Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer.

Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.

Effect and safety of intraoperative intraperitoneal chemotherapy on patients suffering from colorectal cancer.

BACKGROUND: Colorectal cancer (CRC), the third most commonly diagnosed malignant carcinoma and the third most common cause of carcinoma-related mortality, continues to be a major international health problem. And approximately 33% of patients suffer from recurrence after radical surgery. Free malignant cell implanting in the peritoneum is generally accepted as one of the main reasons of such outcome. We did this present clinical study with the aim of evaluating the effects and safety of intraoperative intraperitoneal chemotherapy (IOC) on patients suffering from colorectal cancer, with hoping to find a novel, effective, and available approach to deal with malignant cell implanting during surgeries. METHODS: In total, 391 patients who went through colorectal radical surgery were considered eligible between June 1, 2017, and December 31, 2018. 220 patients were treated with surgery without IOC, while other 171 patients received surgery plus IOC. Clinical characteristics, operative findings, postoperative short-term outcomes, disease-free survival (DFS), and overall survival (OS) were compared between these above 2 groups in the selected population. RESULT: The present research included 391 patients (251 men and 140 women) who underwent surgery without IOC (n = 171) or surgery plus IOC (n = 220), with a mean (SD) age of 60.4 (9.7) years in the surgery without IOC group and 60.6 (8.7) in the surgery plus IOC group (P=.85). No significant differences were witnessed between the two groups in surgery-related information and postoperative complications. It is worth noting that IOC independent of other factors was associated with a favor prognosis in CRC patients with stage II/III (HR 0.50, 95%CI 0.30-0.82, P=.006). Moreover, for patients with stage II colorectal carcinoma, DFS did not differ between two groups (P=.553, Kaplan-Meier log-rank), and OS was no exception. In stage III CRC patients, the estimated DFS rate for patients receiving IOC was 82.2% and patients without IOC was 66.4% after 3 years, which demonstrated that IOC was associated with a favorable prognosis in stage III patients (P=.012, Kaplan-Meier log-rank). Furthermore, the differences were still remained between the two groups when considering the influence about postoperative chemotherapy (P=.014, Kaplan-Meier log-rank). IOC can also significantly improve patients' overall survival whether they get treatment with POC (P=.006, Kaplan-Meier log-rank; P=.025, Kaplan-Meier log-rank). CONCLUSIONS: In the present study, we have found that surgery plus IOC generated a favorable prognosis for stage III CRC patients but not stage II without any side-effects when the dosage of lobaplatin was 0.1g/L. As a new, safe, and simple procedure, IOC therapy is easily performed-and does not require any special devices or techniques. Thus, IOC is a promising and exciting therapeutic strategy for patients with CRC.

Short-term outcomes of laparoscopic intersphincteric resection with intraoperative radiotherapy using low-energy X-rays for primary locally advanced low rectal cancer: a single center experience.

