Left-sided Colorectal Cancer Research Articles

ScRNA-seq of colorectal cancer shows regional immune atlas with the function of CD20+ B cells

Colorectal cancer (CRC) from different regions exhibits different histological, genetic characteristics, and molecular subtypes, even in response to conventional chemotherapies and immunotherapies. To characterize the immune landscape in different regions of CRC and search for potential therapeutic targets, we analyzed 39,484 single-cell transcription data from 19 samples of CRC and paired normal tissues from four regions to identify the immune characteristics of CRC among anatomic locations, especially in B cells. We discovered that immune cell infiltration in tumors significantly varied among different regions of CRC. B cells from right- and left-sided CRC had different development trajectories, but both had extensive interactions with myeloid cells and T cells. Survival analysis suggested that CD20+ B cells correlated with good prognosis in CRC patients, especially on the right side. Furthermore, the depletion of CD20+ B cells demonstrated that anti-CD20 promoted tumor growth progression and reversed the tumor-killing activity of anti-PD-1 treatment in vivo and in vitro. Our results highlight the characterization of the immune landscape of CRC in different regions. CD20+ B-cell infiltration has been associated with CRC patient prognosis and may promote the tumor-killing role of PD-1 antibodies.

Real-world evidence of FOLFIRI combined with anti-angiogenesis inhibitors or anti-EGFR antibodies for patients with early recurrence colorectal cancer after adjuvant FOLFOX/CAPOX therapy in Japan: A retrospective observational study using administrative database.

110 Background: Oxaliplatin-containing regimens (FOLFOX or CAPOX) are the most common adjuvant treatments after curative resection of colorectal cancer (CRC). However, real-world evidence (RWE) of treatment sequence/outcomes for patients with early recurrence CRC after receiving adjuvant chemotherapy are limited. Methods: This retrospective cohort study was based on an administrative database in Japan. The primary objective was to describe the treatment sequence for patients with early recurrence CRC and treated by combination of FOLFIRI and anti-angiogenesis inhibitors (AAIs) or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) after adjuvant FOLFOX or CAPOX therapy. The study included patients with CRC who underwent surgical resection, started adjuvant chemotherapy ≤3 months (mo) after the first surgery, had early recurrence of CRC (defined as initiation of FOLFIRI + AAIs/anti-EGFR mAbs second line [2L] regimen) within 1 year after adjuvant chemotherapy ended. Patient characteristics at baseline of 2L (60 days prior to 2L initiation) and treatment sequence were summarized descriptively; time to discontinuation (TTD) for adjuvant and 2L therapy were analyzed using Kaplan-Meier method. Cox proportional hazard model was used to identify risk factors associated with TTD of 2L regimen. Results: The cohort included 832 patients: median (range) age was 67 (24-86) years, 56.4% males, 65.5% with left-sided CRC. Most patients received CAPOX (71.3%) as adjuvant therapy. Median (95% CI) duration of adjuvant therapy was 5.4 mo (5.3-5.5). As 2L therapy, 72.5% and 27.5% of patients received FOLFIRI + AAIs (AAIs group) and FOLFIRI + anti-EGFR mAbs (anti-EGFR group), respectively. Median TTD (95% CI) of the AAIs and anti-EGFR groups in 2L were 6.2 mo (5.8-6.9) and 6.1 mo (5.2-7.4), respectively. Among patients with recurrence within 6 mo (72.6%), the median TTD (95% CI) for AAIs and anti-EGFR groups were 6.1 mo (5.5- 6.5) and 5.8 mo (5.1-7.8), respectively. Among patients with recurrence during 6 to 12 mo (27.4%), the median TTD (95% CI) of AAIs and anti-EGFR groups were 8.1 mo (6.1-9.2) and 6.2 mo (4.6-8.0), respectively. Age ≥70 years was negatively associated with TTD of 2L, HR = 1.19 (95% CI: 1.02-1.39); p=0.03. Conclusions: This is the first RWE based on administrative data on treatment sequence/ outcomes for patients with early recurrence CRC treated by FOLFIRI + AAIs/anti-EGFR mAbs after adjuvant FOLFOX/CAPOX therapy in Japan. The treatment outcomes for patients with early recurrence CRC were similar to previous clinical trials in 2L advanced CRC. The results suggested that these two 2L regimens had similar TTD; however, the timing of relapse may influence the efficacy of AAIs and anti-EGFR mAbs.

Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors.

TPS227 Background: Aberrant transcription in cancer can be reversed by targeting critical epigenetic regulators. For example, in acute leukemias driven by increased HOX gene expression, inhibition of the menin-KMT2A interaction by revumenib induced remission in patients with heavily pretreated disease (Issa et al 2023). In solid tumors promoted by the aberrant activation of the Wnt/β-catenin pathway, in vitro data and in vivo studies have shown that small molecule inhibition of the menin-KMT2A interaction restricts growth, with potential therapeutic benefit in colorectal cancer (CRC), castration-resistant prostate cancer, estrogen receptor–positive breast cancer, gastrointestinal stromal tumors, and Ewing sarcoma. To test the therapeutic strategy of inhibiting the menin-KMT2A interaction in solid tumor malignancies, this study (NCT05731947) will evaluate revumenib in patients with CRC and other solid tumors. Revumenib is an oral, potent, selective inhibitor of the menin-KMT2A interaction. Methods: This phase 1/2 study is evaluating revumenib in adults aged ≥18 years with locally recurrent or metastatic CRC who have failed ≥1 prior line of therapy and in patients with other solid tumors who have failed available standard therapies. Inclusion criteria include diagnosis of microsatellite stable/proficient mismatch repair CRC or other solid tumors. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti–epidermal growth factor receptor therapy. The primary phase 1 objectives are to determine the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose of revumenib in patients with CRC and other solid tumors and to assess its antitumor effects. The phase 2 primary objective is to assess the antitumor effects of revumenib by blinded radiographic review. Phase 1 consists of all-comers’ dose escalation (phase 1a), and signal-seeking expansion in CRC (phase 1b). Using a rolling 6 design, the revumenib starting dose will be 163 mg 3 times daily in 28-day cycles. Up to 6 patients will be enrolled in a dose cohort. Dose escalation cohorts may be expanded and used for signal seeking in non-CRC tumor types. Phase 1b in CRC will begin when a potential phase 2 dose has been identified. The disease control rate at 6 cycles and overall response rate will be used to assess antitumor activity and will determine initiation of phase 2. In phase 2, patients with advanced CRC will be randomized 2:1 to revumenib or investigator's choice of 1 of 2 standard-of-care therapies. Patients will be followed for progression-free survival, with response assessments evaluated locally and confirmed by blinded radiographic review. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947 .

High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of RAS/BRAF mutation status or tumor sidedness.

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S >40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]

Circulating tumor DNA (ctDNA) positivity and its association with clinicopathological characteristics by novel blood-based test for colorectal cancer (CRC) screening from a multi-center large cohort: COSMOS-CRC-01.

