Transcriptome-wide profiling identifies colon cancer-associated m6A transcripts and potential RNA methyl modifiers.

BACKGROUND: N6-methyladenosine (m6A) is a prevalent and crucial RNA methylation modification that plays a significant role in various biological and pathological processes. The dysregulation of m6A has been linked to the initiation, progression, and metastasis of several cancer types, including colon cancer. The transcriptome of colon cancer indeed provides insight into dysregulated coding and non-coding RNAs, but it does not reveal the mechanisms, such as m6A modifications, that determine post-transcriptional and pre-translational regulations. This study using MeRIP sequencing aims to explain the distribution of m6A modification across altered gene expression and its association with colon cancer. METHODS AND RESULTS: The levels of m6A in different colon cancer cell lines were quantified and correlated with the expression of m6A modifiers such as writers, readers, and erasers. Our results showed that global m6A levels in colon cancer were associated with METTL14, YTHDF2, and YTHDC1. We performed Epi-transcriptome profiling of m6A in colon cancer cell lines using Methylated RNA Immunoprecipitation (MeRIP) sequencing. The differential methylation analysis revealed 7312 m6A regions among the colon cancer cell lines. Our findings indicated that the m6A RNA methylation modifications were mainly distributed in the last exonic and 3' untranslated regions. We also discovered that non-coding RNAs such as miRNA, lncRNA, and circRNA carry m6A marks. Gene set enrichment and motif analysis suggested a strong association of m6A with post-transcriptional events, particularly splicing control. Overall, our study sheds light on the potential role of m6A in colon cancer and highlights the importance of further investigation in this area. CONCLUSION: This study reports m6A enrichment in the last exonic regions and 3' UTRs of mRNA transcripts in colon cancer. METTL14, YTHDF2, and YTHDC1 were the most significant modifiers in colon cancer cells. The functions of m6A-modified genes were found to be RNA methylation and RNA capping. Overall, the study illustrates the transcriptome-wide distribution of m6A and its eminent role in mRNA splicing and translation control of colon cancer.

Sarcomatoid Carcinoma Metastasis to the Colon from a Small Renal Mass: Case Report with Review of Literature.

A third of patients with renal cell carcinoma (RCC) present with metastatic disease. Metastasis in RCC from small renal mass (SRM) (≤4 cm) is rare. We report a case of stage cT1a clear-cell RCC with low-risk features on pathology presenting with disproportionately large synchronous solitary metastasis to the transverse colon. He underwent resection of the mass with the involved transverse colon and adjoining mesocolon. Intestinal continuity was restored, following which partial nephrectomy was performed for the right renal tumor. Final pathology of the right renal mass confirmed clear-cell RCC. The large mass after immunohistochemistry profile confirmed metastasis from the renal tumor.

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

Enhanced recovery after surgery (ERAS) in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): a cross-sectional survey.

OBJECTIVES: Enhanced recovery after surgery (ERAS) protocols have been questioned in patients undergoing cytoreductive surgery (CRS) with/without hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies. This survey was performed to study clinicians' practice about ERAS in patients undergoing CRS-HIPEC. METHODS: An online survey, comprising 76 questions on elements of prehabilitation (n=11), preoperative (n=8), intraoperative (n=16) and postoperative (n=32) management, was conducted. The respondents included surgeons, anesthesiologists, and critical care specialists. RESULTS: The response rate was 66% (136/206 clinicians contacted). Ninety-one percent of respondents reported implementing ERAS practices. There was encouraging adherence to implement the prehabilitation (76-95%), preoperative (50-94%), and intraoperative (55-90%) ERAS practices. Mechanical bowel preparation was being used by 84.5%. Intra-abdominal drains usage was 94.7%, intercostal drains by 77.9% respondents. Nasogastric drainage was used by 84% of practitioners. The average hospital stay was 10 days as reported by 50% of respondents. A working protocol and ERAS checklist have been designed, based on the results of our study, following recent ERAS-CRS-HIPEC guidelines. This protocol will be prospectively validated. CONCLUSIONS: Most respondents were implementing ERAS practices for patients undergoing CRS-HIPEC, though as an extrapolation of colorectal and gynecological guidelines. The adoption of postoperative practices was relatively low compared to other perioperative practices.

The colorectal cancer-associated faecal microbiome of developing countries resembles that of developed countries.