BACKGROUND: Even with the augmentative application of anal-preservation surgery in low rectal cancer, the role and indications of laparoscopic intersphincteric resection (Lap ISR) are still under debate, especially for T3 or node-positive (T3N0M0, T1-3N+M0) cancer, mainly due to the oncological safety and functional outcomes. INTRABEAM (Carl Zeiss, Germany) intraoperative radiotherapy (IORT) using low-energy X-rays features in accurate irradiation, less exposure, and reduced complications. Taking advantages of Lap ISR and INTRABEAM IORT, this innovative approach aims to increase the probability of the anal preservation with acceptable postoperative outcomes. MATERIALS AND METHODS: From December 2015 to August 2019, we retrospectively analyzed the short-term outcomes of 12 patients evaluated preoperatively with T3 or node-positive (T3N0M0, T1-3N+M0) primary locally advanced low rectal cancer. They all had received Lap ISR and INTRABEAM IORT with a dose of 16-18 Gy applied by an applicator through the anus (natural orifice). Then, with no pre- or postoperative radiotherapy given, the patients were suggested to receive 6-8 cycles of the XELOX chemotherapy regimen (oxaliplatin, 130 mg/m2 and capecitabine, 1000 mg/m2). RESULTS: All patients achieved R0 resection. The median radiation time was 27 min and 15 s, and the mean radiative dose was 17.3 Gy (range 16-18 Gy). The median follow-up time was 18.5 months (range 3-45 months). Two patients experienced local recurrence. Two male patients experienced anastomotic stenosis. Furthermore, one of them experienced perianal abscess and the other one experienced pulmonary metastasis after refusing to receive chemotherapy. One female patient with internal anal sphincter invasion experienced distant metastases to the liver and gluteus maximus muscle 35 months after IORT. No acute radiation injuries or symptoms were observed. Although they experienced a reduction in anal function, every patient was satisfied with the postoperative outcomes. CONCLUSIONS: For patients evaluated preoperatively with T3 or node-positive (T3N0M0, T1-3N+M0) primary locally advanced low rectal cancer, Lap ISR with INTRABEAM IORT may be a safe and feasible approach for anal preservation without compromising oncological outcomes.

Laparoscopic intersphincteric resection with intraoperative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer.

BACKGROUND: In order to overcome the shortcomings of laparoscopic intersphincteric resection (Lap ISR), an alternative method of delivering intraoperative radiotherapy by Intrabeam X-rays radiotherapy system (XRS) is proposed in this paper. Intrabeam XRS is a device that uses low-energy X-rays source generated by a mobile controller unit, which is featured in accurate irradiation, reduced complications, and less exposure. The purpose of this study is to discuss the feasibility of Lap ISR with intra-operative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer in Asian woman. This novel proposed method will greatly increase the anus preserving probability and improved the quality of life. METHODS: A 53-year-old woman diagnosed with rectal adenocarcinoma had a strong desire to preserve the anal function and presented at the Jilin University Second Hospital, Jilin, China. The tumor's size was 4 cm × 3 cm. It was located 2 cm from the anus merge and invaded the levator ani muscle. Preoperative clinical staging was T4N1M0 and could be reached R0 resection. After the consent form was signed by the patient, Lap ISR combined with the applicator put through the anus (natural orifice) to the tumor bed was performed and prophylactic ileostomy synchronized the anastomosis. Patient only received 1-cycle chemotherapy regimen of oxaliplatin with capecitabine postoperatively due to personal reasons. Pre- or postoperative radiotherapy was not given. RESULTS: After clinical follow-up, until now, there is not any sign of local recurrence. Anus function and short-term complications are acceptable. The short-term effect is satisfying and we look forward to further assess the long-term effect. CONCLUSION: Laparoscopic intersphincteric resection with IORT using low-energy X-rays for the patients with late-stage ultra-low rectal cancer could provide an opportunity of preserving the anus function, and it is feasible for the selected patients. TRIAL REGISTRATION: Retrospectively registered; Trial registration: NCT03393234 ; Registered time: 05 January 2017.

Transperineal pelvic drainage combined with lateral position to promote perineal wound healing after abdominoperineal resection: A prospective cohort trial.