69 Background: Blood-based CRC screening has yielded performance comparable to stool-based screening tests and may be a modality that addresses the adherence gap in CRC screening. To investigate the diagnostic performance and its clinical relevance, we evaluated the test performance of a blood-based CRC screening test in a large cohort of individuals enriched for advanced colorectal neoplasia and early CRCs. Methods: 501 individuals presenting to ten institutions in Japan from 2020 to 2021 for treatment of advanced adenomas (AAs) or CRCs were consented and provided a pre-treatment blood sample (40mL whole blood in Streck cfDNA blood collection tubes). All eligible individuals underwent surgery or endoscopic resection within 30 days after sample collection and the pathological specimens were reviewed to determine cancer histology and stage, as well as AA histology. Pre-treatment blood samples were analyzed with a multi-modal (genomic and epigenomic) cfDNA CRC detection assay (Shield, Guardant Health, USA). Final cfDNA results were correlated with clinical data to determine the association of clinicopathological characteristics with test sensitivity. This study is registered as a clinical trial under UMIN000037765. Results: 451/501 (90%) individuals met inclusion/exclusion criteria and provided adequate blood samples that passed testing quality control criteria. Median age at consent was 67.4 years (range 31 – 92). 44% were female. 214/451 (47%) had a prior positive fecal occult blood test (FOBT). Of individuals with a negative or unknown FOBT testing, 161/237 (68%) had GI symptoms (e.g. abdominal pain, bloody/narrowing stool, constipation/diarrhea). The test identified 88% (268/305) of CRCs, including 71% (79/111) Stage I, 98% (87/89) Stage II, 97% (90/93) Stage III, and 100% (12/12) Stage IV. Overall sensitivity in detecting Stage I-III was 87%. The test identified 37% (54/146) of AAs, including 49% (33/68) of carcinoma in situs and 24% (9/37) of AAs with high-grade dysplasia. Sensitivity for right-sided CRC was 84% (61/73), 87% (59/68) for left-sided CRC, and 90% (148/164) for rectal tumors. Stage I test sensitivity was significantly associated with tumor size (>20mm; p<0.01), left-sided or rectal tumor location (p<0.05), and tumor depth (p<0.01) in univariate analysis, whereas the tumor depth (T2) was the sole factor associated with test positivity (p<0.05) in multivariate analysis. Specificity on this assay is 90% as determined in the ECLIPSE clinical study (NCT04136002). Conclusions: This study evaluates the performance of a blood-based test for CRC and its clinicopathological relevance in a large-scale cohort. In this population enriched for early colorectal neoplasia, the sensitivity was 88% for CRC and 37% for AAs. This performance is consistent with previous reports. Clinical trial information: UMIN000037765 .

Gut mucosal microbiota profiles linked to development of positional-specific human colorectal cancer

<p>Colorectal cancer (CRC) continuously ranks as the third most common cause of cancer-related deaths worldwide. Based on anatomical classifications and clinical diagnoses, CRC is classified into right-sided, left-sided, and rectal CRC. Importantly, the three types of positional-specific CRC affect the prognosis outcomes, thus indicating that positional-specific treatments for CRC are required. Emerging evidence suggests that besides host genetic and epigenetic alterations, gut mucosal microbiota is linked to gut inflammation, CRC occurrence, and prognoses. However, gut mucosal microbiota associated with positional-specific CRC are poorly investigated. Here, we report the gut mucosal microbiota profiles associated with these three types of CRC. Our analysis showed that the unique composition and biodiversity of bacterial taxa are linked to positional-specific CRC. We found that a combination of bacterial taxa can serve as potential biomarkers to distinguish the three types of CRC. Further investigations of the physiological roles of bacteria associated with positional-specific CRC may help understand the mechanism of CRC progression in different anatomical locations under the impact of gut mucosal microbiota.</p>

Prevalence of PIK3CA Mutation Based on Tumour Locations Among Colorectal Cancer Patients in Bali

Colorectal tumour location is important in determining therapeutic strategies because the location of the tumour will affect the histological and molecular characteristics of the cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a gene known to be associated with colorectal cancer location. The prevalence of PIK3CA mutations in colorectal cancer (CRC) ranges from 10-20%. Although the prevalence is small, this gene has a potential as a predictive and prognostic biomarker in the management of CRC. 80% of PIK3CA mutations occur in exon 9 (codon 542 and 545) and exon 20 (codon 1047). This study aimed to determine the prevalence of PIK3CA gene mutations based on tumour location among colorectal cancer patients in Bali, especially in Prof. dr. I G.N.G. Ngoerah Hospital, Denpasar, Bali. DNA was isolated from formalin-fixed-paraffin embedded (FFPE) blocks of colorectal cancer samples which were stored in the Department of Pathology of Prof. dr. I G.N.G. Ngoerah Hospital. Mutation was detected using polymerase chain reaction (PCR) and direct sequencing. Data on age, gender, and tumour location were recorded from patient medical records. Our findings on 31 colorectal cancer samples showed 26 samples (96.3%) were found with heterozygous mutation in exon 9 with AC genotype, but no mutation was found on exon 20. Based on tumor location, among 26 samples with mutation, 16 samples (61.5%) were left colorectal cancer and 10 samples (38.5%) were right colorectal cancer. Further studies are needed to identify the association of this mutation with colorectal cancer location and the other clinicopathological aspects of CRC. Keywords: Colorectal cancer, PIK3CA gene mutation, PIK3CA exon 9, PIK3CA exon 20, colorectal cancer location, left-sided colorectal cancer, right-sided colorectal cancer

