Implementation of a clinical pathway for the surgical treatment of colorectal cancer during the COVID-19 pandemic.

AIM: This report summarizes the early experience of implementing elective colorectal cancer surgery during the COVID-19 pandemic. METHODS: A pathway to minimize the risk of including COVID-19-positive patients for elective surgery was established. Prioritization and additional safety measures were introduced into clinical practice. Minimal invasive surgery was used where appropriate. RESULTS: Thirty-eight patients were prioritized, and 23 patients underwent surgery (eight colon, 14 rectal and one anal cancer). The minimal invasive surgery rate was 78%. There were no major postoperative complications or patients diagnosed with COVID-19. Histopathological outcomes were similar to normal practice. CONCLUSION: A safe pathway to offer standard high-quality surgery to colorectal cancer patients during the COVID-19 pandemic is feasible.

Selection, drift, and introgression shape MHC polymorphism in lizards.

The major histocompatibility complex (MHC) has long served as a model for the evolution of adaptive genetic diversity in wild populations. Pathogen-mediated selection is thought to be a main driver of MHC diversity, but it remains elusive to what degree selection shapes MHC diversity in complex biogeographical scenarios where other evolutionary processes (e.g. genetic drift and introgression) may also be acting. Here we focus on two closely related green lizard species, Lacerta trilineata and L. viridis, to address the evolutionary forces acting on MHC diversity in populations with different biogeographic structure. We characterized MHC class I exon 2 and exon 3, and neutral diversity (microsatellites), to study the relative importance of selection, drift, and introgression in shaping MHC diversity. As expected, positive selection was a significant force shaping the high diversity of MHC genes in both species. Moreover, introgression significantly increased MHC diversity in mainland populations, with a primary direction of gene flow from L. viridis to L. trilineata. Finally, we found significantly fewer MHC alleles in island populations, but maintained MHC sequence and functional diversity, suggesting that positive selection counteracted the effect of drift. Overall, our data support that different evolutionary processes govern MHC diversity in different biogeographical scenarios: positive selection occurs broadly while introgression acts in sympatry and drift when the population sizes decrease.

A critical survey of a dedicated craniofacial surgery outpatient's clinic within a public health service structure.

The management of craniofacial conditions, especially in the setting of a large general hospital, is ideally achieved by a focused team in a multidisciplinary clinic. The purpose of this article was to present the design, modus operandi and outcomes of a newly formed dedicated craniofacial multidisciplinary outpatients' clinic at the first year of operation endpoint within a public healthcare structure.

Transperineal retropubic approach in total pelvic exenteration for advanced and recurrent colorectal and anal cancer involving the penile base: technique and outcomes.

BACKGROUND: Complete pathological resection of locally advanced and recurrent anorectal cancer is considered the most important determinant of survival outcome. Involvement of the retropubic space with cancer threatening or involving the penile base poses specific challenges due to the potential for margin involvement and blood loss from the dorsal venous plexus. In the present study we evaluate a new transperineal surgical approach to excision of anterior compartment organs involved or threatened by cancer which facilitates exposure and visualisation of the bulbar urethra and the deep vein of the penis caudal to the retropubic space and penile base. METHODS: A retrospective study was performed on male patients with tumour extension into the penile base treated at our institution using the transperineal surgical approach. Descriptive data for patient demographics, radiology, operative details, postoperative histology, complications and outcomes were collated. RESULTS: Ten male patients with tumour extension into the penile base were identified. Two patients had recurrent anal cancer, 6 had locally advanced primary rectal cancer and 2 had recurrent rectal cancer. All patients had exenterative surgery with excision of the penile base utilising the transperineal approach. All patients had R0 resection. No local recurrence developed after a median follow up period of 15 months. CONCLUSIONS: The transperineal approach to the penile base and retropubic space allows for high rates of R0 resection margin status with direct visualisation of the dorsal venous plexus, thereby minimising blood loss. In our experience, this technique is the preferred approach to excision of cancers threatening and involving the penile base and also for most male patients requiring total pelvic exenteration.

