A systematic review of oncosurgical and quality of life outcomes following pelvic exenteration for locally advanced and recurrent rectal cancer.

INTRODUCTION: Pelvic exenteration (PE) is now the standard of care for locally advanced (LARC) and locally recurrent (LRRC) rectal cancer. Reports of the significant short-term morbidity and survival advantage conferred by R0 resection are well established. However, longer-term outcomes are rarely addressed. This systematic review focuses on long-term oncosurgical and quality of life (QoL) outcomes following PE for rectal cancer. METHODS: A systematic review of the PubMed®, Cochrane Library, MEDLINE® and Embase® databases was conducted, in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Studies were included if they reported long-term outcomes following PE for LARC or LRRC. Studies with fewer than 20 patients were excluded. FINDINGS: A total of 25 papers reported outcomes for 5,489 patients. Of these, 4,744 underwent PE for LARC (57.5%) or LRRC (42.5%). R0 resection rates ranged from 23.2% to 98.4% and from 14.9% to 77.8% respectively. The overall morbidity rates were 17.8-87.0%. The median survival ranged from 12.5 to 140.0 months. None of these studies reported functional outcomes and only four studies reported QoL outcomes. Numerous different metrics and timepoints were utilised, with QoL scores frequently returning to baseline by 12 months. CONCLUSIONS: This review demonstrates that PE is safe, with a good prospect of R0 resection and acceptable mortality rates in selected patients. Morbidity rates remain high, highlighting the importance of shared decision making with patients. Longer-term oncological outcomes as well as QoL and functional outcomes need to be addressed in future studies. Development of a core outcomes set would facilitate better reporting in this complex and challenging patient group.

Colorectal resections during the COVID-19 pandemic: a national survey of practice during first lockdown.

INTRODUCTION: The first wave of the COVID-19 pandemic led to an unprecedented time for the management of colorectal cancer, with uncertainty as to cancer-specific risks and the circumventing of gold standard oncological strategies. Our study aimed to acquire a snapshot of the practice of multidisciplinary team (MDT) management and variability in response to rapidly emerging guidelines. METHODS: The survey was disseminated to 150 colorectal cancer MDTs across England and Wales taken from the National Bowel Cancer Audit data set between 15 April and 30 June 2020 for completion by colorectal surgeons. RESULTS: Sixty-seven MDTs responded to the survey. Fifty-seven centres reported that they continued to perform colorectal cancer resections during the initial lockdown period. Fifty centres (74.6%) introduced routine preoperative COVID-19 testing and 50 (74.6%) employed full personal protective equipment for elective cases. Laparoscopic resections were continued by 25 centres (42.1%), whereas 28 (48.3%) changed to an open approach. Forty-nine (79.0%) centres reported experiencing patient-led surgical cancellations in 0-25% of their listings. If surgery was delayed significantly then 24 centres (38.7%) employed alternative neoadjuvant therapy, with short-course radiotherapy being their preferred adjunct of choice for rectal cancer. Just over 50% of the MDTs stated that they were uncomfortable or very uncomfortable with their management strategies. CONCLUSIONS: Our study demonstrates variability in the MDT management of colorectal cancer during the initial COVID-19 lockdown, incorporating adaptive patient behaviour and initially limited data on oncological safety profiles leading to challenging decision-making.

Metformin as a radiosensitiser for pelvic malignancy: A systematic review of the literature.

BACKGROUND: The treatment of pelvic malignancies has continued to improve over recent years, with neoadjuvant radiotherapy often considered the gold standard to downstage disease. Radiosensitisers are routinely employed in an attempt to improve response of cancers to radiotherapy. Previous preclinical evidence has suggested a role for metformin, a commonly used drug for type 2 diabetes. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string 'Metformin' AND ('Radiosensitivity' OR 'radiosensitising' OR 'radiosensitising'). Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated proforma. The review was registered on the PROSPERO database (ID: CRD42020199066). RESULTS: A total of 242 papers were identified, 11 of which were included in this review; an additional 5 papers were obtained from reference searches. Metformin has been demonstrated to reduce cell-viability post-radiotherapy in both rectal and prostate cancer cell lines, with an enhanced effect in tumours with a p53 mutation and increased apoptosis post-radiotherapy for cervical cancer. Clinical trials demonstrate improved tumour and nodal downstaging and pCR rates for rectal cancer using metformin as a radiosensitiser. CONCLUSION: With an increasing understanding of the underlying mechanism of the effects on metformin prospective studies are required to assess the effect of routine use on cancer related outcomes. Progressive future studies may be better served by the use of predictive biomarker guided treatment to enable identification of the appropriate cohort to target.

Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence.

INTRODUCTION: Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel "off-target" effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. METHOD: A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. RESULTS: A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). CONCLUSIONS: With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.

Early anastomotic complications in colorectal surgery: a systematic review of techniques for endoscopic salvage.

BACKGROUND: Anastomotic complications following colorectal surgery are associated with significant morbidity and mortality. For patients in whom systemic sepsis is absent or well controlled, minimal access techniques, such as endoscopic therapies, are being increasingly employed to reduce the morbidity of surgical re-intervention. In this review, we aim to assess the utility of endoscopic management in the acute setting of colorectal anastomotic complications, focusing on anastomotic leak. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "colorectal anastomotic ("leak" OR "bleed"), "endoscopy", endoscopic management". Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated pro-forma. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: A total of 89 papers were identified, 16 of which were included in this review; an additional 14 papers were obtained from reference searches. In patients who are not physiologically compromised, there are promising data regarding the salvage rate of stents, over-the-scope endoscopic clips, vacuum therapy and fibrin glue in the early management of colorectal anastomotic leak. There is no consensus regarding the optimal approach, and data to assist the physician in patient selection are lacking. Whilst data on salvage (i.e. healing and avoidance of surgery) are well understood, no data on functional outcomes are reported. CONCLUSION: Endoscopic therapy in the management of stable patients with colorectal anastomotic leaks appears safe and in selected patients is associated with high rates of technical success. Challenges remain in selecting the most appropriate strategy, patient selection, and understanding the functional and long-term sequelae of this approach. Further evidence from large prospective cohort studies are needed to further evaluate the role of these novel strategies.

Repeated screening for breast cancer.

In a screening service for breast cancer the results of routine repeat tests of women will contribute more than the results of their initial tests. A comparison of first and subsequent screens in a group of high risk women suggests that the sensitivity of screening declines between first and subsequent visits, whereas its specificity improves. Despite improved specificity, the ratio of benign biopsies to cancer was worse at repeated screening (21 to 1) than at first screening (6 to 1). This was because between first and subsequent screens the yield of cancers fell to a greater extent than the yield of benign disease. The patients with breast cancer diagnosed during this study were remarkable for their good prognosis, 92% being still alive and 86% free from recurrence at their last follow up, the follow up intervals ranging from four to eight years.

Non-A, non-B hepatitis in West London.

Acute and convalescent sera from 368 patients drawn from a 3-year survey of viral hepatitis in West London were tested for radioimmunoassay for evidence of recent infection with hepatitis A or B and, if neither was found, antibody to Epstein-Barr (EB) virus and cytomegalovirus. In 215 patients (58%) there was evidence of hepatitis A, in 98 (27%) hepatitis B, and in 5 both A and B. 2 patients with evidence of recent EB virus infection were excluded, leaving 48 (13%) attributed to non-A, non-B hepatitis. This illness was milder than hepatitis B as judged by duration of jaundice and peak serum bilirubin alanine-aminotransferase levels. The ratio of men to women was 1.4 to 1, but there was an excess of women in their twenties, most of whom were single. Only one had received blood, and none was a drug addict.

Excess morbidity and mortality associated with influenza in England and Wales.

By means of a stepwise regression analysis, an estimate was made of the number of deaths and new sickness benefit claims associated with influenza in the winters of 1976--79. In the moderately widespread outbreak of 1976---76 there were 22250 estimated excess deaths, of which 19590 were in the age group 65 years and over. In the same winter there were 908000 estimated excess sickness benefit claims. The smaller outbreaks of the winters of 1976--79 were associated with between 4000 and 6000 excess deaths. An estimate of the effect of winter temperatures on mortality in the cold winter of 1978--79 gave a figure of 4500 deaths in excess of the number in the previous winter.

