MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase.

Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.

No need to abandon focused parathyroidectomy: a multicenter study of long-term outcome after surgery for primary hyperparathyroidism.

OBJECTIVE: The aim of this study was to investigate long-term outcomes after focused parathyroidectomy (FPTX) and open 4-gland parathyroid exploration (OPTX) for primary hyperparathyroidism (pHPT). BACKGROUND: Concerns about increased long-term recurrence rates after FPTX in conjunction with decreased operative times for OPTX have led some groups to abandon FPTX in favor of routine 4-gland exploration. METHODS: This is a multicenter retrospective cohort study of patients undergoing parathyroidectomy for pHPT from 1990 to 2013. The patient cohort was divided into 2 groups, FPTX and OPTX, based on intention-to-treat analysis. The primary outcome measure was the persistence of pHPT. Secondary outcome measures were differences in the long-term recurrence rate of persisting pHPT and surgical complications. RESULTS: A total of 4569 patients (3585 females) were included. The overall persistence and recurrence rates were 2.2% and 0.9%, respectively, after a median follow-up of 6.5 years. There were 2531 FPTX cases and 2038 OPTX cases. The initial persistence rate was higher for FPTX than for OPTX (2.7% vs 1.7%, P = 0.036); however, the long-term recurrence rate was not different (5-year 0.6% vs 0.4%, log-rank P = 0.08). Complications were more common in OPTX than in FPTX (7.6% vs 3.6%, P < 0.001). CONCLUSIONS: FPTX was associated with fewer operative complications and an equivalent rate of long-term recurrence than with OPTX. Although initial persistence rates were higher after FPTX than after OPTX, most were readily resolved with subsequent early reoperation. FPTX should not be abandoned in patients with positive preoperative localization.

Management of choledocholithiasis in an emergency cohort undergoing laparoscopic cholecystectomy: a single-centre experience.

INTRODUCTION: Minimally-invasive options for the management of choledocholithiasis in patients undergoing laparoscopic cholecystectomy include laparoscopic and endoscopic approaches. This study reviews the effectiveness of both approaches in an emergency setting. METHODS: A retrospective chart review was performed for a cohort of patients who underwent laparoscopic cholecystectomy. Outcomes assessed were duct clearance, the number of procedures performed (NPP), length of stay (LOS) and complication rate. RESULTS: A total of 182 patients who underwent emergency laparoscopic cholecystectomies received intervention for choledocholithiasis. The duct clearance rate was lower in the laparoscopic group, 63% versus 86% (P = 0.001). However, the median NPP was also lesser in the laparoscopic group, 1 (interquartile range (IQR) 1-2) versus 2 (IQR 2-2) (P < 0.001), as was the median LOS, 5 days (IQR 3-8) versus 7 days (IQR 6-10) (P = 0.009). Forty-eight laparoscopic endobiliary stents were attempted; stent deployment was successful in 37 patients. A larger proportion of patients with laparoscopic endobiliary stents had duct clearance by endoscopic retrograde cholangiopancreatography (ERCP) compared with those without, although this was not statistically significant (P = 0.208). CONCLUSION: Laparoscopic clearance is not as effective as post-operative ERCP in an emergency cohort, but is associated with fewer procedures required and a shorter inpatient stay. Thus, laparoscopic clearance may still be an attractive option for surgeons especially where conditions are favourable during an emergency laparoscopic cholecystectomy.

A Case Report on a Hybrid Approach to Managing Acute Large Bowel Obstruction Secondary to Spigelian Hernia.

Spigelian hernias are an uncommon type of primary ventral hernia and are defined as a defect in the Spigelian aponeurosis (fascia). Herein, we present an uncommon case of Spigelian hernia to highlight the potential complications of these hernias and the need for surgical management. This is a case report of an 86-year-old gentleman presenting post-fall with an acute rib fracture and an incidental Spigelian hernia seen on a CT trauma pan scan. The Spigelian hernia surgical treatment was planned for elective management due to the anesthetic risks associated with an elderly patient and acute rib fractures. Ultimately, the patient developed a large bowel obstruction secondary to the Spigelian hernia and required emergency operative management to relieve the obstruction. The patient had an uncomplicated recovery following his emergency surgery. This case report highlights the importance of assessing anesthetic risks versus surgical risks when it comes to surgical planning. Clinicians should recognize occult hernias and continue ongoing clinical reviews with a high index of suspicion, as symptoms of Spigelian hernia obstruction might be non-specific.

The management of clinically suspicious para-aortic lymph node metastasis in colorectal cancer: A systematic review.

