The use of adjuvant chemotherapy is not associated with recurrence or cancer-specific death following curative resection for stage III rectal cancer: a competing risks analysis.

BACKGROUND: The role of adjuvant chemotherapy (AC) in stage III rectal cancer (RC) has been argued based on evidence from its use in colon cancer. Previous trials have analysed disease-free and overall survivals as endpoints, rather than disease recurrence. This study compares the competing risks incidences of recurrence and cancer-specific death between patients who did and did not receive AC for stage III RC. METHODS: Consecutive patients who underwent a potentially curative resection for stage III RC (1995-2019) at Concord Hospital, Sydney, Australia, were studied. AC was considered following multidisciplinary discussion. Primary outcome measures were the competing risks incidences of disease recurrence and cancer-specific death. Associations between these outcomes and use of AC (and other variables) were tested by regression modelling. RESULTS: Some 338 patients (213 male, mean age 64.4 years [SD12.7]) were included. Of these, 208 received AC. The use of AC was associated with resection year (adjusted OR [aOR] 1.74, 95%CI 1.27-2.38); age ≥75 years (aOR0.04, 95%CI 0.02-0.12); peripheral vascular disease (aOR0.08, 95%CI 0.01-0.74); and postoperative abdomino-pelvic abscess (aOR0.23, 95%CI 0.07-0.81). One hundred fifty-seven patients (46.5%) were diagnosed with recurrence; death due to RC occurred in 119 (35.2%). After adjustment for the competing risk of non-cancer death, neither recurrence nor RC-specific death was associated with AC (HR0.97, 95%CI 0.70-1.33 and HR0.72, 95%CI 0.50-1.03, respectively). CONCLUSION: This study found no significant difference in either recurrence or cancer-specific death between patients who did and did not receive AC following curative resection for stage III RC.

Redefining the high-grade B cell lymphoma with double/triple rearrangements of MYC and BCL2/BCL6 genes. Learning from a case report.

We report a patient initially diagnosed with a triple hit high-grade B cell lymphoma (HGBL-TH), in which further morphologic, immunohistochemical, and next-generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC-DLBCL) with BCL2/BCL6 gene translocations, PVT1-deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break-apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH-lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double-hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

Apical Node Involvement Does Not Influence Prognosis After Potentially Curative Resection for Stage III Colorectal Cancer: A Competing Risks Analysis.

OBJECTIVE: To examine the independent prognostic value of ALN status in patients with stage III CRC. SUMMARY OF BACKGROUND DATA: Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. METHODS: Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. RESULTS: In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). CONCLUSIONS: No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Recurrence and colon cancer-specific death in patients with large bowel obstruction requiring urgent operation: a competing risks analysis.

AIM: Clinical presentation with large bowel obstruction has been proposed as a predictor of poor long-term oncological outcomes after resection for colorectal cancer. This study examines the association between obstruction and recurrence and cancer-specific death after resection for colon cancer. METHOD: Consecutive patients who underwent resection for colon cancer between 1995 and 2014 were drawn from a prospectively recorded hospital database with all surviving patients followed for at least 5 years. The outcomes of tumour recurrence and colon cancer-specific death were assessed by competing risks multivariable techniques with adjustment for potential clinical and pathological confounding variables. RESULTS: Recurrence occurred in 271 of 1485 patients who had a potentially curative resection. In bivariate analysis, obstruction was significantly associated with recurrence [hazard ratio (HR) 2.23, CI 1.52-3.26, p < 0.001] but this association became nonsignificant after adjustment for confounders (HR 1.53, CI 0.95-2.46, p = 0.080). Colon cancer-specific death occurred in 238 of 295 patients who had a noncurative resection. Obstruction was not significantly associated with cancer-specific death (HR 1.02, CI 0.72-1.45, p = 0.903). In patients who had a noncurative resection, the competing risks incidence of colon cancer-specific death was not significantly greater in obstructed than in unobstructed patients (HR 1.02, CI 0.72-1.45, p = 0.903). CONCLUSION: Whilst the immediate clinical challenge of an individual patient presenting with large bowel obstruction must be addressed by the surgeon, the patient's long-term oncological outcomes are unrelated to obstruction per se.

A high-stringency blueprint of the human proteome.

The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP's tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.

A novel next generation sequencing approach to improve sarcoma diagnosis.