Comparative effects of denosumab or bisphosphonate treatment on bone mineral density and calcium metabolism in postmenopausal women.

OBJECTIVES: To clarify potential differences between denosumab (DNS) and bisphosphonates (BIS) in terms of bone density and bone metabolism, in a sample of postmenopausal women. METHODS: A total of 113 postmenopausal women aged 53-66 years were treated with either DNS or BIS for 12 months. Bone densitometry and laboratory tests were compared between baseline and follow-up. RESULTS: Femoral neck BMD increased in both treatment-arms (FN-BMD, DNS: 0.69±0.07 g/cm2 to 0.75±0.09 g/cm2; BIS: 0.69±0.06 g/cm2 to 0.71±0.07 g/cm2; p≤0.001 in both cases). Lumbar spine BMD (LS-BMD) increased significantly only in the DNS-group (0.83±0.14 g/cm2 to 0.89±0.14 g/cm2, p=0.0001). Only women under treatment with DNS had a significant increase in serum parathyroid hormone (PTH: 44.87±17.54 pg/mL to 53.27±15.77 pg/mL, p=0.04), independently of baseline vitamin D levels. DNS-administration resulted in higher increase from baseline in FN-BMD compared to BIS (DNS vs BIS: 8.7%±8.5 vs 3.8%±7.3, p=0.004). Finally, baseline 25OH vitamin D levels did not determine the extent of PTH-increase following administration of DNS- or BIS-treatment. CONCLUSIONS: Both treatments increased BMD, however, the effect of DNS on FN-BMD was superior compared to that of BIS. DNS-treatment increased serum PTH. Baseline 25OH vitamin D levels did not predict the extent of PTH increase at follow-up.

Acute Haemodynamic and Echocardiographic Effects of Multiple Configurations of Left Ventricular Pacing Sites in Acute Myocardial Infarction: Experimental Study.

BACKGROUND: Left ventricular (LV) pacing is unsuccessful in a significant number of patients, mainly due to sub-optimal LV pacing location. Nevertheless, data about the impact of different pacing sites on LV function in ischaemic myocardium are scarce. The purpose of this study was to investigate the effect of combinations of alternative LV pacing sites on LV mechanics after experimental acute anterior myocardial infarction (AMI), in order to define the optimal configuration. METHODS: Atrioventricular epicardial pacing at alternative pacing sites was performed in 16 healthy pigs simultaneously, after experimental AMI. Standard right ventricular (RV) apical pacing was combined with: i) LV apex lateral wall; ii) LV basal posterior wall; iii) LV basal anterior wall, and; iv) LV basal anterior wall + LV basal posterior wall. Moreover the pacing configurations of, v) LV basal posterior wall + LV apex lateral wall; vi) LV basal posterior wall + LV basal anterior wall, and; vii) LV basal anterior wall + LV apex lateral wall were also investigated. Haemodynamic parameters, together with classic and novel echocardiographic indices were used, to evaluate the effect of each pacing combination. A speckle tracking technique using EchoPAC software was used. RESULTS: After AMI, the pacing combination of LV apex lateral wall and LV basal posterior wall had the most favourable effect on LV function, leading to similar haemodynamic and torsional effects with sinus rhythm (all variables p>0.05). CONCLUSIONS: In pig hearts after AMI, the combination of pacing LV apex lateral wall and LV basal posterior wall managed to maintain the LV function at a level comparable to the sinus rhythm.

High subcortical sacrectomy: a novel approach to facilitate complete resection of locally advanced and recurrent rectal cancer with high (S1-S2) sacral extension.