Neoadjuvant calcium electroporation for potentially curable colorectal cancer.

The development of new perioperative treatment modalities to activate the immune system in colorectal cancer might have a beneficial effect on reducing the risk of recurrence after surgery. Calcium electroporation is a promising treatment modality that potentially modulates the tumor microenvironment. The aim of this study was to evaluate the safety of the procedure in the neoadjuvant setting in localized left-sided colorectal cancer (CRC). The study included patients with potentially curable sigmoid or rectal cancer with no indication for other neoadjuvant treatment. Patients were offered calcium electroporation as a neoadjuvant treatment before elective surgery. Follow-up visits were conducted on the preoperative day before elective surgery, POD2, POD14, and POD30, with an evaluation of adverse events, impact on elective surgery, clinical examination, and quality of recovery. Endoscopic calcium electroporation was performed as an outpatient procedure in all 21 cases, with no procedure-related complications reported. At follow-up, five adverse events were registered, two of which were classified as serious adverse events. Surgery was performed as planned in 19 patients (median time to surgery, 8days), and the final two patients underwent surgery with a delay due to adverse events (14 and 33days). No significant impact on the quality of recovery scores nor inflammatory markers were seen before and after calcium electroporation, nor baseline and POD30. Endoscopic calcium electroporation is a safe and feasible procedure in patients with potentially curable CRC. The study showed limited side effects and limited impact on the following elective surgical resection.

Prognostic impact of colorectal cancer patients with bone metastases: a single-center experience.

The incidence of bone metastasis (BM) in colorectal cancer (CRC) patients is low and the prognosis is poor. There is no clear conclusion on the risk factors affecting the survival of CRC patients with BM. The aim of this study was to investigate the factors that may affect the prognosis of CRC patients with BM. The clinical and pathological data of CRC patients with BM were retrospectively analyzed. The overall survival after BM diagnosis was estimated using the Kaplan-Meier method and Log-rank test, and a multivariable cox regression model was used to identify the prognostic factors of overall survival. This study included 178 CRC patients with BM, of whom 151 had left-sided CRC and 27 had right-sided colon cancer. 1124 CRC patients with BM from the SEER database were included to perform a sensitivity analysis of the primary outcome. Multivariate analysis showed that the N staging, site of BM, and primary tumor sidedness (PTS) were independent prognostic factors for CRC with BM. Among them, right-sided colon cancer patients with BM had a poorer prognosis. Sensitivity analyses showed that PTS was an independent prognostic factor in CRC patients with BM. Primary tumor sidedness and N stage may be potential prognostic markers for BM of CRC. The prognosis of N0 stage CRC with BM is better, while the prognosis of right-sided colon cancer is poor.

Sidedness-Dependent Prognostic Impact of Gene Alterations in Metastatic Colorectal Cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN).

The treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC. Patients enrolled between April 2017 and March 2019 were included in this study. Those excluded were individuals whose tumor tissues were obtained after chemotherapy and those who were enrolled in the study more than six months after starting first-line chemotherapy. Finally, we assessed 531 patients who underwent complete gene sequencing. The study revealed a significant difference in overall survival between individuals with left-sided CRC (n = 355) and right-sided colon cancer (CC) (n = 176) when considering the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant, and MYC amplification. Multivariate analysis on each side revealed that the TP53 GOF and KRAS variants were independent poor prognostic factors for left-sided CRC (p = 0.03 and p < 0.01, respectively), and the TP53 non-GOF variant, BRAF V600E, and MYC amplification for right-sided CC (p < 0.05, p < 0.01, and p = 0.02, respectively). The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC.