Approximately 1%-2% of patients with colorectal cancer (CRC) develop para-aortic lymph node (PALN) metastases, which are typically considered markers of systemic disease, and are associated with a poor prognosis. The utility of PALN dissection (PALND) in patients with CRC is of ongoing debate and only small-scale retrospective studies have been published on this topic to date. This systematic review aimed to determine the utility of resecting PALN metastases with the primary outcome measure being the difference in survival outcomes following either surgical resection or non-resection of these metastases. A comprehensive systematic search was undertaken to identify all English-language papers on PALND in the PubMed, Medline, and Google Scholar databases. The search results identified a total of 12 eligible studies for analysis. All studies were either retrospective cohort studies or case series. In this systematic review, PALND was found to be associated with a survival benefit when compared to non-resection. Metachronous PALND was found to be associated with better overall survival as compared to synchronous PALND, and the number of PALN metastases (2 or fewer) and a pre-operative carcinoembryonic antigen level of <5 was found to be associated with a better prognosis. No PALND-specific complications were identified in this review. A large-scale prospective study needs to be conducted to definitively determine the utility of PALND. For the present, PALND should be considered within a multidisciplinary approach for patients with CRC, in conjunction with already established treatment regimens.

Mechanical bowel preparation with pre-operative oral antibiotics in elective colorectal resections: an Australian single institution experience.

BACKGROUND: Anastomotic leaks (AL) and surgical site infections (SSI) are serious complications after colorectal resection. Studies have shown the benefits of pre-operative oral antibiotics (OAB) with mechanical bowel preparation (MBP) in reducing AL and SSI rates. We aim to investigate our experience with the short-term outcomes of AL and SSI following elective colorectal resections in patients receiving OAB with MBP versus MBP only. METHODS: A retrospective analysis was performed from our database for patients who underwent elective colorectal resection between January 2019 and November 2021. Prior to August 2020, OAB was not used as part of MBP. After 2020, Neomycin and Metronidazole were used in conjunction with MBP. We evaluated differences in AL and SSI between both groups. RESULTS: Five hundred and seventeen patients were included from our database with 247 having MBP while 270 had OAB and MBP. There was a significantly lower rate of AL in patients receiving MBP and OAB as compared to MBP alone (0.4% versus 3.0%, P-value = 0.03). The SSI rate at our institution was 4.4%. It was lower in patients with MBP and OAB as compared to MBP alone, but this was not clinically significant (3.3% versus 5.7%, P-value = 0.19). CONCLUSION: The association in the reduction of AL with the addition of OAB to the MBP protocol seen here reinforces the need for future randomized controlled trials in the Australasian context. We recommend colorectal institutions in Australian and New Zealand consider OAB with MBP as part of their elective colorectal resection protocol.

Right hemicolectomy for colon cancer: does the anastomotic configuration affect short-term outcomes?

OBJECTIVES: Right hemicolectomy is a common colorectal operation for resection of cancers of the right colon. The ileocolic anastomosis may be created using a stapled end-to-side, stapled side-to-side or handsewn technique. Anastomotic leak and post-operative bleeding are uncommon but serious causes of morbidity and mortality, while post-operative ileus contributes to prolonged length of stay. The aim of this study was to evaluate differences in short-term outcomes between different anastomotic configurations following right hemicolectomy for colon cancer. METHODS: We conducted a retrospective study using data from the Bowel Cancer Outcomes Registry (BCOR), including 94 hospitals across Australia and New Zealand, of all patients who underwent right hemicolectomy or extended right hemicolectomy for colon cancer with formation of a primary anastomosis between 2007 and 2021. RESULTS: We included 8164 patients in the analysis. There was no significant difference in rates of anastomotic leak and anastomotic bleeding based on anastomotic technique. A stapled end-to-side anastomosis was associated with a lower rate of post-operative ileus than stapled side-to-side anastomosis (6.5% vs. 7.2%; P = 0.03). CONCLUSION: Both handsewn and stapled anastomosis techniques may be utilized for oncologic right hemicolectomy, with comparable rates of anastomotic leak and post-operative bleeding. Stapled end-to-side anastomosis resulted in lower rates of prolonged ileus compared to stapled side-to-side anastomoses.

Novel extraction technique to remove a penile constriction device.