Therapeutic trial of intracisternal human tetanus immunoglobulin in clinical tetanus.

A trial has been conducted of the efficacy of human tetanus immunoglobulin (250 I U) administered intrathecally (intracisternally) in addition to standard treatment (equine antitoxin intravenously, penicillin, anticonvulsants). The trial was analysed sequentially and was stopped for 120 patients when there was no longer any chance of achieving a statistically significant difference in favour of intrathecal administration. The sequential plan was modified during the trial. A prognostic correlation was found between onset of the first symptom and admission to hospital.

A three-year survey of viral hepatitis in West London.

During a total population survey of viral hepatitis in the London Boroughs of Hounslow, Richmond and Ealing, 784 patients were seen in three years from 1 March 1972 to 28 February 1975. A diagnosis of viral hepatitis was accepted in 489. The annual incidence was 24 per 100 000. 455 of the patients were tested for the hepatitis B surface antigen (HBsAg) by a radioimmunoassay technique and 93 (20%) of these were positive. The majority of the patients with type B hepatitis were in their third or fourth decades. None was under the age of 16. The male to female ratio among patients with hepatitis B was 2 to 1 in those under the age of 30 and 5 to 1 in those aged 30 and over. The seasonal distribution of viral hepatitis showed a peak in the spring, solely from an increased incidence of non-B hepatitis, and a second, smaller peak in the autumn. There was no appreciable clustering of patients except for one local outbreak in a housing estate during the first year affecting mainly children going to the same primary school, and their parents. Patients with hepatitis B had a longer pre-icteric illness (p less than 0.05), greater duration of jaundice (p less than 0.001) and higher peak levels of serum bilirubin (p less than 0.0005) and serum alanine amino transferase (A1T) (p less than 0.03) than patients with non-B hepatitis. The finding of the surface antigen was also associated with a higher frequency of skin rash (p less than 0.0005) and a greater duration of arthralgia (p less than 0.03). Among the HBsAg negative patients the incidence of arthralgia increased with age (p less than 0.0005). Abdominal pain (p less than 0.005) and vomiting (p less than 0.005) were more common in the young. The injection experience of patients with hepatitis B showed a high proportion of 'non-therapeutic' exposure such as drug addiction. Significantly more HBsAg positive men were single than in the local community (p less than 0.001) or among the HBsAg negative men (p less than 0.01). There was no significant difference between the proportions of single women among the antigen positive and negative patients. Many of the HBsAg positive single men were either known to be or strongly suspected of being homosexual. The ad subtype of the HBsAg was found more often in males (p less than 0.01), particularly over the age of 30. All eight drug addicts tested for subtype were ay, as were two non-addicted female consorts. The association between addiction and ay subtype was highly significant in the males (p less than 0.001). The ad subtype was found in all 11 of the admitted homosexual HBsAg positive men and in all but one of the 17 strongly suspected of being homosexual.

Subjective sexual experience in college women.

A random sample of 100 undergraduate women were interviewed about their subjective sexual experience. Sexual sensations during masturbation, oral sex, intercourse, and intercourse with concurrent clitoral massage were summarized and differentiated. Sensations labeled "orgasm" by a majority of the subjects were identified, and the suggestion was made that experiences other than that outlined by Masters and Johnson may be considered orgasmic by women in a more general population. Some support was found for Singer and Singer's typology of orgasm at a subjective level. Most subjects who experienced multiple orgasms found them no more satisfying than single ones. Clitoral and vaginal orgasms may be distinguished subjectively, but no clear preference for one or the other emerged from a consensus of the subjects. Orgasm rate was significantly related (p less than 0.001) to satisfaction during intercourse and oral sex, but not during masturbation. Some evidence was found supporting the role of social learning in developing sensitivity in the clitoris and vagina and possibly the breasts.