AIM: R0 resection of locally advanced or recurrent rectal cancer is the key determinant of outcome. Disease extension high on the sacrum has been considered a contraindication to surgery because of associated morbidity and difficulty in achieving complete pathological resection. Total sacrectomy has a high morbidity with poor function. METHOD: We describe a novel technique of high subcortical sacrectomy (HiSS) to facilitate complete resection of disease extending to the upper sacrum at S1 and S2 to avoid high or total sacrectomy or a nonoperative approach to management. Details of patient demographics, radiology, operative details, postoperative histology, length of hospital stay and complications were entered into a prospectively maintained electronic patient database. All patients had had preoperative chemoradiotherapy. RESULTS: During 2013-2014, five patients, including three with advanced primary cancer and two with recurrent rectal cancer, underwent excision using this approach. All patients had an R0 resection. Four patients had a minor postoperative complication (Clavien-Dindo Grades I and II) and one had a major complication (Clavien-Dindo Grade IIIb). There was no mortality at 90 days, and four patients were disease free at a median of 18 months. CONCLUSION: Patients with locally advanced and recurrent rectal cancer involving the upper sacrum may be rendered suitable for potentially curative radical resection with a modified approach to sacral resection. This pilot series suggests that this novel technique results in a high rate of complete pathological resection with acceptable morbidity in patients for whom the alternatives would have been an incomplete resection, a total sacrectomy or nonoperative management.

Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.

BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Systems biology of cancer: entropy, disorder, and selection-driven evolution to independence, invasion and "swarm intelligence".

Our knowledge of the biology of solid cancer has greatly progressed during the last few years, and many excellent reviews dealing with the various aspects of this biology have appeared. In the present review, we attempt to bring together these subjects in a general systems biology narrative. It starts from the roles of what we term entropy of signaling and noise in the initial oncogenic events, to the first major transition of tumorigenesis: the independence of the tumor cell and the switch in its physiology, i.e., from subservience to the organism to its own independent Darwinian evolution. The development after independence involves a constant dynamic reprogramming of the cells and the emergence of a sort of collective intelligence leading to invasion and metastasis and seldom to the ultimate acquisition of immortality through inter-individual infection. At each step, the probability of success is minimal to infinitesimal, but the number of cells possibly involved and the time scale account for the relatively high occurrence of tumorigenesis and metastasis in multicellular organisms.

BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface.

BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. METHODS: We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting. RESULTS: We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. CONCLUSION: All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

BACKGROUND: Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS: Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS: We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS: These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.

Extended lateral pelvic sidewall excision (ELSiE): an approach to optimize complete resection rates in locally advanced or recurrent anorectal cancer involving the pelvic sidewall.

BACKGROUND: Complete pathological resection of locally advanced or recurrent rectal and anal cancer is regarded as one of the most important determinants of oncological outcome. Disease in the lateral pelvic sidewall has been considered a contraindication for pelvic exenteration surgery owing to the significant likelihood of incomplete resection. METHODS: We describe a novel technique (ELSiE) to resect disease involving the lateral pelvic sidewall. Patient demographics, post-operative histology, length of hospital stay and complications were collected from prospectively maintained electronic patient database. RESULTS: During 2011-2013, six patients underwent pelvic exenteration surgery with the ELSiE approach. All patients had R0 resection. Three patients required sciatic nerve excision. Four patients developed post-operative complications although no major complications occurred. CONCLUSIONS: Patients with locally advanced and recurrent cancer involving the lateral pelvic sidewall may be rendered suitable for potentially curative radical resection with a modification in the approach to the lateral pelvic sidewall. Our pilot series seems to indicate that our novel technique (ELSiE) is feasible, safe and yields high rates of complete pathological resection.

Homeopathy for infertility treatment: a case series.

Homeopathy has been used in the past for treating a broad aspect of diseases. In gynecology, its use remains limited. Taking under consideration its clinical aspects, the authors attempted to use it for treating female sub fertility problems. With this study, the authors present five cases of female infertility treated successfully with the use of homeopathic treatment in a large obstetrics-gynecology Hospital in Athens.

