A longitudinal cohort study of watch and wait in complete clinical responders after chemo-radiotherapy for localised rectal cancer: study protocol.

BACKGROUND: Rectal Cancer is a common malignancy. The current treatment approach for patients with locally advanced rectal cancer involves neoadjuvant chemoradiotherapy followed by surgical resection of the rectum. The resection can lead to complications and long-term consequences. A clinical complete response is observed in some patients after chemoradiotherapy. A number of recent studies have shown that patients can be observed safely after completing chemoradiotherapy (without surgery), provided clinical complete response has been achieved. In this approach, resection is reserved for cases of regrowth. This is called the watch and wait approach. This approach potentially avoids unnecessary surgical resection of the rectum and the resulting complications. In this study, we will prospectively investigate this approach. METHODS: Adult patients with a diagnosis of rectal cancer planned to receive neoadjuvant long course chemoradiotherapy (± subsequent combination chemotherapy) will be consented into the study prior to commencing treatment. After completing the chemoradiotherapy (± subsequent combination chemotherapy), based on the clinical response, subjects will be allocated to one of the following arms: subjects who achieved a clinical complete response will be allocated to the watch and wait arm and others to the standard management arm (which includes resection). The aim of the study is to determine the rate of local failure and other safety and efficacy outcomes in the watch and wait arm. Patient reported outcome measures and the use of biomarkers as part of the clinical monitoring will be studied in both arms of the study. DISCUSSION: This study will prospectively investigate the safety of the watch and wait approach. We will investigate predictive biomarkers (molecular biomarkers and imaging biomarkers) and patient reported outcome measures in the study population and the cost effectiveness of the watch and wait approach. This study will also help evaluate a defined monitoring schedule for patients managed with the watch and wait approach. This protocol covers the first two years of follow up, we are planning a subsequent study which covers year 3-5 follow up for the study population. TRIAL REGISTRATION: Name of the registry: Australia and New Zealand Clinical Trials Registry (ANZCTR). TRIAL REGISTRATION NUMBER: Trial ID: ACTRN12619000207112 Registered 13 February 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376810.

Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study.

PURPOSE: Severe chemotherapy-induced gastrointestinal toxicity (CIGT) is common and results in treatment delays, dose reductions, and potential premature treatment discontinuation. Currently, there is no diagnostic marker to predict CIGT. Proinflammatory cytokines, produced via toll-like receptor signaling, are key mediators of this toxicity. Hence, this pilot study investigated the association between immune genetic variability and severe CIGT risk. METHODS: Genomic DNA from 34 patients (10 with severe CIGT) who had received 5-fluoruracil-based chemotherapy regimens was analyzed for variants of IL-1B, IL-2, IL-6, IL-6R, IL-10, TNF-a, TGF-b, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, and OPRM1. Multivariate logistic regression created a prediction model of severe CIGT risk. RESULTS: There were no significant differences between patients with and without severe CIGT with regards to age, sex, type of cancer, or chemotherapy treatment regimens. The prediction model of severe CIGT risk included TLR2 and TNF-a genetic variability and cancer type (colorectal and gastric). This prediction model was both specific and sensitive, with a receiver operator characteristic area under the curve of 87.3 %. CONCLUSIONS: This is the first report of immune genetic variability, together with cancer type, being predictive of severe CIGT risk. These outcomes are being validated in a larger patient population.

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy.

PURPOSE: Adverse effects following fluoropyrimidine-based chemotherapy regimens are common. However, there are no current accepted diagnostic markers for prediction prior to treatment, and the underlying mechanisms remain unclear. This study aimed to determine genetic and non-genetic predictors of adverse effects. METHODS: Genomic DNA was analyzed for 25 single nucleotide polymorphisms (SNPs). Demographics, comorbidities, cancer and fluoropyrimidine-based chemotherapy regimen types, and adverse effect data were obtained from clinical records for 155 Australian White participants. Associations were determined by bivariate analysis, logistic regression modeling and Bayesian network analysis. RESULTS: Twelve different adverse effects were observed in the participants, the most common severe adverse effect was diarrhea (12.9%). Bivariate analysis revealed associations between all adverse effects except neutropenia, between genetic and non-genetic predictors, and between 8 genetic and 12 non-genetic predictors with more than 1 adverse effect. Logistic regression modeling of adverse effects revealed a greater/sole role for six genetic predictors in overall gastrointestinal toxicity, nausea and/or vomiting, constipation, and neutropenia, and for nine non-genetic predictors in diarrhea, mucositis, neuropathy, generalized pain, hand-foot syndrome, skin toxicity, cardiotoxicity and fatigue. The Bayesian network analysis revealed less directly associated predictors (one genetic and six non-genetic) with adverse effects and confirmed associations between six adverse effects, eight genetic predictors and nine non-genetic predictors. CONCLUSION: This study is the first to link both genetic and non-genetic predictors with adverse effects following fluoropyrimidine-based chemotherapy. Collectively, we report a wealth of information that warrants further investigation to elucidate the clinical significance, especially associations with genetic predictors and adverse effects.

Ultrasound diagnosis of pyogenic flexor tenosynovitis in a 9-month-old infant: a rare case report.

Pyogenic flexor tenosynovitis (PFT) is an aggressive infection of the flexor tendon sheath, requiring prompt intervention to minimize adverse outcomes. The diagnosis of pediatric PFT is often delayed due to the variable presence of Kanavel's signs in children and communication difficulties. A 9-month-old male presented to the emergency department with one of four Kanavel signs. The diagnosis of PFT was delayed until ultrasound was used to identify a fluid collection within the flexor tendon sheath. He was successfully treated with surgical debridement and antibiotic therapy, achieving full recovery by 6-month follow-up. This represents the youngest reported case of PFT. Difficulties with communication and physical exam as well as the variability of Kanavel's signs in young children can delay the diagnosis of pediatric PFT. Ultrasound can be a useful adjunct when clinical history and exam are equivocal, especially in children who present prior to language acquisition.