BACKGROUND: The incidence of colorectal cancer (CRC) is increasing in developing countries, yet limited research on the CRC- associated microbiota has been conducted in these areas, in part due to scarce resources, facilities, and the difficulty of fresh or frozen stool storage/transport. Here, we aimed (1) to establish a broad representation of diverse developing countries (Argentina, Chile, India, and Vietnam); (2) to validate a 'resource-light' sample-collection protocol translatable in these settings using guaiac faecal occult blood test (gFOBT) cards stored and, importantly, shipped internationally at room temperature; (3) to perform initial profiling of the collective CRC-associated microbiome of these developing countries; and (4) to compare this quantitatively with established CRC biomarkers from developed countries. METHODS: We assessed the effect of international storage and transport at room temperature by replicating gFOBT from five UK volunteers, storing two in the UK, and sending replicates to institutes in the four countries. Next, to determine the effect of prolonged UK storage, DNA extraction replicates for a subset of samples were performed up to 252 days apart. To profile the CRC-associated microbiome of developing countries, gFOBT were collected from 41 treatment-naïve CRC patients and 40 non-CRC controls from across the four institutes, and V4 16S rRNA gene sequencing was performed. Finally, we constructed a random forest (RF) model that was trained and tested against existing datasets from developed countries. RESULTS: The microbiome was stably assayed when samples were stored/transported at room temperature and after prolonged UK storage. Large-scale microbiome structure was separated by country and continent, with a smaller effect from CRC. Importantly, the RF model performed similarly to models trained using external datasets and identified similar taxa of importance (Parvimonas, Peptostreptococcus, Fusobacterium, Alistipes, and Escherichia). CONCLUSIONS: This study demonstrates that gFOBT, stored and transported at room temperature, represents a suitable method of faecal sample collection for amplicon-based microbiome biomarkers in developing countries and suggests a CRC-faecal microbiome association that is consistent between developed and developing countries.

Lymph Node Harvest After Neoadjuvant Treatment for Rectal Cancer and Its Impact on Oncological Outcomes.

The aim of this study was to analyze the influence of neoadjuvant treatment on nodal harvest after rectal cancer surgery and its impact on long-term oncological outcomes. A retrospective analysis of patients with rectal cancer who received curative intent treatment from 2002 to 2012 in our institution was performed. Data on various clinic-pathological and treatment details were recovered from the records. The number of nodes harvested after surgery was analyzed. The influence of number of nodes harvested on overall survival and disease free survival was analyzed. Among the 459 patients included in this study, 326 underwent surgery after neoadjuvant treatment (NAT). The mean number of nodes harvested was significantly lower in patients who received NAT compared with those who did not (8.9 ± 5.77 vs 14 ± 9.84, p < 0.001). However, the mean number of pathologically positive nodes was not significantly different. A minimum of 12 nodes were harvested in only 27.9% of patients who received NAT. No lymph nodes were identified in the specimen in 15 patients (4.6%) who underwent surgery after NAT. The only independent factors influencing harvest of a minimum of 12 nodes were patient age and NAT. The 5-year overall survival was not significantly different in patients in whom < 12 or ≥ 12 nodes were harvested (64% vs 69% respectively, p = 0.5). Neoadjuvant chemoradiation significantly reduces nodal harvest in patients undergoing treatment for rectal cancer. However, this reduced nodal harvest did not adversely impact survival in patients. However, every effort must be made by the surgeon and the pathologist to maximize the nodal harvest.

Perioperative versus postoperative chemotherapy for gastric cancer: A propensity score matched analysis.

AIM: In advanced gastric cancer, chemotherapy, given either perioperatively or as an adjuvant treatment, has been shown to improve survival when compared to surgery alone. However, no trial has compared these two approaches head-to-head. Hence, we aimed to compare the short- and long-term outcomes of patients with gastric cancer who received either perioperative chemotherapy or adjuvant chemotherapy. METHODS: Retrospective analysis of patients with gastric cancers treated from 2010 to 2016. Using propensity score matching, resected patients who received perioperative chemotherapy were matched for histology, nodal dissection, and extent of surgery with another cohort of patients who received only adjuvant chemotherapy to create two matched groups of 101 patients each-group A (perioperative) and group B (adjuvant)-and the outcomes were compared between them. RESULTS: The patient demographics were evenly distributed in the two groups. There was no difference in the median number of chemotherapy cycles delivered (6 vs 6, P = .8) or the grade 3-4 toxicity (17.2% vs 12.1%, P = .26) in group A and group B, respectively. We could not demonstrate a significant difference in the postoperative mortality (2.6% vs 0%) or overall postoperative complications (23% vs 19%) between groups A and B. The overall recurrence rate (37% vs 42%), 3-year disease-free survival rate (51% vs 48%), and 3-year overall survival rate (53% vs 55%) were not significantly different in group A and group B, respectively. CONCLUSIONS: We were unable to detect a significant difference in the short-term or long-term outcomes of patients with gastric cancer undergoing either perioperative or adjuvant chemotherapy.