Clinical significance of Bacteroides fragilis as a potential prognostic factor in colorectal cancer

IntroductionBacteroides fragilis (B. fragilis) is considered to act in an anti-inflammatory manner on the intestinal tract. On the contrary, enterotoxigenic B. fragilis (ETBF), a subtype of B. fragilis, produces an enterotoxin (BFT; B. fragilis toxin), leading to asymptomatic chronic infections and colonic tumor formation. However, the impact of B. fragilis and ETBF on the clinical outcome of colorectal cancer (CRC) remains unclear. We aim to assess whether their presence affects the outcome in patients with CRC after curative resection. MethodsWe obtained 197 pairs of matched formalin-fixed paraffin-embedded samples from cancerous and adjacent non-cancerous tissues of patients with pathological stage (pstage) II and III CRC after curative resection. The presence of B. fragilis and ETBF were estimated using real-time polymerase chain reaction, and recurrence-free survival (RFS) and overall survival (OS) of the patients were analyzed. Results16S rRNA for B. fragilis and bft DNA were detected in 120 (60.9%) and 12 (6.1%) of the 197 patients, respectively. B. fragilis-positive patients had better RFS than B. fragilis-negative patients, although that was not statistically significant. In subgroup analysis, better outcomes on RFS were observed in the presence of B. fragilis in pstage II and left-sided CRC. The association of B. fragilis positivity on OS was accentuated in the depth of T4 subgroup. No significant differences were observed in RFS and OS between ETBF and non-toxigenic B. fragilis. ConclusionsOur findings suggest that the presence of B. fragilis is associated with better outcomes in patients with pstage II and III CRC after curative resection.

555MO Modified (m)-FOLFOXIRI plus cetuximab treatment and predictive clinical factors for RAS/BRAF wild-type and left-sided metastatic colorectal cancer (mCRC): The DEEPER trial (JACCRO CC-13)

555MO Modified (m)-FOLFOXIRI plus cetuximab treatment and predictive clinical factors for RAS/BRAF wild-type and left-sided metastatic colorectal cancer (mCRC): The DEEPER trial (JACCRO CC-13)

Serum Cytokine and miRNA Levels Are Differently Expressed in Right- and Left-Sided Colon Cancer.

The tumor location in colorectal cancer (right- or left-sided colon cancer) is a key factor in determining disease progression. Right- and left-sided colon tumors are different in their clinical and molecular characteristics. Dysregulation of serum levels of proinflammatory cytokines, such as Transforming Growth Factor β (TGF-β) and Tumor Necrosis Factor-α (TNF-α), and Peroxisome Proliferator Activated Receptor-γ (PPAR-γ), known to be a growth-limiting and differentiation-promoting factor, as well as changes in miRNAs expression, are the major signaling pathways involved in the pathogenesis of this neoplasia. In the serum from 60 colorectal cancer (CRC) patients, we compared the differences in the expression of the levels of TGF-β, TNF-α, and PPAR-γ and in the expression of the main human miRNAs between right and left CRC. A significant over-expression in the TGF-β and TNF-α levels was observed in the serum from right-sided colon cancer patients. For the PPAR-γ, the patients with CRC located on the right-side showed lower levels than those detected in the serum from left-sided CRC subjects. Furthermore, significant differences also existed in the expression of specific circulating miRNAs between right- and left-sided CRC. In particular, the right upregulated miRNAs were all involved in the cell growth and proliferation related pathways. These findings confirm that the analysis of circulating levels of TGF-β, TNF-α, and PPAR-γ, as well as the study of the specific miRNAs in the serum, are able to identify specific characteristics of CRC patients, useful for choosing a personalized treatment protocol.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16

Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P= 0.036). Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

Colonic Resection, Stoma, or Self-expanding Metal Stents for Obstructive Left Colon Cancer: the CROSCO-1 study protocol.

