Outcome of surgery for recurrent anal cancer: results from a tertiary referral centre.

AIM: Chemoradiotherapy remains the first line of treatment for anal cancer with surgery reserved for cancer recurrence or persistence. The low incidence of anal cancer means that the numbers undergoing surgery is small with centralization for excision to regional cancer centres. We present our experience of abdominal perineal excision, with reconstruction of the perineal defect (APERR), within a tertiary centre. METHOD: Over a 15-year period, data were collected retrospectively from notes of patients who underwent an APERR. The aim was to look at disease-free and overall survival and complications associated with flap reconstruction. RESULTS: In the study period, 29 patients [median age = 62 (range: 42-81; interquartile range: 54-68) years] underwent APERR. Median follow-up was 77 (4-200) months. Thirteen patients died during follow-up; eight from their disease, with a median survival time of 16 (4-63) months. Five-year survival was 67%. Nine (31%) patients had recurrence during the follow up period; this was local (n = 2), regional (n = 4), distant (n = 2) or a combination (n = 1). Sixteen (55%) patients developed 24 complications, including nine (31%) flap complications and 10 (34%) parastomal hernias. Flap complications were flap failure (n = 1) requiring direct closure, flap dehiscence (n = 2), necrosis of flap tip (n = 1), wound infection (n = 4) and a bulky flap (n = 1) requiring liposuction. CONCLUSION: APERR of anal cancer is a feasible technique with excellent oncological treatment and acceptable long-term complications, although a higher than expected rate of parastomal hernia was noted.

Impact of ovarian metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancy originating from appendiceal and colorectal cancer.

AIM: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. METHOD: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. RESULTS: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty-two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low-grade appendiceal tumour or CPM. In women with high-grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. CONCLUSION: Women with ovarian metastases from low-grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long-term survival and cure is feasible in patients amenable to complete tumour removal.

A prospective, randomized, single-blind trial of 5-mm versus 3-mm ports for laparoscopic cholecystectomy: is smaller better?

BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) is said to provide improved cosmesis with a reduction in postoperative pain, but SILC involves a change in operative technique. A single-blind, randomized controlled trial compared cosmetic outcomes and postoperative pain between 3- and 5-mm ports used for laparoscopic cholecystectomy (LC). METHODS: For this study, 80 patients with symptomatic gallstones were recruited from a single center and randomized to a LC using either a 5-mm port and three 3-mm ports (group A) or a 10-mm port and three 5-mm ports (group B). Operative details; pain scores at 1 h, 6 h, and 1 week; and analgesia required during the first week were collected. Cosmetic outcome was assessed at 6 months using a validated questionnaire. RESULTS: For each group, 40 patients were recruited. The two groups were well matched except for sex. Group A had 11 males, and Group B had 4 males. The mean operative time was 49 ± 12 min (range, 24-120 min) in the 3-mm group versus 46 ± 19 min (range, 21-124 min) in the control group (p = 0.40). The two groups did not differ statistically in the day case rate. The pain scores in Group A were 2.5 ± 2.1 at 1 h, 3.2 ± 2.2 at 6 h, and 0.8 ± 2.2 at 1 week versus 4.2 ± 2.9 at 1 h, 3.3 ± 2.4 at 6 h, and 2.1 ± 2.4 at 1 week in Group B (p = 0.003, 0.63, and 0.002, respectively). No difference in the analgesia consumption was observed during the first postoperative week. The patients in Group A had significantly better cosmetic outcome scores at 6 months. CONCLUSION: The use of 3-mm ports is technically feasible in patients undergoing LC for gallstones. The operating times are comparable with those for conventional LC, whereas the pain scores are reduced, and the cosmetic outcome is better.

Prospective randomized trial of laparoscopic (transabdominal preperitoneal-TAPP) versus open (mesh) repair for bilateral and recurrent inguinal hernia: incidence of chronic groin pain and impact on quality of life: results of 10 year follow-up.

PURPOSE: The incidence of chronic groin pain (CGP) and its impact on quality of life (QoL) after hernia repair are not clear with follow-up either being short or retrospective. We present 10-year prospective follow-up of a randomized trial for bilateral and recurrent hernia repair focusing on CGP and its impact on QoL. METHODS: Patients enrolled between 1997 and 2000 were contacted by telephone and asked about the presence of CGP. Those patients with CGP were sent two validated questionnaires: a SF-12v2 Health Survey and a Pain Impact Questionnaire (PIQ-6) (QualityMetric, USA). RESULTS: One hundred and twenty patients were recruited into the original study, and of these, 14 complained of CGP and were sent a PIQ-6 and a SF-12 v2 health survey. Overall, there was a higher incidence of CGP in the laparoscopic group compared with the open group (15 vs. 8 %, ns), but the severity of the pain in the laparoscopic group was less (2 vs. 3.5, p = 0.0558). QoL was significantly reduced in patients with CGP compared with the US norm. The laparoscopic group scored higher in 5 out of 8 of the QoL categories compared with the open group, but this was not significant. Overall age-adjusted scores revealed those under 65 years of age felt they had poorer physical health, and this reduced their QoL compared to normal values. CONCLUSION: CGP following laparoscopic surgery for inguinal hernia repair is less severe than open repair, but this does not translate into a significant improvement in QoLin this study.

