN74. An RNA interference assay of Vav1 revealed that RhoA G17E enhanced cancer cell invasion via Vav1. Furthermore, immunoprecipitation revealed that Vav1 and RhoA G17E specifically bind and function together through matrix metalloproteinase-9. In a peritoneal xenograft model of nude mice, RhoA G17E promoted peritoneal dissemination, whereas Vav1 knockdown suppressed it. Conclusion: Overall, our findings indicate that RhoA G17E associated with Vav1 and promoted cancer invasion via matrix metalloproteinase-9 in gastric cancer cells. Thus, RhoA G17E/Vav1 signaling in diffuse gastric cancer may be a useful therapeutic target.

Colorectal cancer with a Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene mutation is considered to be resistant to anti-EGFR agents. G12D is the most common KRAS mutation in colorectal cancer, followed by G12V and G13D. According to clinical and basic research data, patients with colorectal cancer exhibiting G12D and G12V KRAS mutations are resistant to anti-EGFR agents; however, this is not true of G13D and other minor mutations, which are still not well understood. The current study focused on minor KRAS mutations (G12A, G12C, G12S, Q61H and A146T) and evaluated whether these were resistant to anti-EGFR antibodies using a mix culture assay. The results demonstrated that all KRAS mutations, including minor mutations, were resistant to two anti-EGFR agents: Cetuximab and panitumumab. The combined effect of MEK and BCL-XL inhibition on colorectal cancer cells with KRAS minor mutations were subsequently evaluated. The combined effect of MEK and BCL-XL inhibitors was confirmed in all KRAS minor mutations. The sensitivity of AMG510, a novel KRAS G12C selective inhibitor, was also assessed. The mix culture assay revealed that AMG510 selectively exerted an antitumor effect on colon cancer cells with a G12C KRAS mutation. The combination of MEK and BCL-XL inhibition markedly enhanced the effect of AMG510 in colon cancer cells. The current study suggested that AMG510 may have potential clinical use in combination with MEK and BCL-XL inhibitors in the treatment of patients with colorectal cancer exhibiting the G12C KRAS mutation.

Background: Adhesive small bowel obstruction (ASBO) is one of the major causes of postoperative morbidity. Conservative treatment is generally applied to non-strangulated ASBO. Several factors have been reported to affect the response to conservative treatment in patients with ASBO. However, the association between sex differences and non-strangulated ASBO remains unclear. This study aimed to elucidate the effect of sex differences in non-strangulated postoperative ASBO.Methods: We divided 192 admissions of 99 patients with non-strangulated postoperative ASBO into two groups: the male group (n = 137) and female group (n = 55). Clinical features and prognosis were compared between the two groups.Results: Female patients had significantly poorer performance status (p < 0.001) and lower proportions of esophageal/gastric malignancies (p = 0.002), colorectal malignancies (p = 0.034), and history of ASBO (p = 0.028) than male patients. More female patients failed conservative treatment (p = 0.036) than male patients. Hospital length of stay (LOS) was longer (p = 0.002) in the female group than in the male group. Multiple logistic regression analysis showed that female sex was associated with increased odds of requiring elective surgery (odds ratio 2.381, p = 0.040). The Cox proportional hazards regression model revealed that female sex was an independent predictor of hospital discharge (hazard ratio 0.651, p = 0.015).Conclusion: Female sex adversely affected the response to conservative treatment and LOS in patients with non-strangulated postoperative ASBO.

