Perineal-First Approach in Robotic Abdominoperineal Resection.

INTRODUCTION: Although abdominoperineal resection (APR) is required for rectal cancer invading the levator ani muscle, its curative outcomes remain poorer than those of other rectal surgeries.1-3 In particular, the anatomic complexity around the anterior wall of the rectum increases the technical difficulty during APR, resulting in a high frequency of margin involvement that causes local recurrence. In this video, we present the technical details of a robotic perineal-first APR approach. METHODS: For a 46 year-old man, locally advanced rectal cancer invading the levator ani muscles was diagnosed. Although total neoadjuvant therapy (8 cycles of induction FOLFOXIRI followed by chemoradiotherapy 50.4 Gy) decreased the tumor size, invasion was suspected still to remain. Therefore, robotic APR was performed. Written informed consent was obtained from the patient. For the perineal-first approach, we created a circular incision around the anus, then divided the fat tissues of the ischiorectal fossa until the levator ani muscle was exposed on both sides. Posterior and anterior dissections were performed along the coccyx and external anal sphincter, respectively. After placement of a lap protector to maintain air-tightness, the robotic approach was initiated. Posterior dissection was performed along the coccyx, then was connected to the already-dissected space created earlier by the perineal approach. Next, the levator ani muscle was divided from the dorsal to the lateral side. Finally, anterior dissection was performed along the prostate, followed by division of the rectourethral muscle, the smooth muscle fibers running vertically. The creation of the already-dissected space on the perineal side offers advantages of robotic manipulation from the abdominal side, especially anterior dissection. RESULTS: We performed robotic APR using the perineal-first approach for 17 consecutive patients (12 men and 5 women) between 2019 and 2023. All 17 patients achieved complete total mesorectal excision with negative margins. The mean time required for the perineal approach was about 25 min. In anterior dissection using the robotic approach, division of the smooth muscle fibers at the perineal body (i.e., rectourethral muscle in males4 or muscular intermingling in females5) was reproducibly performed in both males and females. CONCLUSION: Robotic APR with a perineal-first approach can be advantageous in ensuring surgical margin safety (especially for the anterior aspect of the rectum).

The urinary tract reconstruction in a robot-assisted surgery for rectal malignancy with combined prostate and seminal vesicle resection.

INTRODUCTION: In certain cases of rectal malignancy in which invasion is confined to the prostate and/or seminal vesicles, bladder-sparing surgery may be chosen instead of total pelvic exenteration. However, even if the bladder is preserved, postoperative urinary dysfunction and vesicourethral anastomotic leakage are concern. MATERIALS AND SURGICAL TECHNIQUE: We employ various techniques based on robot-assisted radical prostatectomy for reconstructing the urinary tract. These techniques include advanced reconstruction of vesicourethral support, total anatomical reconstruction, and a method called anterior reconstruction. In addition, suture fixation of bladder to the anterior abdominal wall, and re-approximation of bladder by peritoneal suture were done. DISCUSSION: Reliable robot-assisted vesicourethral anastomosis and reinforcement of the anastomotic wall could potentially enhance the self-voiding rate and decrease the risk of anastomotic failure.

Adipsin-dependent adipocyte maturation induces cancer cell invasion in breast cancer.

Adipocyte-cancer cell interactions promote tumor development and progression. Previously, we identified adipsin (CFD) and its downstream effector, hepatocyte growth factor (HGF), as adipokines that enhance adipocyte-breast cancer stem cell interactions. Here, we show that adipsin-dependent adipocyte maturation and the subsequent upregulation of HGF promote tumor invasion in breast cancers. Mature adipocytes, but not their precursors, significantly induced breast tumor cell migration and invasion in an adipsin expression-dependent manner. Promoters of tumor invasion, galectin 7 and matrix metalloproteinases, were significantly upregulated in cancer cells cocultured with mature adipocytes; meanwhile, their expression levels in cancer cells cocultured with adipocytes were reduced by adipsin knockout (Cfd KO) or a competitive inhibitor of CFD. Tumor growth and distant metastasis of mammary cancer cells were significantly suppressed when syngeneic mammary cancer cells were transplanted into Cfd KO mice. Histological analyses revealed reductions in capsular formation and tumor invasion at the cancer-adipocyte interface in the mammary tumors formed in Cfd KO mice. These findings indicate that adipsin-dependent adipocyte maturation may play an important role in adipocyte-cancer cell interaction and breast cancer progression.