INTRODUCTION: Penile strangulation can be a challenging clinical situation and usually requires prompt treatment. The clinician should be aware of the various techniques to remove such devices. AIM: The aim of this article was to describe a new noninvasive technique, the "pseudo-pulley" method, to remove a penile constriction device. METHODS: During an episode of medication-induced hypersexuality, a 63-year-old man presented to the emergency department with a cast iron locking nut of a vehicle towbar lodged at the base of the patient's penis. RESULTS: The utilization of the "pseudo-pulley" method to remove the constriction device negated the need for more invasive measures. We outline a step-by-step description on this new technique. The patient's recovery was complete and uneventful. CONCLUSION: The current case report describes a noninvasive technique for removing a penile constriction device that does not rely on specialized equipment and industrial drills that can cause iatrogenic injury.

Melbourne colorectal collaboration: a multicentre review of the impact of COVID-19 on colorectal cancer in Melbourne, Australia.

BACKGROUND: As coronavirus (COVID-19) cases continue to rise, healthcare workers have been working overtime to ensure that all patients receive care in a timely manner. Our study aims to identify the impact and outcomes of COVID-19 on colorectal cancers presentations across the five major colorectal units in Melbourne, Australia. METHODS: This is a retrospective study from a prospectively collected database from the binational colorectal cancer audit (BCCA) registry, as well as inpatient records. All patients with colorectal cancer between Pre-COVID-19 period (1 July 2018-2030 June 2019) and COVID-19 period (1 July 2020-2030 June 2021) were compared. Benign pathology and other cancer types were excluded. RESULTS: A total of 1609 patients were included in the study (700 Pre-COVID-19 period, 906 COVID-19 period). During COVID-19 period, there was a higher proportion of emergency surgery (28.1% vs. 19.8%; P < 0.001), a higher nodal (P = 0.024) and metastatic stage (P = 0.018) at presentation, but no increase in the rate of return to operating theatres (P = 0.240), inpatient death (P = 0.019) or 30-day readmission (P = 0.000). There was also no difference in the post-operative surgical complications (P = 0.118). Utility of neoadjuvant therapy did not increase during the pandemic (P = 0.613). CONCLUSION: The heightened measures in the healthcare system ensured CRC patients still received their surgery in a timely fashion. With the current rise in the new strain of COVID-19 (Omicron), we have to continue to come up with new strategies to provide timely access to CRC care.

Endoscopic Removal of a Fecalith or Fecomucolith in a Rectal Stump or Pouch.

Fecaliths or fecomucoliths can form in rectal stumps after a Hartmann procedure or in a coloneovaginal conduit. They can cause significant distress to the patient by causing symptoms such as discharge and odor. We describe a novel and effective method of endoscopic obliteration and removal where other techniques such as removal during examination under anesthesia or serial enemas have failed. By using a combination of hydrodissection with a saline injector gun and biopsy forceps and a polypectomy snare to break down the fecomucolith or fecalith, this troublesome problem can be resolved endoscopically. Successful removal of the fecalith/fecomucolith and resolution of the symptoms for the patients were achieved. No complications are reported. We describe an effective and novel method for endoscopic removal of fecaliths and fecomucoliths.

Robotic total mesorectal excision or transanal total mesorectal excision meta-analysis.

BACKGROUNDS: Total mesorectal excision (TME) has been established as the standard for oncologic resection of rectal cancer, and has a direct impact on local recurrence and overall survival. OBJECTIVES: Our meta-analysis aims to evaluate the oncological outcomes of the newer techniques of TME - robotic TME versus Transanal TME (TaTME). Primary outcome measures included CRM positivity, R0 resection status, distal resection margins and lymph node yield. Secondary outcome measures were overall complication rates, anastomotic leak and wound infection rates, post-operative ileus rates and mean operative time. METHODS: A systematic literature search was performed to identify relevant studies through PubMEd and Embase from January 2000 to January 2021. Inclusion criteria included English language articles directly comparing TaTME and robotic TME. RESULTS: Seven hundred and fourteen studies were identified, and only six studies were included for this meta-analysis. A total of 1065 participants, of which 632 (59.3%) underwent robotic TME, and 433 (40.7%) had TaTME. Robotic TME had a statistically significant higher lymph node yield (SMD -0.53, p = 0.020). There were no significant differences in the overall complication rates, wound infection and anastomotic leak rates, post-operative ileus, mean operative time and CRM positivity. CONCLUSION: This is the first meta-analysis assessing the outcomes of robotic TME versus TaTME, and only lymph node yield was statistically higher in robotic TME group. These techniques are potentially complementary rather than competing, and we believe that these two approaches can be adopted after appropriate training.

The prevalence and significance of high-risk human papillomavirus DNA test in southern Malaysia and Singapore.