Introduction Perianal Paget's disease is associated with adenocarcinoma and can spread to the perianal skin. It often requires extensive resection of the perianal skin and rectum. Many studies have shown the efficacy of laparoscopic abdominoperineal resection for lower rectal cancer. However, extensive resection of the dorsal side of the perineal skin is difficult in the lithotomy position. We report a laparoscopic abdominosacral approach using the jackknife position for perianal Paget's disease. Materials and surgical technique Surgery was started using the lithotomy position, and total mesorectal excision with central lymphadenectomy was performed laparoscopically. Pelvic floor muscles were divided 2 cm away from the rectum. The sigmoid colon was then divided with a linear stapler, and a terminal colostomy was made. The sacral approach was then followed with the patient placed in a jackknife position. A skin incision was made 1-2 cm from the negative margin confirmed by preoperative mapping biopsy and resected en-bloc. We used this approach in two patients with a mean operative time of 483 minutes, including 53.5 minutes for the position change. All tumor margins, including the skin, were cancer-free, and primary wound closure was possible in both of the cases. Both patients were doing well without any recurrence 10 and 13 months postoperatively. Conclusion Laparoscopic abdominosacral resection is safe and effective and facilitates extensive perineal skin resection, especially on the dorsal side, with a less invasive laparoscopic procedure.

Introduction: We report a case of successful laparoscopic total gastrectomy with very rare vascular abnormality. Case presentation: A 35-year-old woman was diagnosed with early gastric cancer through a medical checkup. A preoperative computed tomography scan revealed positional variation of the common hepatic artery and splenic vein. The common hepatic artery branched normally from the celiac artery, but the splenic vein was located anterior to it. The patient was successfully treated via laparoscopic total gastrectomy without surgical complications. Conclusion: This vascular abnormality is extremely rare, and to our knowledge, there is no report of surgical cases with this vascular variation. Because of the difficulty in confirming the running pattern of the artery intraoperatively, it is important to ascertain the arterial running pattern preoperatively using computed tomography, including 3-dimensional angiographic imaging.

This study evaluated the relationship between synchronous multiple gastric cancer and other primary malignancies. During 2002-2013, 1094 consecutive surgically treated gastric cancer patients were enrolled. Preoperatively, we performed total colonoscopy and whole-body computed tomography. When malignancies in other organs were suspected, detailed organ-specific examinations were performed. Synchronous multiple gastric cancer occurred in 102 patients (9.3%)which was frequently observed in patients with preoperative other primary malignancies (p < 0.001). Preoperative other primary malignancy was an independent risk factor for synchronous multiple gastric cancer (p = 0.001; hazard ratio: 2.145, 95% confidence interval: 1.354-3.399) and an independent prognostic factor of overall survival in patients undergoing gastrectomy with curative intent (p = 0.021; hazard ratio: 1.481, 95% confidence interval: 1.060-2.070). Thus, patients with preoperative other primary malignancies have a high risk of synchronous multiple gastric cancer. Careful preoperative examination is recommended to improve survival.

Primary malignant melanoma of the esophagus (PMME) is a rare neoplasm. We observed a case of PMME that had occurred at an irradiated site in the thoracic esophagus. The patient was a 74-year-old man who had received definitive chemoradiotherapy for esophageal squamous cell carcinoma at the age of 68, and had completely recovered. Six years later, via periodic upper gastrointestinal endoscopy, he had been diagnosed with esophageal tumors. After the patient underwent esophagectomy, the removed esophageal tumors were immunohistologically diagnosed as PMME, and most of the tumor was observed to be located within the irradiated area corresponding to the previous radiotherapy. The patient has been free of recurrence and metastasis and alive for 20 months after the second surgery without any additional treatment. The clinical course of this patient suggests that therapeutic radiation may be a factor in the occurrence of PMME.

Disseminated carcinomatosis of the bone marrow (DCBM) in colorectal cancer is an extremely rare complication with a poor prognosis. Here, we report a case of DCBM due to rectal cancer successfully treated with a combination of FOLFOX and an anti-epidermal growth factor receptor (EGFR) agent. The patient was a 38-year-old man diagnosed with rectal cancer with multiple bone and para-aortic lymph node metastases complicated by disseminated intravascular coagulation (DIC). He first recovered from DIC following cotreatment with FOLOX plus cetuximab; subsequently, the second attack was successfully treated with FOLFOX plus panitumumab. His initial condition was extremely poor, but he survived with two FOLFOX plus anti-EGFR regimens and died 333 days after introduction of chemotherapy.