Laparoscopic redo surgery for sigmoid volvulus following laparoscopic sigmoidectomy.

BACKGROUND: Sigmoid volvulus (SV) is an acute abdominal condition characterized by torsion of the sigmoid colon around the mesentery, and often results in intestinal obstruction that may progress to bowel ischemia, necrosis, or perforation. Although SV commonly occurs due to predisposing factors like anatomic variations, age-related motility disorders, chronic constipation, and neurologic diseases, its incidence following sigmoid colon cancer surgery has rarely been reported. Herein, we report a rare case of recurrent SV following laparoscopic sigmoidectomy, which was successfully treated by laparoscopic redo surgery. CASE PRESENTATION: The patient was a 77-year-old man who had previously undergone laparoscopic sigmoidectomy for sigmoid colon cancer. Sixteen months postoperatively, he developed an incisional hernia at the umbilical site, which was treated with a laparoscopic repair using an intraperitoneal onlay mesh. After the hernia surgery, the patient had no anastomotic leakage or stenosis on regular follow-ups. However, 65 months after the first surgery, he presented with abdominal pain and distension. A computed tomography revealed that the remnant sigmoid colon was distended in a twisting manner around the anastomosis, leading to the diagnosis of SV. Although endoscopic de-torsion was successful, the SV recurred 2 months later, requiring elective laparoscopic redo surgery. The procedure involved resection of the sigmoid colon including the prior anastomosis with a left pararectal incision and DST re-anastomosis using a 25-mm circular stapler. The operation lasted 165 min with minimal bleeding and no complications. The postoperative course was uneventful. Pathological analysis confirmed fibrosis without malignancy. The patient remains well without recurrence of SV and anastomotic stenosis more than 5 years after surgery. CONCLUSION: SV following sigmoid colon cancer surgery has rarely been reported. This case illustrates the potential need for prophylaxis against postoperative SV, especially in patients with long sigmoid colon undergoing laparoscopic surgery for colorectal cancer. Further, laparoscopic redo surgery following initial laparoscopic surgery for colorectal cancer can be performed with minimal invasiveness, especially if patient selection is properly managed.

Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment.

BACKGROUND: Chemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked. METHODS: We employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1-/-, Cxcr2-/- or Ccr1-/-Cxcr2-/- mice. RESULTS: Myeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1-/-Cxcr2-/- BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1+CXCR2+ myeloid cells led to a higher frequency of CD8+ T cells, whereas the numbers of Ly6G+ neutrophils, FOXP3+ Treg cells and CD31+ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2-/- BM significantly suppressed tumor growth and liver metastasis. CONCLUSION: Dual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.

Effect of Liver Dysfunction on S-1 Therapy Induced Adverse Effects: A Retrospective Cohort Study.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage.

Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

A proposed new Japanese classification of synchronous peritoneal metastases from colorectal cancer: A multi-institutional, prospective, observational study conducted by the Japanese Society for Cancer of the Colon and Rectum.