Sarcoma is a rare disease affecting both bone and connective tissue and with over 100 pathologic entities, differential diagnosis can be difficult. Complementing immune-histological diagnosis with current ancillary diagnostic techniques, including FISH and RT-PCR, can lead to inconclusive results in a significant number of cases. We describe here the design and validation of a novel sequencing tool to improve sarcoma diagnosis. A NGS DNA capture panel containing probes for 87 fusion genes and 7 genes with frequent copy number changes was designed and optimized. A cohort of 113 DNA samples extracted from soft-tissue and bone sarcoma FFPE material with clinical FISH and/or RT-PCR results positive for either a translocation or gene amplification was used for validation of the NGS method. Sarcoma-specific translocations or gene amplifications were confirmed in 110 out of 113 cases using FISH and/or RT-PCR as gold-standard. MDM2/CDK4 amplification and a total of 25 distinct fusion genes were identified in this cohort of patients using the NGS approach. Overall, the sensitivity of the NGS panel is 97% with a specificity of 100 and 0% failure rate. Targeted NGS appears to be a feasible and cost-effective approach to improve sarcoma subtype diagnosis with the ability to screen for a wide range of genetic aberrations in one test.

Fistulae involving the appendix: a systematic review of the literature.

BACKGROUND: The appendix has a unique place in surgical history. Although the first ever appendicectomy involved a fistula to the skin, fistulae involving the appendix remain uncommon and can lead to unique surgical considerations. METHODS: A systematic review of the literature was performed for case reports of appendiceal fistulae. We excluded cases in which the patient had a history of appendicectomy. Cases were categorized by site and aetiology, with information regarding relative frequency and demographics obtained. RESULTS: A total of 301 case reports of fistula involving the appendix were found. The most common sites of these fistulae were to the bladder (148 cases), skin (40 cases), vasculature (19 cases), umbilicus (16 cases) and to the gastrointestinal tract. The most common aetiology in sub-analysis was appendicitis alone (150 cases), with less common causes including appendiceal adenocarcinoma (32 cases) and congenital abnormalities (18 cases). There were significantly more appendiceal fistulae in males than in females, with a ratio of 1.7:1. In patients with appendiceal adenocarcinoma as a cause for fistula, there were significantly more females than males with a ratio of 2.3:1. CONCLUSION: In conducting a systematic review of case reports of fistulae involving the appendix, we identified 301 unique case reports, with a range of different sites and aetiologies.

Systematic evaluation of PAXgene® tissue fixation for the histopathological and molecular study of lung cancer.

Whilst adequate for most existing pathological tests, formalin is generally considered a poor DNA preservative and use of alternative fixatives may prove advantageous for molecular testing of tumour material; an increasingly common approach to identify targetable driver mutations in lung cancer patients. We collected paired PAXgene® tissue-fixed and formalin-fixed samples of block-sized tumour and lung parenchyma, Temno-needle core tumour biopsies and fine needle tumour aspirates (FNAs) from non-small cell lung cancer resection specimens. Traditionally processed formalin fixed paraffin wax embedded (FFPE) samples were compared to paired PAXgene® tissue fixed paraffin-embedded (PFPE) samples. We evaluated suitability for common laboratory tests (H&E staining and immunohistochemistry) and performance for downstream molecular investigations relevant to lung cancer, including RT-PCR and next generation DNA sequencing (NGS). Adequate and comparable H&E staining was seen in all sample types and nuclear staining was preferable in PAXgene® fixed Temno tumour biopsies and tumour FNA samples. Immunohistochemical staining was broadly comparable. PFPE samples enabled greater yields of less-fragmented DNA than FFPE comparators. PFPE samples were also superior for PCR and NGS performance, both in terms of quality control metrics and for variant calling. Critically we identified a greater number of genetic variants in the epidermal growth factor receptor gene when using PFPE samples and the Ingenuity® Variant Analysis pipeline. In summary, PFPE samples are adequate for histopathological diagnosis and suitable for the majority of existing laboratory tests. PAXgene® fixation is superior for DNA and RNA integrity, particularly in low-yield samples and facilitates improved NGS performance, including the detection of actionable lung cancer mutations for precision medicine in lung cancer samples.

Fine tuning of the default depth and rate of ablation of the epithelium in customized trans-epithelial one-step superficial refractive excimer laser ablation.