BACKGROUND: For the rectal cancer <5 cm from anal margin, extralevator abdominoperineal resection (eAPR) has been accepted widely by surgeons. However, the rate of perineal infection following up eAPR is approximately 70%. We did the study with the aim of evaluating the effect and safety of transperineal pelvic drainage combined with lateral position (TPDLP) on perineal wound in patients undergoing eAPR. METHODS: Patients were randomly assigned to N-TPDLP group (standard arm) or TPDLP group (intervention arm). In the standard arm, surgery was completed after abdominal drainage tube was placed in pelvic. Comparatively, an additional transperineal wound drainage tube was applied in the experimental arm. Postoperatively, patients of both 2 groups were informed not to sit to reduce perineal compression until the perineal wound healed. But lateral position was demanded in the intervention arm. The primary endpoint was the rate of uncomplicated perineal wound healing defined as a Southampton wound score of <2 at 30 days postoperatively. Patients were followed for 6 months. RESULTS: In total, 60 patients were randomly assigned to standard arm (n = 31) and intervention arm (n = 29). The mean perineal wound healing time was 34.2 (standard deviation [SD] 10.9) days in TPDLP arm, which significantly differ from 56.4 (SD 34.1) in N-TPDLP arm (P = .001). At 30 days postoperatively, 3 (10%) of 29 patients undergoing TPDLP were classified into grade 4 according to Southampton wound score, however, 16 (52%) of 31 patients were classified into grade 4 in control arm, and significantly difference was observed between randomization groups (P = .001). What's more, perineal wound pain was assessed at 30 days postoperatively, and it is discovered that the pain degree of patients in control arm was significantly more severe than the interventive arm (P = .015). CONCLUSION: In the present study, we found that TPDLP generated a favorable prognosis for perineal wounds with acceptable side-effects.

Multidimensional Analysis of the Role of Charged Multivesicular Body Protein 7 in Pan-Cancer.

BACKGROUND: Charged multivesicular body protein 7 is briefly referred to as CHMP7, and it plays a significant role in the endosomal sorting pathway. CHMP7 can form a complex with ESCRTIII to jointly complete the process of contraction, shear bud neck and final membrane shedding. METHODS: TCGA, GEO and CPTAC were chosen for the analysis of the role of CHMP7 in pan-cancer. Role of CHMP7 in pan-cancer was analyzed using R software and tools such as TIMER, GEPIA, UALCAN, String and DiseaseMeth. It includes differential expression analysis of CHMP7, survival analysis, genetic variation analysis, DNA methylation analysis, post-translationally modified protein phosphorylation analysis and functional enrichment analysis. RESULTS: CHMP7 presents low expression in the majority of tumor tissues and the prognosis is poor in the low expression group. The common gene mutation in CHMP7 is deep deletion, which may lead to frameshift mutations, resulting in a poor prognosis. Functional alterations due to DNA methylation and post-transcriptional protein modifications may be closely associated with tumors. GO analysis revealed that CHMP7-related genes are involved in the composition of the various ESCRT complexes. In terms of molecular function, they mainly bind to GTP, exert GTPase activity and promote multivesicular bodies assembly. In the KEGG enrichment analysis, the main pathways expressed by CHMP7 and related genes were endocytosis, gap junction and phagosome. CONCLUSION: Pan-cancer analysis showed that CHMP7 expression was statistically correlated with clinical prognosis, DNA methylation, protein phosphorylation and immune cell infiltration, which may provide new ideas or targets for the diagnosis or treatment.

Metachronous primary colon and periampullary duodenal cancer: A case report.

RATIONALE: Primary periampullary duodenal cancer accounts for 3% to 17% of periampullary cancers. There are no previous reports of metachronous primary colon and periampullary duodenal cancer. PATIENT CONCERNS: We present a case of primary periampullary duodenal cancer that occurred metachronously after colon cancer. DIAGNOSES: Imaging and endoscopic examinations, serum tumor marker levels, and pathology confirmed metachronous colon and periampullary duodenal cancer, with 14-month interval between the diagnoses of the 2 malignancies. INTERVENTION: The patient received right hemicolectomy combined with mFOLFOX6 chemotherapy for colon cancer and pancreatoduodenectomy for periampullary duodenal cancer. OUTCOMES: The patient has been followed up for 6 years since the pancreatoduodenectomy and shows no signs of recurrence or metastasis. LESSONS: The risk of developing a second malignancy may be associated with the site of the first tumor. Patients with right colon cancer may have particularly high risk of developing small intestinal cancer, including duodenal cancer. Early detection and active surgical treatments can improve prognosis. Long-term regular follow-up is necessary to detect new malignancies occurring after the diagnosis colon cancer.