Colorectal cancer (CRC) is one of the most common cancers worldwide. There are several causes of a mechanical left bowel obstructive but CRC accounts for approximately 50% of cases and in 10-30% of whom it is the presenting syndrome. In most cases, the left colon is involved. At present, the range of therapeutic alternatives in the management of obstructive left CRC in emergency conditions (primary resection vs. staged resection with applied self-expanding metallic stents) is broad, whereas internationally validated clinical recommendations in each condition are still lacking. This enormous variability affects the scientific evidence on both the immediate and long-term surgical and oncological outcomes. CROSCO-1 (Colonic Resection, Stoma or Self-expanding Metal Stents for Obstructive Left Colon Cancer) study is a national, multi-center, prospective observational study intending to compare the clinical results of all these therapeutic regimens in a cohort of patients treated for obstructive left-sided CRC. The primary aim of the CROSCO-1 study is the 1-year stoma rate of patients undergoing primary emergency surgical resection (Hartmann procedure or primary resection and anastomosis) compared with patients undergoing staged resection. Secondary outcomes are 30-day and 90-day major morbidity and mortality, 1-year quality of life and the timing of chemotherapy initiation in the two groups. Future CROSCO studies will follow in which, instead, we will evaluate the long-term oncological outcomes of the two treatment strategies. The results of a large prospective cohort study which will analyze what really happens in the common clinical practice of managing patients with obstructive left CRC will have the aim of understanding which is the best strategy in terms of surgical and oncological outcomes. Indeed, the CROSCO-1 study will analyze the early surgical outcomes for patients with obstructed left CRC. Future CROSCO studies will follow in which, instead, we will evaluate the long-term oncological outcomes of the two treatment strategies.

Robotic Anterior Resection for Rectosigmoid Colon Cancer using Single Port Access.

Single-port laparoscopic surgery (SPLS) and a robotic surgical system have recently been included in contemporary colorectal surgical practice. 1-4 SPLS may result in better cosmetic outcomes, reduced postoperative incisional pain, fewer incisional hernias, minimal organ damage, and fewer wound complications. 2,5 However, SPLS for left-sided colorectal cancer is a challenging technique, even for experienced laparoscopic colorectal surgeons, owing to the difficulty of constructing instrument triangulation and using endo-staplers in the pelvic cavity from a single umbilical port with adequate distal margins. The Da Vinci Si Single-Site ® system (Intuitive Surgical, Sunnyvale, CA) was specifically developed to overcome SPLS limitations. Since the robotic instruments are crossed at the port site, but the software "reassigns" them to the surgeon's hand on the robotic console, the platform can easily create instrument triangulation while minimizing external robotic arm collisions. 6-8 Due to the lack of wrist articulation, the limited range of motion of the semi-rigid robotic instruments, and the limited choice of instruments, the Single-Site ® platform has not yet been widely utilized for colorectal diseases. A novel robotic technique, the da Vinci SP ® system (Intuitive Surgical, Sunnyvale, CA, USA), was designed for single-site surgery. This platform has a robotic arm with a high degree of freedom that is introduced directly into the peritoneal cavity through a single incision. The benefits of the single-port da Vinci robot platform include a holographic display of the instrument location, wristed articulation and flexible elbows, a console-controlled camera, and three-dimensional optics. This robotic system for single-port access can perform lymph node dissection around the inferior mesenteric artery using 4-arm wrist articulation while preserving the autonomic nerves during left-sided colorectal cancer surgery.