PURPOSE: To fine tune the default depth and rate of ablation of the epithelium in cTen™ customized trans-epithelial one-step superficial refractive surgery by the comparison between the attempted post-operative ideal corneal shape and the achieved corneal shape. METHODS: 88 consecutive eyes in 64 patients undergoing trans-epithelial superficial excimer ablation using the iVis laser Suite for either myopic/astigmatic or hyperopic/astigmatic refractive error. Each patient had at least 3 months of post-operative follow-up. Topographic examination of all eyes was carried out pre-operatively and at least 3 months post-operatively using the Precisio™ surgical topographer. The comparison of these two measurements yielded values for depth, volumes and rates of ablated corneal tissue. By determining the different ablation rates of stroma and epithelium, a refinement of the depth of epithelium to be removed and a refinement of the stromal ablation were calculated.The mathematical model was applied on each one of the 88 clinical cases and the parameters for the fine tuning of the default depth and rate of ablation of the epithelium were determined using the least squares method. RESULTS: The calculated pure stromal ablation rate was less than the average epithelium/stroma ablation rate used in planning the treatments by a factor of 0.96. The epithelial thickness predefined ablation assumption used to plan removal of the epithelium was adjusted considering the measured ablation and a radial adjustment function established for the fine tuning of the laser radial efficiency and allowing for the normal thickening of the epithelium in the peripheral cornea. From a clinical point of view, this methodology produces an improvement of the efficacy and a reduction of the variance of the clinical results. CONCLUSION: Comparison of accurately measured pre and postoperative topographies yields accurately established ablation rates of stroma and epithelium in trans-epithelial one step superficial ablation.

Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS.

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

When does curatively treated colorectal cancer recur? An Australian perspective.

BACKGROUND: While most colorectal cancer (CRC) recurrences reportedly occur within 3 years following curative treatment, many studies are limited by short-term follow-up. This study examines the time to recurrence of CRC in a large Australian cohort with a long follow-up period and assesses whether time to recurrence has changed over time. METHODS: A comprehensive prospective database of patients undergoing resection for CRC is maintained at Concord Hospital, Sydney. Demographic and time to recurrence data were extracted for patients who developed a recurrence following potentially curative resection for colon cancer from 1995 to 2010 and rectal cancer from 1971 to 2010. Non-deceased patients had a minimum of 5 years follow-up. RESULTS: Between 1995 and 2010, 2575 patients with CRC underwent surgery. After exclusions, 386 had recurrence following potentially curative resection, ranging from 1 to 172.5 months (median 20.3) after treatment. Within 1 year, 27.5% recurred, 57.5% by 2 years, 74.6% by 3 years, 85.5% by 4 years and 89.6% by 5 years. There was no difference in time to recurrence between colon and rectal cancers (P = 0.674). Among patients having a potentially curative resection for rectal cancer between 1971 and 2010, 386 recurred. There was no difference in time to recurrence by decade (P = 0.863). CONCLUSION: The majority of recurrences occurred within 3 years of curative treatment. Had surveillance been limited to 5 years, detection of more than 10% of recurrences would have been delayed. Time to recurrence for rectal cancer has not changed in over 40 years, despite treatment advances.

Peristomal pyoderma gangrenosum: 12-year experience in a single tertiary referral centre.

BACKGROUND: Peristomal pyoderma gangrenosum (PPG) is an unusual but potentially devastating condition that is difficult to diagnose and manage. METHODS: This was a single centre, retrospective review of a prospectively collected database. Included were consecutive patients referred to a stoma therapy clinic at a single institution between 2005 and 2016. Main outcomes of interest were management strategies and outcome of patients with PPG including time to healing and recurrence. RESULTS: Of 1295 consecutive patients who underwent stoma formation, 12 patients with PPG were identified. The mean age at the time of diagnosis of PPG was 43.5 years (range 19-72 years). Five cases (41.7%) were associated with Crohn's disease and five cases (41.7%) with ulcerative colitis. The median duration of days between stoma formation and PPG diagnosis was 101.5 days (mean duration was 670 days (range 14-2641 days)). Nearly all patients (91.7%) were referred to a dermatologist. Majority (66.7%) were managed in an outpatient setting. For those requiring inpatient management, the mean length of stay was 13.5 days (range 3-31 days). Five patients had a biopsy and seven patients were diagnosed with PPG by dermatologist without biopsy. A range of oral and topical steroids, steroid injections, dressings, anti-inflammatories, antibiotics, tacrolimus and analgesia was used in the management of PPG. All patients achieved complete healing of PPG, with only one patient developing a recurrence of PPG. The mean duration of time to achieve complete healing of PPG was 282 days (range 28-1751 days). DISCUSSION: Medical management of PPG was effective with complete healing and low recurrence. The average duration to complete healing of PPG was approximately 9 months.