Skeletal muscle metastasis with bone metaplasia from colon cancer: A case report and review of the literature.

BACKGROUND: Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon. Lymphatic and hematogenous metastases occur frequently in colon cancer and the most common metastatic sites include the liver, lung, peritoneum, bone, and lymph nodes. As a manifestation of advanced tumor spread and metastasis, soft tissue metastasis, especially skeletal muscle metastasis with bone metaplasia caused by colon cancer, is rare, accounting for less than 1% of metastases. CASE SUMMARY: A 43-year-old male patient developed skeletal muscle metastasis with bone metaplasia of the right proximal thigh 5 mo after colon cancer was diagnosed. The patient was admitted to the hospital because of pain caused by a local mass on his right thigh. Positron emission tomography-computed tomography showed many enlarged lymph nodes around the abdominal aorta but no signs of lung or liver metastases. Color ultrasound revealed a mass located in the skeletal muscle and the results of histological biopsy revealed a poorly differentiated adenocarcinoma suspected to be distant metastases from colon cancer. Immunohistochemistry showed small woven bone components that were considered to be ossified. CONCLUSION: This case reminds us that for patients with advanced colorectal tumors, we should be alert to the possibility of unconventional metastasis.

Gastric tumorigenesis after radical resection combined with adjuvant chemotherapy for colorectal cancer: two case reports and a literature review.

Radical resection with or without adjuvant chemotherapy is a common option for stage II and III colorectal cancer. Few reports exist regarding gastric tumorigenesis, including gastric cancer, gastric intraepithelial neoplasia, and gastric stromal tumor, in patients who received this protocol as the standard treatment for colorectal cancer. We present two cases of gastric tumorigenesis in patients with colorectal cancer following radical resection combined with adjuvant chemotherapy. Both patients underwent gastrectomy and D2 lymphadenectomy for their gastric tumors; neither patient developed recurrence up to 2 years after treatment. These cases indicate that patients should be monitored closely for gastric tumorigenesis after treatment for colorectal cancer. Early detection and active surgical treatment can provide satisfactory results for colorectal cancer followed by gastric tumorigenesis. Long-term follow-up and regular examinations, especially gastroscopy, are necessary to detect gastric tumorigenesis after colorectal cancer. The focus on monitoring colorectal cancer alone in colorectal cancer patients should be changed to include a broader range of cancers in addition to precancers and other tumors, such as gastric stromal tumor.

Subtotal colectomy with antiperistaltic cecosigmoidal anastomosis may be another suitable option for slow transit constipation: Experiences from Chinese people.

The objective of this paper is to demonstrate, considering the experiences from Chinese people, if slow transit constipation (STC) can be accurately diagnosed, choosing patients qualifying for surgery, subtotal colectomy with antiperistaltic cecosigmoidal anastomosis (STC-Anti-CSA) may come with more acceptable short and long-term outcomes.A retrospective study was performed at a department of colorectal and anal surgery. A cohort of 29 patients were coming with up to 5 years' follow-up care, who were in a diverse range of age, BMI, laxative medicine histories, including both males and females. Pre-surgery work-up strictly followed a protocol designed to rule out the patients who were not suitable for surgery treatments. Classification of STC was followed after diagnosis. STC-Anti-CSA was performed in all cases. The operative time, blood loss, average post-operative length of stay (LOS), frequency of BMs, stool consistency and patients satisfaction, by using Wexner constipation score (WCS), numerical rating scale (NRS), and abdominal bloating score (ABS), over the study period were recorded.In this study, there were 14 males and 15 females, with mean age 51, and BMI from 20.14 to 31.62 kg/m. The period of laxative medicine history was 4.8 years (2-13 years). The mean operative time was 152 ±â€Š34 min, and the mean perioperative blood loss was 123 ±â€Š51 mL. Average post-operative LOS (LOS) was 8 days. There were no severe post-operative complications, peri-operative mortality, anastomotic leaks, or revisions of the original surgery. Initial post-operative BMs averaged 6 times/day. During the period of 1 month to 12 months follow-up care, BMs fell down to 2 or 3 times/day. By the 1st to 3rd year follow-up care, BMs averaged 5 to 7 times/week. However, from the 4th year to 5th year, constipations recurred somehow. However, most patients were satisfied with their bowel patterns.STC-Anti-CSA can receive acceptable postoperative outcomes as long as the patients can be accurately diagnosed and classified as severe STC. Among the surgical procedures for STC, this procedure may be another suitable option, especially for Chinese people.