Dysbiosis of gut microbiota during fecal stream diversion in patients with colorectal cancer

BackgroundThe effect of fecal stream diversion on the gut microbiota is still uncertain. The present study was designed to assess the effect of fecal stream diversion on the composition of the gut microbiota in patients with colorectal cancer. We included patients undergoing left-sided colorectal cancer surgery with (ileostomy group) or without (control group) diverting ileostomy. Fecal samples were collected from 10 patients in each group before surgery (t1) and after ileostomy repair in the ileostomy group and 6–12 months after the initial surgery in the control group (t2). The fecal microbiota was assessed using 16S rRNA sequencing, and changes in the composition of the fecal microbiota were compared between the two groups.ResultsAlpha diversity analysis revealed that the complexity of fecal microbiota decreased between t1 and t2 only in the ileostomy group. Beta diversity analysis also showed dissimilarity between t1 and t2 only in the ileostomy group. The composition of the microbiota was similar between the two groups at t1. However, at t2, the ileostomy group had lower proportion of beneficial bacteria (Lachnospiraceae, 3.8% vs. 29.9%, p < 0.001; Ruminococcaceae, 0.6% vs. 18.4%, p < 0.001; Blautia, 0.1% vs. 9.1%, p < 0.001; Faecalibacterium, 0.2% vs. 7.5%, p < 0.001) and a higher proportion of harmful bacteria (Proteobacteria, 17.9% vs. 5.1%, p = 0.006; Clostridium, 16.2% vs. 1.1%, p = 0.013; Streptococcus, 17.7% vs. 1.6%, p = 0.002) than the control group.ConclusionsFecal stream diversion was closely associated with less diversity and dysbiosis of the gut microbiota.

HER2 Status in RAS and BRAF Wild-Type Metastatic Colorectal Cancer: A Portuguese Study.

Colorectal cancer (CRC) is the second-most deadly cancer worldwide. However, there remains a scarcity of precision treatmentsavailable for this type of cancer. Amplification or overexpression of human epidermal growth factor receptor 2 (HER2+) is a well-established therapeutic target in gastric and breast cancer. HER2is positive in approximately 5% of CRC cases and has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies. The aim of this study was to evaluate HER2 status in RAS and BRAF wild-type metastatic CRC (mCRC) and its correlation with survival outcomes. A single-center retrospective analysis of RAS and BRAF wild-type mCRC patients undergoing systemic treatment was conducted from July 2014 to September 2020. Tissue HER2 status was determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) and/or chromogenic in situ hybridization (CISH). HER2+ was defined as IHC3 (+) or IHC2 (+) through FISH or CISH (+). Fifty-nine patients were included. The median age of all the included patients was 64 years (33-82). Four patients had HER2+ tumors (7%). Four patients had HER2+ tumors (7%).The majority of HER2+ mCRC cases were males (n=3) and left-sided CRC (n=3). All patients received FOLFIRI plus cetuximab as first-line treatment. At the median follow-up of 24.0 months, patients with HER2-negative mCRC presented with a median overall survival (mOS) of 39.4 months (95% confidence interval (CI) 32.7-46.0) and the four patients with HER2+ mCRC had a mOS of 20.4 months(95% CI; 9.5-31.3; p=0.07). In HER2-negative patients, themedian PFS (mPFS) was 11.3 months (95% CI; 9.2-13.4) vsHER2-positive patients with a mPFS of 10.9 months (95% CI; 1.3-20.4;p=0.47). To our knowledge, this is the first study reporting HER2+ in mCRC patients in a Portuguese population and the HER2+ rate was consistent with previous studies. Our study suggests that HER2+ may potentially be a marker that is able to predict poor prognosis in RAS and BRAF wild-type mCRC.