Prognostic Factors and Survival Outcomes of Surgical Resection of Huge Hepatocellular Carcinomas.

INTRODUCTION: The aim of the study was to analyze the various prognostic factors that influence survival and clinical outcomes in patients undergoing liver resection for huge hepatocellular carcinomas. MATERIALS AND METHODS: The records of patients who underwent curative surgery between 1991 and 2011 for huge hepatocellular carcinoma were analyzed. Various prognostic factors that influenced the survival were studied. The patients were followed up till November 2016. RESULTS: The number of patients who underwent liver resection with huge hepatocellular carcinoma during the study period was 17; this included 14 males and 3 females. The median age of the study population was 52 years. The median serum AFP in the study population was 132.3 ng/ml (range 2 to 187,000 ng/ml). 41.2% of the patients were hepatitis B positive. The overall morbidity was 6%. The mortality rate was nil. The mean size of the resected specimen was 13.9 cm ± 3.6 cm. The overall recurrence rate was 76.5%. The local recurrence rate was 29.4%. The median time to recurrence was 8 months. The 5-year disease-free survival and overall survival of the study group were 26% and 32%, respectively. The factors that predicted an adverse survival outcome after the log-rank test for univariate analysis using life-table method were presence of lymphovascular invasion (p = 0.047), age ≤ 55 years (p = 0.021), and raised serum AFP (p = 0.041). CONCLUSION: The factors that predict an adverse outcome after surgery in patients with huge hepatocellular carcinomas were the presence of lymphovascular invasion, raised serum AFP, and age ≤ 55 years.

Society of Onco-Anaesthesia and Perioperative Care consensus guidelines for perioperative management of patients for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for primary peritoneal malignancies or peritoneal spread of malignant neoplasm is being done at many centres worldwide. Perioperative management is challenging with varied haemodynamic and temperature instabilities, and the literature is scarce in many aspects of its perioperative management. There is a need to have coalition of the existing evidence and experts' consensus opinion for better perioperative management. The purpose of this consensus practice guideline is to provide consensus for best practice pattern based on the best available evidence by the expert committee of the Society of Onco-Anaesthesia and Perioperative Care comprising perioperative physicians for better perioperative management of patients of CRS-HIPEC.

Perineal Wound Complications Following Extralevator Abdominoperineal Excision: Experience of a Regional Cancer Center.

Extralevator abdominoperineal excision (ELAPE) results in a large perineal defect which needs reconstruction by a flap or biological mesh. The incidence of perineal wound complications is thought to be higher following an ELAPE compared to conventional abdominoperineal excision (APE). WE aimed to analyze the perineal wound complications following ELAPE in our institution. This was a retrospective analysis of all consecutive patients who underwent an APE (conventional and ELAPE) procedure in our institution between 2012 and 2015. We retrieved the demographic data, treatment data, and pathological data from the case records. Reconstruction of the perineal defect after a prone perineal dissection was performed using a local muscle flap. The incidence of perinealwound complications, hospital stay, and time to initiate adjuvant chemotherapy was compared between the two groups. A total of 71 patients underwent APE over a period of 41 months of which 21 patients underwent ELAPE. The perineal dissection during ELAPE was done in the prone position in 18 patients and in the supine position in 3 patients. Perineal wound complications were seen in 9 patients (42%) who underwent ELAPE compared to 17 patients (34%) who underwent conventional APE (p = 0.52). The mean duration of hospital stay was significantly longer in patients who underwent ELAPE when compared to those who underwent conventional APE (22.9 ± 3.6 days vs 14.6 ± 1.0 days, p = 0.03). The median interval between ELAPE and initiation of adjuvant chemo was 54 days (range 32-120 days) compared to 50 days (range 30-100 days) in patients undergoing conventional APE. A delay in initiating adjuvant chemotherapy of more than 12 weeks was seen in 4 patients (19%) following ELAPE. The incidence of perineal wound complications following ELAPE in this study was comparable to that reported in literature. Although the hospital stay following ELAPE was significantly longer than that following conventional APE in our institution, it did not unduly prolong initiation of adjuvant chemotherapy. Improving the perineal reconstruction techniques and selecting patients who will benefit from ELAPE may help to reduce the wound complications.

Gastrointestinal mucormycosis in a child with acute lymphoblastic leukemia: An uncommon but ominous complication.