Estimating single nucleotide polymorphism associations using pedigree data: applications to breast cancer.

BACKGROUND: Pedigrees with multiple genotyped family members have been underutilised in breast cancer (BC) genetic-association studies. We developed a pedigree-based analytical framework to characterise single-nucleotide polymorphism (SNP) associations with BC risk using data from 736 BC families ascertained through multiple affected individuals. On average, eight family members had been genotyped for 24 SNPs previously associated with BC. METHODS: Breast cancer incidence was modelled on the basis of SNP effects and residual polygenic effects. Relative risk (RR) estimates were obtained by maximising the retrospective likelihood (RL) of observing the family genotypes conditional on all disease phenotypes. Models were extended to assess parent-of-origin effects (POEs). RESULTS: Thirteen SNPs were significantly associated with BC under the pedigree RL approach. This approach yielded estimates consistent with those from large population-based studies. Logistic regression models ignoring pedigree structure generally gave larger RRs and association P-values. SNP rs3817198 in LSP1, previously shown to exhibit POE, yielded maternal and paternal RR estimates that were similar to those previously reported (paternal RR=1.12 (95% confidence interval (CI): 0.99-1.27), P=0.081, one-sided P=0.04; maternal RR=0.94 (95% CI: 0.84-1.06), P=0.33). No other SNP exhibited POE. CONCLUSION: Our pedigree-based methods provide a valuable and efficient tool for characterising genetic associations with BC risk or other diseases and can complement population-based studies.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.

BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression.

BACKGROUND: Despite the advent of highly active antiretroviral therapy, anal cancer remains a significant health problem in human immunodeficiency virus (HIV) patients. We present the clinical features and treatment outcomes of anal cancer in 60 HIV-positive patients over a 20-year period. PATIENTS AND METHODS: A prospective database of all HIV-positive individuals managed in a specialist unit since 1986 includes 11 112 patients (71 687 person-years of follow-up). Sixty patients with anal cancer were identified. Their clinicopathological and treatment details were analysed. RESULTS: At anal cancer diagnosis, the mean age was 44 years (range: 28-75 years) and the median CD4 cell count was 305 mm(-3) (range: 16-1252 mm(-3)). Fifty (83%) had chemoradiotherapy (CRT). Forty-six (92%) responded, of whom 10 (22%) subsequently relapsed with locoregional (70%), metastatic disease (10%) or both (20%). The overall 5-year survival is 65% (95% confidence interval 51% to 78%). The median CD4 count fell from 289 mm(-3) before CRT to 132 mm(-3) after 3 months and to 189 mm(-3) after 1 year (P<0.05). Six patients in remission of anal cancer died of acquired immunodeficiency syndrome defining illnesses. CONCLUSIONS: The management of anal cancer with CRT achieves similar outcomes as the general population. CRT is associated with significant prolonged CD4 suppression that may contribute to late deaths of patients in remission.

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers.

Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.

Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers.

Germline mutations in BRCA1 and BRCA2 confer high risks of female breast and ovarian cancer. However, there is strong evidence that these risks are modified by other factors, including familial or genetic factors. Genome-wide association studies have identified several breast cancer genetic susceptibility variants in the general population that are also associated with breast cancer risk for mutation carriers. The patterns of association for these variants vary between BRCA1 and BRCA2 mutation carriers and this variation appears to be driven by their differential associations with breast cancer subtypes defined by estrogen receptor status. We review the latest evidence regarding genetic modifiers of cancer risk for female BRCA1 and BRCA2 mutation carriers emerging from candidate gene studies, variants found in genome-wide association studies (GWAS) to be associated with cancer risk in the general population and GWAS specifically in mutation carriers. We also discuss the implications of these findings for cancer risk prediction in these women. BRCA1 and BRCA2 mutation carriers could potentially be among the first groups of individuals for whom clinically applicable risk profiling could be developed using the common breast cancer susceptibility variants identified through GWAS.