Anatomical classification of and laparoscopic surgery for left-sided colorectal cancer with persistent descending mesocolon

Objective: To investigate anatomical morphology and classification of persistent descending mesocolon (PDM) in patients with left-sided colorectal cancer, as well as the safety of laparoscopic radical surgery for these patients. Methods: This is a descriptive study of case series. Relevant clinical data of 995 patients with left colon and rectal cancer who had undergone radical surgery in Fujian Medical University Union Hospital from July 2021 to September 2022 were extracted from the colorectal surgery database of our institution and retrospectively analyzed. Twenty-four (2.4%) were identified as PDM and their imaging data and intra-operative videos were reviewed. We determined the distribution and morphology of the descending colon and mesocolon, and evaluated the feasibility and complications of laparoscopic surgery. We classified PDM according to its anatomical characteristics as follows: Type 0: PDM combined with malrotation of the midgut or persistent ascending mesocolon; Type 1: unfixed mesocolon at the junction between transverse and descending colon; Type 2: PDM with descending colon shifted medially (Type 2A) or to the right side (Type 2B) of the abdominal aorta at the level of the origin of the inferior mesentery artery (IMA); and Type 3: the mesocolon of the descending-sigmoid junction unfixed and the descending colon shifted medially and caudally to the origin of IMA. Results: The diagnosis of PDM was determined based on preoperative imaging findings in 9 of the 24 patients (37.5%) with left-sided colorectal cancer, while the remaining diagnoses were made during intraoperative assessment. Among 24 patients, 22 were male and 2 were female. The mean age was (63±9) years. We classified PDM as follows: Type 0 accounted for 4.2% (1/24); Type 1 for 8.3% (2/24); Types 2A and 2B for 37.5% (9/24) and 25.0% (6/24), respectively; and Type 3 accounted for 25.0% (6/24). All patients with PDM had adhesions of the mesocolon that required adhesiolysis. Additionally, 20 (83.3%) of them had adhesions between the mesentery of the ileum and colon. Twelve patients (50.0%) required mobilization of the splenic flexure. The inferior mesenteric artery branches had a common trunk in 14 patients (58.3%). Twenty-four patients underwent D3 surgery without conversion to laparotomy; the origin of the IMA being preserved in 22 (91.7%) of them. Proximal colon ischemia occurred intraoperatively in two patients (8.3%) who had undergone high ligation at the origin of the IMA. One of these patients had a juxta-anal low rectal cancer and underwent intersphincteric abdominoperineal resection because of poor preoperative anal function. Laparoscopic subtotal colectomy was considered necessary for the other patient. The duration of surgery was (260±100) minutes and the median estimated blood loss was 50 (20-200) mL. The median number of No. 253 lymph nodes harvested was 3 (0-20), and one patient (4.2%) had No.253 nodal metastases. The median postoperative hospital stay was 8 (4-23) days, and the incidence of complications 16.7% (4/24). There were no instances of postoperative colon ischemia or necrosis observed. One patient (4.2%) with stage IIA rectal cancer developed Grade B (Clavien-Dindo III) anastomotic leak and underwent elective ileostomy. The other complications were Grade I-II. Conclusions: PDM is frequently associated with mesenteric adhesions. Our proposed classification can assist surgeons in identifying the descending colon and mesocolon during adhesion lysis in laparoscopic surgery. It is crucial to protect the colorectal blood supply at the resection margin to minimize the need for unplanned extended colectomy, the Hartmann procedure, or permanent stomas.

Usefulness of blood flow evaluation by indocyanine green fluorescence in laparoscopic or robot-assisted surgery for colorectal cancer with persistent descending mesocolon.

A persistent descending mesocolon is defined as a congenital fixation anomaly caused by the defective membrane fusion of the descending colon and the lateral abdominal wall. Anatomically, in persistent descending mesocolon, the left colonic artery is often shortened, and joins the marginal artery soon after its bifurcation from the inferior mesenteric artery, while the colonic mesentery often adheres firmly to the mesentery of the small intestine. As a result of these characteristics, anatomical knowledge of the persistent descending mesocolon and preservation of bowel blood flow are important during surgery for left-sided colorectal cancer to avoid adverse events. Moreover, indocyanine green based blood flow assessment is useful for the detailed evaluation of bowel ischemia at the anastomotic site. Here we report the usefulness of blood flow evaluation using indocyanine green fluorescence in laparoscopic or robot-assisted surgery for three patients with colorectal cancer and persistent descending mesocolons.