Aim: To establish a new Japanese classification of synchronous peritoneal metastases from colorectal cancer. Methods: This multi-institutional, prospective, observational study enrolled patients who underwent surgery for colorectal cancer with synchronous peritoneal metastases. Overall survival rates were compared according to the various models using objective indicators. Each model was evaluated by Akaike's information criterion (AIC). The region of peritoneal metastases was evaluated by the peritoneal cancer index (PCI). Results: Between October 2012 and December 2016, 150 patients were enrolled. The AIC of the present Japanese classification was 1020.7. P1 metastasis was defined as confined to two regions. The minimum AIC was obtained with the cutoff number of 10 or less for P2 metastasis and 11 or more for P3 metastasis. As for size, the best discrimination ability between P2 and P3 metastasis was obtained with a cutoff value of 3 cm. The AIC of the proposed classification was 1014.7. The classification was as follows: P0, no peritoneal metastases; P1, metastases localized to adjacent peritoneum (within two regions of PCI); P2, metastases to distant peritoneum, number ≤10 and size ≤3 cm; P3, metastases to distant peritoneum, number ≥11 or size >3 cm; P3a, metastases to distant peritoneum, number ≥11 and size ≤3 cm, or number ≤10 and size >3 cm; P3b, metastases to distant peritoneum, number ≥11 and size >3 cm. Conclusion: This objective classification could improve the ability to discriminate prognosis in patients with synchronous peritoneal metastases from colorectal cancer.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK-dependent colorectal cancer.

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context-dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP-rich environment based on curation of two publicly available RNA-sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA-approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders to this regimen.

Novel and efficient method for culturing patient-derived gastric cancer stem cells.

Experimental techniques for patient-derived cancer stem-cell organoids/spheroids can be powerful diagnostic tools for personalized chemotherapy. However, establishing their cultures from gastric cancer remains challenging due to low culture efficiency and cumbersome methods. To propagate gastric cancer cells as highly proliferative stem-cell spheroids in vitro, we initially used a similar method to that for colorectal cancer stem cells, which, unfortunately, resulted in a low success rate (25%, 18 of 71 cases). We scrutinized the protocol and found that the unsuccessful cases were largely caused by the paucity of cancer stem cells in the sampled tissues as well as insufficient culture media. To overcome these obstacles, we extensively revised our sample collection protocol and culture conditions. We then investigated the following second cohort and, consequently, achieved a significantly higher success rate (88%, 29 of 33 cases). One of the key improvements included new sampling procedures for tumor tissues from wider and deeper areas of gastric cancer specimens, which allowed securing cancer stem cells more reproducibly. Additionally, we embedded tumor epithelial pieces separately in both Matrigel and collagen type-I as their preference to the extracellular matrix was different depending on the tumors. We also added a low concentration of Wnt ligands to the culture, which helped the growth of occasional Wnt-responsive gastric cancer stem-cell spheroids without allowing proliferation of the normal gastric epithelial stem cells. This newly improved spheroid culture method may facilitate further studies, including personalized drug-sensitivity tests prior to drug therapy.

Total pelvic exenteration for mucinous adenocarcinoma arising from an implantation cyst 26 years after surgery for rectal cancer.

A 47-year-old man underwent low anterior resection for rectal cancer and was surveilled for 5 years without metastasis. Twenty-four years later, the patient developed an implantation cyst at the anastomotic site. Two years after the diagnosis, colonoscopy revealed a disintegrated area in the lesion, and pathological examination of the biopsy specimen revealed adenocarcinoma. Due to the suspicion of invasion into the surrounding organs, the patient underwent laparoscopic total pelvic exenteration after neoadjuvant chemoradiotherapy. A transabdominal and transperineal endoscopic approach was used for safe en bloc excision of the tumor. Pathological examination of the specimen confirmed mucinous adenocarcinoma arising from the implantation cyst. Although an implantation cyst is considered benign, it is important to suspect malignant transformation when its appearance changes. For the accurate diagnosis of implantation cysts, surgeons, endoscopists, and radiologists should be aware of this disease.

Factors Affecting the Comprehension of Outpatients Receiving Cancer Chemotherapy.