Solitary adrenal metastasis from advanced gastric cancer invading duodenal bulb with situs inversus totalis: A case report.

RATIONALE: Situs invsersus totalis (SIT) is a rare anomaly featured by complete inversion of abdominal and thoracic organs. Adrenal metastasis is often encountered as part of advanced systemic dissemination, which is usually unresectable. Few published cases reported the adrenal metastasis from gastric cancer with SIT and the treatment of gastrectomy combined with adrenalectomy, especially with intraoperative radiotherapy (IORT). PATIENT CONCERNS: A 61-year-old SIT man found a mass on the right clavicle and the biopsy revealed a metastatic cancer. Around 14 years ago, he had a rectal cancer resection surgery and no sign of occurrence. Five months later, the patient had a pain in his right low abdomen and abdominal CT found a right adrenal mass. DIAGNOSES: Gastroscopy and the pathology revealed the gastric antrum cancer invading the duodenal bulb. Abdominal enhanced CT suspected the adrenal mass as a hematoma, but positron emission tomography computed tomography suspected it as the metastases of gastric cancer which is consistent with the pathology results. Finally, the SIT patient was diagnosed with primary gastric cancer invading duodenal bulb with solitary right adrenal metastasis. INTERVENTIONS: The patient was treated with curative distal gastrectomy and Billroth-II anastomosis with D2 lymphadenectomy. A total 18 Gy intraoperative radiotherapy (IORT) using low energy x-rays by Intrabeam were given after resection. OUTCOMES: The patient had liver metastasis in the seventh month after surgery but there is no sign of local recurrence until now. LESSONS: Gastric cancer with adrenal metastasis, especially with SIT is rare and intractable. The result suggested that active surgical treatment for resectable gastric cancer and solitary adrenal metastatic tumor, especially in combination with IORT may be an option in controlling local relapse and prolonging survival in selected patients.

Rectal adenocarcinoma coexisting with incidentally found microscopic gastrointestinal stromal tumor: A case report.

RATIONALE: Adenocarcinoma coexists with adjacent microscopic gastrointestinal stromal tumor (micro-GIST) is rare, especially in the rectum, where the gastrointestinal stromal tumors (GISTs) have the lower incidence rate. It is easy to ignore the concurrent micro-GIST due to the untypical symptoms. PATIENT CONCERNS: A 77-year-old male patient suffered from lower abdominal pain for 20 days and presented with per rectal bleeding for 10 days. He had the medical history of hypertension and diabetes for more than 25 years. DIAGNOSES: Endoscopy revealed that the patient had rectum adenocarcinoma and multiple rectum polyps. Besides, the gastrointestinal stromal tumor was diagnosed by the pathologist. INTERVENTIONS: The patient underwent surgery of laparoscopic rectum resection and prophylactic ileostomy and took 6 courses of Capecitabine tablets orally. OUTCOMES: One year after surgery, the patient had no local relapse by the CT scan. However, not long after the CT examination, he died of cardiovascular disease. LESSONS: Although micro-GIST may be noninvasive and asymptomatic, it may have the potential for transforming to malignancies. More attention should be paid to the patients diagnosed with gastrointestinal malignancy coexisting with micro-GIST.