Complications of transanal endoscopic microsurgery (TEMS): a prospective audit.

BACKGROUND: The aim of this study was to determine the postoperative complications of Transanal Endoscopic Microsurgery (TEMS) excision of rectal lesions. METHOD: A prospective audit of 262 consecutive TEMS procedures performed by a single surgeon between 1999 and 2008. RESULTS: The mean age of patients was 72 years. The mean area of the lesions excised was 17.5 cm(2) with a mean diameter of 4.5 cm at a mean distance of 7.4 cm from the dentate line. There were 201 full thickness excisions, 51 partial thickness excisions and nine were mixed or unclassified. Thirty-three (13%) patients developed 41 complications. There were two (0.8%) deaths within 30 days. Pelvic sepsis occurred in seven (3%) patients and was significantly more common after excision of low lesions within 2 cm of the dentate line. Postoperative haemorrhage occurred in seven (3%) patients and was significantly less common when dissection was performed with ultrasonic dissection than with diathermy. Fourteen (5%) patients developed acute urinary retention. Four (1.5%) patients developed rectal stenosis and four (1.5%) suffered uncomplicated surgical emphysema that required no treatment. CONCLUSIONS: Transanal endoscopic microsurgery is a safe operation with a low mortality and morbidity. Pelvic sepsis is more common after excision of lesions within 2 cm of the dentate line. Ultrasonic dissection is associated with less postoperative haemorrhage than diathermy.

The creation of a peritoneal defect in transanal endoscopic microsurgery does not increase complications.

INTRODUCTION: During Transanal Endoscopic Microsurgical (TEMS) full-thickness excision of a rectal lesion above the peritoneal reflection, entrance to the peritoneal cavity is inevitable. This has been regarded as a complication that requires conversion to an open procedure. We describe our experience of full thickness intraperitoneal excision of rectal lesions where the peritoneal defect was sutured endoscopically. METHOD: Data were collected prospectively on 15 patients in whom a peritoneal defect was created intraoperatively during TEMS excision of a rectal lesion. When a defect was recognized, it was closed by endoscopic suture. If there was any doubt regarding security of the closure, a defunctioning loop stoma was fashioned. RESULTS: Between November 1998 and January 2008, a total of 257 patients underwent TEMS during which a peritoneal defect was created in 15 patients. Six patients had a defunctioning stoma formed at the time of TEMS. No patient was defunctioned postoperatively and there were no deaths. The mean hospital stay was 8 days (range 3 to 19 days). A contrast enema showed sub-clinical leaks in two patients for which no treatment was required. No patient developed pelvic or peritoneal sepsis, but one patient had to return to theatre for postoperative bleeding when a single bleeding vessel was coagulated. CONCLUSION: Full thickness excision of lesions in the intraperitoneal rectum with endoscopic suture of the defect is a safe procedure. Lesions in the upper rectum should not be excluded from TEMS excision because of the chance of peritoneal breach.

Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels.

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is increasingly being recognized as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role of genetic influence on plasma tHcy levels, are still not well understood. In the current investigation, we studied 1025 individuals with respect to the effect of the 68-bp insertion (844ins68 variant) of the cystathionine beta-synthase (CBS) gene, the A(2756)G transition of the B(12)-dependent methionine synthase (MS) gene and the C(677)T transition of the methylenetetrahydrofolate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individuals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) were heterozygous for the G(2756) allele and 122 (11.9%) were homozygous for the C(677)T transition. Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations, while individuals homozygous for the A(2756)G transition had significantly lower fasting tHcy levels. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A(2756)G transition for either fasting tHcy or PML increase in tHcy, confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive. The effects are opposite but additive with the C(677)50% of all individuals in this study carried polymorphic traits, which predisposed them to either higher or lower plasma tHcy concentrations, thus providing new evidence of the importance of genetic influences as determinants of tHcy levels.

Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine beta-synthase gene, and pyridoxal-5'-phosphate concentration.

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is recognized as a risk factor for coronary artery diseases (CAD). Cystathionine beta-synthase (CBS), a key enzyme in the transsulfuration pathway, is important for the metabolism of homocysteine. In recent years, a relatively prevalent mutation, the 844ins68 (68-bp insertion), was found to be carried by about 12% of the general population. In the current investigation, we studied 741 individuals with respect to the effect of the 68-bp insertion of the CBS gene on fasting and PML tHcy, and also determined the level of pyridoxal-5'-phosphate (vitamin B(6)), a cofactor of the CBS enzyme. Our results showed that the mean fasting and PML increase in tHcy levels were lower in individuals carrying the 844ins68 variant compared to those without the insertion; although only the difference in PML increase in tHcy reached statistical significance (P = 0.02). When these individuals were divided into two groups based on vitamin B(6) concentration, the PML increase in tHcy was significantly lower in individuals heterozygous for the insertion compared to those without the insertion only in the group of individuals whose vitamin B(6) concentrations were below the sample median (38.0 nmol/L). We speculate that the 68-bp insertion is associated with somewhat higher levels of CBS enzyme activity, and that the effect of this becomes more pronounced in the presence of relatively low concentrations of pyridoxal-5'-phosphate, a cofactor of the CBS enzyme.

Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases.

Elevated plasma homocysteine is increasingly being recognized as a risk factor for coronary artery disease (CAD). Although there is general agreement on the importance of micronutrients and genetic predisposition to elevated plasma homocysteine, the exact influence of the known prevalent mutations in genes which regulate homocysteine metabolism is not clear. We studied 376 cases of individuals with premature CAD with respect to their fasting and post-methionine load (PML) total homocysteine (tHcy) concentrations. We also determined the presence or absence of the T833C and G919A mutations of the cystathionine-beta-synthase (CBS) gene, the C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, and the A2756G transition of the B12 dependent methionine synthase (MS) gene. Our objectives were therefore both to confirm the relationship of plasma homocysteine with premature CAD and to examine the importance of genetic influence on both fasting and PML homocysteine. Approximately 32% of the CAD patients had fasting hyperhomocysteinemia and 16% had PML hyperhomocysteinemia. Of these, 8.5% had both forms of hyperhomocysteinemia (combined hyperhomocysteinemia). The T133C mutation in the CBS gene and the thermolabile C677T mutation in the MTHFR gene seem to play an important role in the subset of individuals with combined hyperhomocysteinemia. The A2756G transition in the MS gene is not associated with elevated plasma tHcy. Many cases (47%) of hyperhomocysteinemia are not associated with micronutrient deficiencies, impaired renal function, and/or currently known genetic mutations. Further work is needed to study whether unknown mutations, particularly those residing in the intronic sequences of the genes involved in homocysteine metabolism, other environmental factors, or interaction of gene, nutrient, and environmental factors may be the cause of currently unexplained cases of mild hyperhomocysteinemia.

Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria.

We used single-strand conformational polymorphism and nucleotide sequencing to characterize defective cystathionine beta-synthase gene alleles in 18 independent Irish patients with homocystinuria. Six mutations were detected, three of which have been reported previously and three of which were novel. The novel mutations include T302C (L101P), C684G (N228K), and G1063C (A354P). Of the three, only T302C (L101P) was somewhat prevalent, being found in 3 of 37 independent alleles.

A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506).

Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.

High prevalence of a mutation in the cystathionine beta-synthase gene.

We found that a mutation previously described by Sebastio et al., involving a 68-bp insertion in the coding region of exon 8 of the cystathionine-beta-synthase (CBS) gene in a single patient with homocystinuria, is highly prevalent. In our control population, 11.7% (9/77) of the individuals were heterozygous carriers of this mutation. In contrast to the previous report, which assumed that the 68-bp insertion introduced a premature-termination codon and resulted in a nonfunctional CBS enzyme, we found that the presence of this mutation is not associated with hyperhomocysteinemia. Assay of CBS activity in transformed lymphocytes from individuals who were heterozygous or homozygous for this mutation showed normal activity. Furthermore, reverse-transcripion-PCR showed that individuals carrying this mutation have normal size mRNA. Our results suggest that the insertion creates an alternate splicing site, which eliminates not only the inserted intronic sequences but also the T833C mutation associated with this insertion. The net result is the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. Although the mutation does not seem to affect the activity of the CBS enzyme, the prevalence is somewhat increased in patients with premature coronary-artery disease, although the difference is not statistically significant.

Simultaneous detection and screening of T833C and G919A mutations of the cystathionine beta-synthase gene by single-strand conformational polymorphism.

OBJECTIVE: We used single-strand conformational polymorphism (SSCP) to screen for mutations at nucleotides 833 and 919 of the cystathionine beta-synthase (CBS) gene in 13 patients with homocystinuria and 11 of their relatives. METHODS: Exon 8 of genomic DNA was selectively amplified by PCR using primers derived from intronic sequences of the human CBS gene. SSCP analysis was performed on the amplified products. Genotypes identified by SSCP were confirmed by DNA sequencing and an allele-specific PCR method. RESULTS: SSCP identified 5 patterns corresponding to five genotypes. We confirmed that the different genotypes result from mutations at nucleotides 833 and 919 of the CBS gene, and that these 2 mutations account for approximately 50% of affected alleles in homocystinuria patients. CONCLUSION: Our recent elucidation of intron-exon borders and intronic sequences of the CBS gene has made possible the use of SSCP to screen for known/unknown mutations in the CBS gene. Because T833C and G919A represent the two most common mutations and both are located within exon 8 of the CBS gene, SSCP of exon 8 allows screening of the heterozygous carrier state of these mutations in a large population, to determine the importance of heterozygosity of CBS mutations as the cause of mild hyperhomocyst(e)inemia associated with premature vascular diseases.