AIM OF STUDY: To investigate the prevalence of high-risk human papillomavirus (HPV) and its associated cytological abnormalities among women attending cervical screening clinics in southern Malaysia and Singapore. METHOD: Laboratory results of Hybrid Capture-II (Digene) HPV DNA and liquid-based cytology tests of consecutive women who had screening performed between January 2004 and December 2006 were studied retrospectively. RESULTS: Of 2364 women studied, the overall prevalence of high-risk HPV DNA detection rate was 25.6%. The prevalence peaked at 49.1% for women between 20 and 24 years old and declined to 23% among women between the age of 30 and 49 years. A small second peak of prevalence rate of 30% was observed among women above the age of 50 years old. 76.1% of the high-risk HPV infection regressed within the study period. An incidence infection rate of 16% was noted among a small group of women who had a second HPV DNA test. A total of 1153 women had both the HPV DNA and the cytology tests. Cytological abnormality (ASCUS or more) was detected in 8.9% in HPV DNA-positive group and in 3.1% in HPV DNA-negative group (P < 0.001). The risk ratio for HSIL was 9.8 for HPV-positive women compared to HPV-negative women. The prevalence of cytological abnormalities increased with increasing age of the women. CONCLUSION: The epidemiology and clinical impact of high-risk HPV infection for women in Southern Malaysia and Singapore were indistinguishable from experience elsewhere. The apparent moderately high incidence of cervical cancer was explainable by suboptimal screening program.

Very rare case of synchronous volvulus of the sigmoid colon and caecum causing large-bowel obstruction.

Large-bowel obstruction caused by volvulus is potentially life threatening if not managed promptly. Sigmoid colon is the most common site of volvulus followed by caecum. Synchronous double colonic volvulus is an exceedingly rare entity, with only five cases published previously. We present the case of a 77-year-old man with a synchronous sigmoid and caecal volvulus. He underwent total colectomy with ileostomy formation with a view to reverse the ileostomy at a later date.

A rare case of ascending colon adenocarcinoma incarcerated in an inguinoscrotal hernia: case report and literature review.

BACKGROUND: Inguinal hernias and colorectal cancers are common conditions, but the presentation of a loop of bowel containing cancer within a hernia is rare. Principles of surgery include oncological resection of the involved colonic segment as well as lymphatic drainage. Based on case reports of the last several decades, there have been no reports of a case where the reduction of an inguinoscrotal hernia and oncological colectomy were performed completely laparoscopically. We present the first instance of a completely laparoscopically assisted resection and hernia repair on a patient with T4 ascending colon cancer. A literature search on recent case reports over the last 30 years has also been presented with a focus on trends in treatment. CASE PRESENTATION: An 83-year-old man presented for further investigation of his iron deficiency anaemia and was diagnosed with adenocarcinoma of the ascending colon. This was demonstrated radiologically to be found within a large right inguinoscrotal hernia. He underwent a laparoscopically assisted right hemicolectomy and laparoscopic closure of the internal ring and recovered well. CONCLUSIONS: Colorectal cancers within inguinal hernias are rare and can often present with complications such as perforation. As such, treatment has mostly involved an open operation. The last few years have shown feasibility of a laparoscopic approach and can be attempted safely when indicated.

Post-operative telephone review is safe and effective: prospective study - Monash outpatient review by phone trial.

INTRODUCTION: Studies have shown that post-operative telephone follow-up is satisfactory and effective. As high quality evidence is scant, we conducted a randomized controlled trial to compare it against outpatient clinic review for emergency laparoscopic appendicectomy or cholecystectomy. METHOD: Patients who received emergency laparoscopic appendicectomy or cholecystectomy were eligible for this study. Once recruited, they were randomly allocated to either clinic review or telephone follow-up on discharge. Participants were reviewed at 2 weeks after operation and contacted again at 4 weeks after initial follow-up for satisfaction survey. RESULTS: One hundred and seventy-nine participants were recruited with one withdrawn consent and six excluded. Ninety-six underwent laparoscopic appendicectomy and 76 had laparoscopic cholecystectomy. Ninety-six attended clinic review and 76 had telephone follow-up. The two groups were similar in baseline variables. Non-attendance rate was higher for clinic review cohort (24% vs 6.6%, P = 0.002). Participants who received telephone review reported higher satisfaction level (9.31 vs 8.85, P = 0.002), and most patients prefer telephone follow-up (73.1%, P < 0.0001). No difference was detected for missed complications (P = 0.354). CONCLUSION: Telephone follow-up post laparoscopic appendicectomy or cholecystectomy is safe, satisfying and effective.