Symptomatic Lead Toxicity and Joint Pain Because of Migration of Shotgun Pellets into the Hip 12 Years After Injury: A Case Report.

CASE: We describe a case of mild lead poisoning in a 25-year-old woman because of intra-articular migration of lead shot 12 years after gunshot injury to the left hip, ameliorated by arthroscopic foreign body removal. Retained lead can cause systemic symptoms of lead toxicity, supranormal blood lead concentration, and increasingly painful and destructive local arthritis even years after gunshot injury. CONCLUSION: This report shows that lead fragments should be monitored closely if located near joint spaces. We demonstrate curative therapy for lead poisoning through the use of minimally invasive arthroscopic techniques for removal of retained intra-articular lead missiles.

Comminuted Distal Radius Fracture with Concomitant Median Nerve Transection: A Case Report and Literature Review.

CASE: A 41-year-old woman sustained a distal radius fracture with concomitant median nerve transection. The wound was consistent with an inside-to-outside mechanism with noted metaphyseal bone loss at the level of the median nerve injury. The median nerve was not amenable to primary repair, and given concern for inability to define the zone of the injury, the patient underwent delayed reconstruction of the nerve. CONCLUSION: A review of the literature highlights the rare incidence of this combined injury that can be undetected or misdiagnosed as an acute carpal tunnel syndrome or stretch injury to the median nerve.

A physical map of the chicken genome.

Strategies for assembling large, complex genomes have evolved to include a combination of whole-genome shotgun sequencing and hierarchal map-assisted sequencing. Whole-genome maps of all types can aid genome assemblies, generally starting with low-resolution cytogenetic maps and ending with the highest resolution of sequence. Fingerprint clone maps are based upon complete restriction enzyme digests of clones representative of the target genome, and ultimately comprise a near-contiguous path of clones across the genome. Such clone-based maps are used to validate sequence assembly order, supply long-range linking information for assembled sequences, anchor sequences to the genetic map and provide templates for closing gaps. Fingerprint maps are also a critical resource for subsequent functional genomic studies, because they provide a redundant and ordered sampling of the genome with clones. In an accompanying paper we describe the draft genome sequence of the chicken, Gallus gallus, the first species sequenced that is both a model organism and a global food source. Here we present a clone-based physical map of the chicken genome at 20-fold coverage, containing 260 contigs of overlapping clones. This map represents approximately 91% of the chicken genome and enables identification of chicken clones aligned to positions in other sequenced genomes.

The Importance of Medical Readiness Training Exercises: Maintaining Medical Readiness in a Low-Volume Combat Casualty Flow Era.

INTRODUCTION: Ringed external fixation has demonstrated promising results in the management of severe combat-related extremity injuries. The purpose of this study was to identify and compare rates of wartime-related surgical cases at times of high and low casualty time periods, and then compare these case numbers with those performed during a 2-week Medical Readiness Training Exercise (MEDRETE) in Honduras. MATERIALS AND METHODS: A retrospective review was performed of patients treated at a single Military Treatment Facility with definitive ringed external fixators during a 2-year period of high-volume combat casualty flow (January 2009-December 2010) and a subsequent 2-year period of low-volume combat casualty flow (January 2013-December 2014). These data were then compared with cases performed over a 2-week period during a MEDRETE in 2011 to Honduras. RESULTS: Sixty-one cases were identified as having definitive treatment using ringed external fixation at the Military Treatment Facility during the high- and low-volume eras. During the high-volume era, 47 ringed external fixators were used as a definitive treatment. During the low-volume era, only 14 of the definitive ringed external fixation were identified. Of the 32 total cases performed during the 2-week MEDRETE to Honduras, 11 cases of definitive ringed external fixator placement were performed. This accounted for 34.4% of all cases performed during this 2-week period. CONCLUSION: Appropriately planned MEDRETEs can provide a concentrated case volume to allow maintenance of complex surgical skills related to the management of severe combat-related extremity injuries. These training exercises will be vital to maintain surgical skills during a low-volume combat casualty flow era.

Integrated and sequence-ordered BAC- and YAC-based physical maps for the rat genome.

As part of the effort to sequence the genome of Rattus norvegicus, we constructed a physical map comprised of fingerprinted bacterial artificial chromosome (BAC) clones from the CHORI-230 BAC library. These BAC clones provide approximately 13-fold redundant coverage of the genome and have been assembled into 376 fingerprint contigs. A yeast artificial chromosome (YAC) map was also constructed and aligned with the BAC map via fingerprinted BAC and P1 artificial chromosome clones (PACs) sharing interspersed repetitive sequence markers with the YAC-based physical map. We have annotated 95% of the fingerprint map clones in contigs with coordinates on the version 3.1 rat genome sequence assembly, using BAC-end sequences and in silico mapping methods. These coordinates have allowed anchoring 358 of the 376 fingerprint map contigs onto the sequence assembly. Of these, 324 contigs are anchored to rat genome sequences localized to chromosomes, and 34 contigs are anchored to unlocalized portions of the rat sequence assembly. The remaining 18 contigs, containing 54 clones, still require placement. The fingerprint map is a high-resolution integrative data resource that provides genome-ordered associations among BAC, YAC, and PAC clones and the assembled sequence of the rat genome.

A physical map of the mouse genome.

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.