KRAS‑mutant colorectal cancer (CRC) is a highly malignant cancer with a poor prognosis, however specific therapies targeting KRAS mutations do not yet exist. Anti‑epidermal growth factor receptor (EGFR) agents, including cetuximab and panitumumab, are effective for the treatment of certain patients with CRC. However, these anti‑EGFR treatments have no effect on KRAS‑mutant CRC. Therefore, new therapeutic strategies targeting KRAS‑mutant CRC are urgently needed. To clarify the direct effect of KRAS gene mutations, the present study transduced mutant forms of the KRAS gene (G12D, G12V and G13D) into CACO‑2 cells. A drug‑screening system (Mix Culture assay) was then applied, revealing that the cells were most sensitive to the MEK inhibitor trametinib among tested drugs, Cetuximab, Panitumumab, Regorafenib, Vemurafenib, BEZ‑235 and Palbociclib. Trametinib suppressed phosphorylated ERK (p‑ERK) expression and inhibited the proliferation of KRAS‑mutant CACO‑2 cells. However, low‑dose treatment with trametinib also increased the expression of the anti‑apoptotic protein Bcl‑xL in a dose‑dependent manner, leading to drug resistance. To overcome the resistance of KRAS‑mutant CRC to apoptosis, the combination of trametinib and the Bcl‑xL antagonist ABT263 was assessed by in vitro and in vivo experiments. Compared with the effects of low‑dose trametinib monotherapy, combination treatment with ABT263 had a synergistic effect on apoptosis in mutant KRAS transductants in vitro. Furthermore, in vivo combination therapy using low‑dose trametinib and ABT263 against a KRAS‑mutant (G12V) xenograft synergistically suppressed growth, with an increase in apoptosis compared with the effects of trametinib monotherapy. These data suggest that a low dose of trametinib (10 nM), rather than the usual dose of 100 nM, in combination with ABT263 can overcome the resistance to apoptosis induced by Bcl‑xL expression, which occurs concurrently with p‑ERK suppression in KRAS‑mutant cells. This strategy may represent a promising new approach for treating KRAS‑mutant CRC.

Introduction Patients with mixed connective tissue disease (MCTD) have higher rates of pulmonary arterial hypertension (PAH) than the general population. PAH is a risk for perioperative respiratory and heart failure, and marked edema of colonic stoma after sigmoidectomy. We report a case of sigmoidectomy for sigmoid colon cancer in a patient with PAH associated with MCTD for whom perioperative treatment was planned to control pulmonary arterial pressure (PAP), and a surgical strategy to avoid complications attributable to PAH and MCTD was employed. Case presentation A 52-year-old woman with sigmoid cancer and severe PAH associated with MCTD underwent surgery. We controlled PAH by using intravenous epoprostenol. We selected open surgery without laparoscopy and Hartmann's operation. After surgery, severe perioperative complications were not detected, and the patient discharged from hospital 17 days after the operation. Discussion During surgery under general anesthesia, the mortality rate of PAH is high because of heart and respiratory failure. We planned to switch the PAH treatment from an oral agent to intravenous epoprostenol only in the preoperative period, and selected open surgery. We ligated the inferior mesenteric artery (IMA) and inferior mesenteric vein (IMV) below the branch of LCA to avoid marked edema of stoma. Consequently, we could avoid severe intraoperative and postoperative complications. Conclusions Controlling PAP using epoprostenol, open surgery, stoma and the ligation level for the IMA and IMV preventing are important to avoid perioperative complications of sigmoid colon cancer complicated by severe PAH., Highlights • The patient with PAH complicated by MCTD underwent Hartman’s operation for sigmoid colon cancer. • Control of PAH by epoprostenol preoperatively is important to prevent perioperative cardiac complications. • The level of ligation of the IMA and the LCA is important to avoid severe edema of stoma.