Major Abdominal and Perianal Surgery in Crohn's Disease: Long-term Follow-up of Australian Patients With Crohn's Disease.

BACKGROUND: Most patients with Crohn's disease still require surgery despite significant advances in medical therapy, surveillance, and management strategies. OBJECTIVE: The purpose of this study was to assess surgical strategies and outcomes in Crohn's disease, including surgical recurrence and emergency surgery. DESIGN: This was a multicenter, retrospective review of a prospectively collected database. SETTINGS: A specialist-referred cohort of patients with Crohn's disease between 1970 and 2009 was studied. PATIENTS: Included were 972 patients with Crohn's disease who were referred to the Sydney Inflammatory Bowel Disease cohort database. MAIN OUTCOME MEASURES: Main outcomes of interest were the rates of major abdominal and perianal surgery between decades (1970-1979, 1980-1989, 1990-1999, and 2000-2009), indications for surgery, types of procedure performed, rate of elective and emergency surgery, risk of surgical recurrence, and predictive factors for surgery. RESULTS: Between 1970 and 2009, the overall risks of surgery within 5, 10, and 15 years of diagnosis were 31.7%, 43.3%, and 48.4%. The median time to first surgery from time of diagnosis was 2 years (range, 0-31 years). A total of 6.7% of patients required emergency surgery within 5 years of diagnosis. In total, 8.8% of patients required emergency surgery within 15 years. The overall risk of surgical recurrence was 35.9%. The risk of major abdominal surgery significantly decreased between 2000 and 2009 when compared with the 1970 to 1979 period (OR = 0.49 (95% CI, 0.34-0.70). However, the rate of perianal surgery significantly increased (OR = 5.76 (95% CI, 2.54-13.06)). The main indications for surgery were enteric stricture or obstruction, perianal disease, and intra-abdominal fistulas/abscess. Of the 972 patients over 4 decades, only 11 patients (1.1%) were diagnosed with colorectal cancer. LIMITATIONS: This was a specialist-referred cohort, not a population-based study. CONCLUSIONS: The rate of major abdominal surgery has decreased, with surgery reserved for more severe and complicated disease. The natural history of patients with more complicated Crohn's disease and severe phenotypes puts them at higher risk of surgical recurrence and emergency surgery. There has been no reduction in emergency surgery rates and there has been an increase in surgical recurrence despite the reduction in surgical rate morbidity. See Video Abstract at http://links.lww.com/DCR/A483.

Laparoscopic peritoneal lavage or surgical resection for acute perforated sigmoid diverticulitis: A systematic review and meta-analysis.

BACKGROUND: Laparoscopic peritoneal lavage (LPL) has been proposed as an alternative, less invasive technique in the treatment of acute perforated sigmoid diverticulitis (APSD). The aim of this meta-analysis is to compare the effectiveness of LPL versus surgical resection (SR) in terms of morbidity and mortality in the management of APSD. METHODS: A comprehensive search was conducted for randomised controlled trials (RCTs) comparing LPL versus SR in the treatment of APSD. The end points included peri-operative mortality, severe adverse events, overall mortality, post-operative abscess, percutaneous reinterventions, reoperation, operative time, postoperative stay, and readmissions. RESULTS: Three RCTs with a total of 372 patients, randomised to either LPL or SR were included. There was no significant difference in peri-operative mortality between LPL and SR (OR 1.356, 95% CI 0.365 to 5.032, p = 0.649), or serious adverse events (OR = 1.866, 95% CI = 0.680 to 5.120, p = 0.226). The LPL required significantly less time to complete than SR (WMD = -72.105, 95% CI = -88.335 to -55.876, p < 0.0001). The LPL group was associated with a significantly higher rate of postoperative abscess formation (OR = 4.121, 95% CI = 1.890 to 8.986, p = 0.0004) and subsequent percutaneous interventions (OR = 5.414, 95% CI 1.618 to 18.118, p = 0.006). CONCLUSION: Laparoscopic peritoneal lavage is a safe and quick alternative in the management of APSD. In comparison to SR, LPL results in higher rates of postoperative abscess formation requiring more percutaneous drainage interventions without any difference in perioperative mortality and serious morbidity.