Invasive fungal infections constitute a major cause of morbidity and mortality in children undergoing therapy for hematological malignancies. We report a 1-year-old boy who was receiving chemotherapy for acute lymphoblastic leukemia. His clinical course was complicated by a clinical syndrome consistent with neutropenic enterocolitis to which he succumbed. Histopathology of the surgically resected bowel revealed evidence of mucormycosis. Gastrointestinal mucormycosis is an unusual presentation which requires high degree of clinical suspicion and aggressive management.

Laparoscopic versus open surgery for rectal cancer after neoadjuvant chemoradiation: Long-term outcomes of a propensity score matched study.

BACKGROUND AND OBJECTIVES: Laparoscopic resection for rectal cancer has short-term benefits when compared to open resection. The aim of this study was to compare the long-term oncological outcomes of laparoscopic and open resection for rectal cancer following neoadjuvant chemoradiation (NCRT). METHODS: In this propensity matched study, a series of 72 patients who underwent laparoscopic surgery for rectal cancer following NCRT between 2004 and 2010 (Lap group) were matched with 72 patients who underwent open surgery for rectal cancer in the same period (Open group). The survival and recurrence patterns were compared between the two groups. RESULTS: After a median follow-up of 69.5 months (range 1-138 months), local recurrence rate was observed in 4 patients (5.5%) and 7 patients (9.7%) in the Lap and Open groups, respectively (P = 0.35). The 5- and 10-year disease-free survival in the Lap and Open groups were 61.3% versus 47.9% and 48.8% versus 41%, respectively (P = 0.16). The 5- and 10-year overall survival was 66.9% versus 60.2% and 49% versus 46.2% in the Lap and Open groups, respectively (P = 0.38). CONCLUSION: Laparoscopic surgery following NCRT for low and mid third rectal cancers was associated with similar long-term oncological outcomes when compared to open surgery.

Long-Term Functional and Oncological Outcomes Following Intersphincteric Resection for Low Rectal Cancers.

Surgery for low rectal cancer often involves a permanent stoma. Intersphincteric resection (ISR) with colo-anal anastomosis is a valuable sphincter sparing surgical procedure that avoids the need for permanent stoma in patients with low rectal cancer. The aim of this study was to analyze the long-term functional and oncological outcomes following ISR. This was a retrospective analysis of patients with low rectal cancer who underwent ISR with colo-anal anastomosis in our institution between 2007 and 2015. All patients had a diversion stoma. Bowel function outcomes were assessed prospectively using Wexner incontinence score, low anterior resection syndrome score (LARS), and the Cancer Institute Quality of Life (QoL) questionnaire. The histological reports were reviewed to assess the oncological adequacy of the surgery. Patterns of recurrence and survival were analyzed in this group of patients. Thirty-three patients who underwent an ISR were eligible for this study. Laparoscopic resection was performed in five patients. All the patients received neoadjuvant chemoradiation except the two who received short course radiation and one who did not receive any neoadjuvant treatment. The median distance from the anal verge to the distal edge of the tumor was 3 cm (range 1.5-5 cm). Distal resection margins and circumferential resection margins were negative in all the patients. The 30-day post-operative mortality rate was 3.03%. In 20 patients with a median follow-up of 48 months, the 3-year overall survival was 95%. One patient had recurrence in the para-aortic nodes. No patient had a local recurrence. Bowel function was assessed in 18 patients who had a minimum stoma free period of 1 year. After a median of 43 months following stoma closure, the median Wexner score was 3.56 (range 0-19), median LARS score was 4.78 (range 0-33), and the mean Cancer Institute QoL score was 151.56 ± 15.741. The QoL was average to very high with an overall acceptable quality of life. In this study, ISR was associated with acceptable long-term functional and oncological outcomes. It can be considered as a safe alternative to a permanent stoma in selected patients with low rectal cancer.

Gastric Mucormycosis Masquerading as Gastric Malignancy.

Mucormycosis is an opportunistic fungal infection usually seen in immunocompromised patients. We report a case of gastric mucormycosis in an immune-competent lady that mimicked a gastric malignancy, presenting a diagnostic challenge. A high index of suspicion is required for the diagnosis and successful treatment of this potentially life-threatening condition.

Postoperative Morbidity and Mortality Following D2 Gastrectomy-an Audit of 456 Cases.