Pharmaceutical consultation targeting outpatients at the Fujita Health University Hospital (Japan) provides support to patients undergoing anticancer drug treatment. This study aimed to explore factors that affect the comprehension of cancer chemotherapy among outpatients who received cancer treatment at our hospital. A questionnaire survey was conducted, and comprehension was scored on a scale of 1-5 (1, no comprehension; 5, full comprehension). When factors other than age and sex [the influence of which on comprehension has been reported in previous reports] were noted, differences in comprehension between the questionnaire items were comparatively analyzed according to the presence/absence of the relevant factors. Overall, 536 patients were included. Age (<70 years) and pharmacist interventions were identified as factors contributing to a comprehension score. The levels of comprehension regarding the name of the cancer chemotherapy, content/schedule of the treatment, purposes of the prescribed drugs, and objectives of blood tests were significantly higher in the group that received the pharmaceutical interventions; conversely, the level of comprehension for the self-management of adverse events was significantly lower in this group than in the group that did not receive any pharmaceutical interventions. Age and interventions by the pharmacist affected the comprehension of cancer chemotherapy by patients.

Efficacious Combination Drug Treatment for Colorectal Cancer That Overcomes Resistance to KRAS G12C Inhibitors.

Recent advances in combinatorial chemistry led to the discovery of inhibitors targeting the KRAS G12C-mutant protein. However, efficacy of its monotherapy on colorectal cancer is limited. Thus, effective combination drugs should be explored for applicable patients with colorectal cancer to fully benefit from the KRAS G12C inhibitor treatment. Here we used a patient-derived colorectal cancer stem cell (PD-CRC-SC) spheroid culture and showed that three-drug combination of inhibitors against KRAS G12C, EGFR, and FGFR synergistically suppressed the growth of colorectal cancer cells carrying the KRAS G12C mutation. Likewise, a combination of KRAS G12C and SHP2 inhibitors was also effective. Importantly, activation of the PI3K/AKT pathway in heregulin-responsive colorectal cancer cells canceled out the effect of KRAS G12C inhibition, which was largely overcome by PI3K inhibitors. These results reveal that evaluating efficacy of combination therapies with PD-CRC-SC spheroids can be a promising strategy to find the best regimen for patients with colorectal cancer.

Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity.

Dynamic changes in cell properties lead to intratumor heterogeneity; however, the mechanisms of nongenetic cellular plasticity remain elusive. When the fate of each cell from colorectal cancer organoids was tracked through a clonogenic growth assay, the cells showed a wide range of growth ability even within the clonal organoids, consisting of distinct subpopulations; the cells generating large spheroids and the cells generating small spheroids. The cells from the small spheroids generated only small spheroids (S-pattern), while the cells from the large spheroids generated both small and large spheroids (D-pattern), both of which were tumorigenic. Transition from the S-pattern to the D-pattern occurred by various extrinsic triggers, in which Notch signaling and Musashi-1 played a key role. The S-pattern spheroids were resistant to chemotherapy and transited to the D-pattern upon drug treatment through Notch signaling. As the transition is linked to the drug resistance, it can be a therapeutic target.

Long-term results of a phase 2 study of neoadjuvant chemotherapy with molecularly targeted agents for locally advanced rectal cancer.

BACKGROUND: We previously reported the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Here, we report the results of a long-term follow-up study. METHODS: This was a multi-institutional, prospective phase 2 study of patients with locally advanced rectal cancer. Patients received neoadjuvant chemotherapy with molecularly targeted agents before undergoing total mesorectal excision. Six cycles of modified FOLFOX (mFOLFOX6) with bevacizumab were administered to KRAS-mutant patients, and mFOLFOX6 with cetuximab was administered to KRAS-wild-type patients. Here, we report the secondary end points of overall survival, relapse-free survival, and local recurrence rate. RESULTS: Sixty patients were enrolled in this study. R0 resection was achieved in 98.3% (59/60) patients, and pathological complete response was achieved in 16.7% (10/60) patients. After a median follow-up of 5.4 years, the 5 year overall survival was 81.6%, the 5 year relapse-free survival was 71.7%, and the 5 year local recurrence rate was 12.6%. None of the patients who achieved pathological complete response developed recurrence within 5 years. CONCLUSIONS: The use of molecularly targeted agents in the neoadjuvant setting for locally advanced rectal cancer has an acceptable prognosis.