BACKGROUND: D2 gastrectomy is routinely performed in Japanese centres for carcinoma stomach with low morbidity and mortality. There were concerns in Western centres with regard to D2 gastrectomy in view of high morbidity and mortality rates. This study was aimed to study the postoperative morbidity and mortality following D2 gastrectomy for carcinoma stomach in a high volume centre in India. METHODS: It was a retrospective analysis of all the patients who underwent D2 gastrectomy from 1991 to 2010. RESULTS: D2 gastrectomy was performed in 456 patients during this period. Respiratory events were the most common cause of morbidity in the study group (2.4 %). Male gender (p = 0.007), presence of gastric outlet obstruction (p = 0.01) and pathological T4 (p = 0.05) independently predicted increased post operative morbidity in multivariate analysis. The morbidity and mortality rates declined with increase in hospital volume and experience of the surgeon. CONCLUSION: D2 gastrectomy for carcinoma stomach can be performed safely in specialized centres with low morbidity and mortality rates.

The Initial Indian Experience with Cytoreductive Surgery and HIPEC in the Treatment of Peritoneal Metastases.

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used for nearly 3 decades to treat peritoneal metastases (PM), improve quality of life, and prolong survival substantially in selected patients. In India, the use of the combined modality of treatment dates back a decade with majority of the efforts taking place within the last 5 years. The first PSOGI workshop (India) held in April 2015, at Bangalore, India offered an opportunity for Indian surgeons performing CRS and HIPEC to share their experience. To study the methodologies of CRS and HIPEC (hospital set up, equipment, training and surgical background) as well as the outcomes in terms of perioperative morbidity and mortality and short and long term survival of patients treated in India, Indian surgeons who had treated at least 10 patients with this combined modality were invited to present their experience. Data collection was retrospective. Analysis of the pooled data was carried out. Eight surgeons treated 384 patients with CRS and HIPEC over a period of 10 years. The commonest primary sites were ovary (as first line therapy n = 124), followed by appendix, including pseudomyxoma peritonei (n = 99), colorectum (n = 77), recurrent ovary (as second line therapy, n = 33), stomach (n = 15), primary peritoneal cancer (n = 10), peritoneal mesothelioma (n = 9) and rare tumors in 17 patients. The weighted mean PCI for all 384 patients was 18.25. 349/384 patients (90.88 %) had a complete cytoreduction (completeness of cytoreduction score of CC-0/1). Grade 3-5 complications developed in 108 patients (27.34 %) and 30 day mortality occurred in 28 (7.29 %) patients. This study showed that CRS and HIPEC can be performed with an acceptable morbidity and mortality in Indian patients. Most of the surgeons are on the learning curve and further improvement in these outcomes is expected over a period of time. Pooling of data related to both common and rare peritoneal cancers would be useful in knowing the disease behavior, response to treatment and outcomes in Indian patients. The 2015 PSOGI meeting provided a unique platform for data presentation with feedback from international experts in the field of peritoneal surface oncology. Future meetings are planned to expand the evaluation of Indian data and progress.

The Role of Hyperthermic Intraperitoneal Chemotherapy in Gastric Cancer.

Peritoneal metastasis, either synchronous or metachronous, is commonly seen in gastric cancer. It is associated with a poor prognosis, with a median survival of less than one year. The outcomes are not significantly improved by the use of systemic chemotherapy. We review the relevant literature on the role of HIPEC in gastric cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used in three situations in gastric cancer. Besides its role as a definitive treatment in patients with established peritoneal metastasis (PM), it has been used as a prophylaxis against peritoneal recurrence after curative surgery and also as a palliative treatment in advanced peritoneal metastasis with intractable ascites. While prophylactic HIPEC has been shown to reduce peritoneal recurrence and improve survival in many randomised trials, palliative HIPEC can reduce the need for frequent paracentesis. Although CRS with HIPEC has shown promise in increasing the survival of selected patients with established PM from gastric cancer, larger studies are needed before this can be accepted as a standard of care.

Diagnostic Laparoscopy in the Pre-operative Assessment of Patients Undergoing Cytoreductive Surgery and HIPEC for Peritoneal Surface Malignancies.

The introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has led to an improvement in the survival of select patients with peritoneal surface malignancies (PSM). However, it is important to carefully identify patients who will benefit from this procedure and to avoid an unnecessary laparotomy in those who will not. The currently available imaging modalities are unable to accurately predict the peritoneal cancer index (PCI) score or the completeness of cytoreduction. In this article, we review the current status of staging laparoscopy in the assessment of patients with PSM who are planned for CRS & HIPEC. We discuss the patient selection, techniques, complications and efficacy of staging laparoscopy. To summarise, staging laparoscopy is a safe and feasible method of pre-operative assessment of patients with PSM. It has a high sensitivity and positive predictive value in identifying patients who can undergo a complete cytoreduction, thereby preventing many patients from undergoing an unnecessary laparotomy. With the exception of pseudomyxoma peritonei, it should be considered as a part of the routine assessment of patients with PSM who are being considered for CRS & HIPEC.