Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports.

Diagnosis, testing, treatment, and outcomes among patients with advanced non-small cell lung cancer in the United States.

INTRODUCTION: Characteristics of patients in clinical trials may differ from those of real-world patients. Our objective was to describe biomarker testing and outcomes among patients with advanced non-small cell lung cancer (aNSCLC) in a real-world setting. METHODS: This retrospective cohort study included patients ≥18 years old, diagnosed with stage IIIB/C or IV NSCLC, and in the TEMPUS oncology dataset from January 1, 2012, to December 31, 2020. Patient characteristics associated with biomarker testing were evaluated in patients with positive biomarkers using univariate logistic regression models. Cox proportional hazard models were used to estimate median survival. RESULTS: Of 9540 patients included, 41.7% had biomarker testing, and 2158 had a positive biomarker result. Men (vs women; odds ratio [OR], 0.82; 95% CI: 0.74-0.91), Black patients (vs White; OR, 0.83; 95% CI: 0.72-0.97), patients with squamous (OR, 0.22; 95% CI: 0.19-0.25) or unknown histology (OR, 0.53; 95% CI: 0.45-0.61) (vs non-squamous histology), and patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2+ (OR, 0.69; 95% CI: 0.57-0.84) or missing (OR, 0.56; 95% CI: 0.48-0.66) (vs ECOG PS of 0) were less likely to undergo biomarker testing. Patients with positive biomarkers who received NCCN-recommended treatment options (55.7%) had significantly longer median overall survival (OS) (hazard ratio [HR], 0.84; 95% CI: 0.75-0.95) and real-world progression-free survival (rwPFS) (HR, 0.68; 95% CI: 0.62-0.75). CONCLUSION: More than 50% of patients were untested for biomarkers. Patients who were less likely to be tested included men, Black patients, current smokers, patients with squamous aNSCLC, and patients with an ECOG PS of 2+. Patients with positive biomarkers who received NCCN-recommended treatment options had significantly longer OS and PFS.

Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments.

Introduction: Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC). We reviewed the epidemiology and disease characteristics associated with primary and secondary METamp, as well as the testing procedures used to identify METamp, in advanced NSCLC. Economic and humanistic burdens, and the practice patterns and treatments under investigation for METamp were also examined. Methods: Embase and Medline (via ProQuest), ClinicalTrials.gov, and Cochrane Controlled Register of Trials (2015-2022) were systematically searched. Conference abstracts were searched via Embase and conference proceedings websites (2020-2022). The review focused on evidence from the United States; global evidence was included for identified evidence gaps. Results: The median rate of primary METamp in NSCLC across the references was 4.8% (n=4 studies) and of secondary METamp (epidermal growth factor receptor [EGFR]-mutant NSCLC) was 15% (n=10). Next-generation sequencing (NGS; n=12) and/or fluorescence in situ hybridization (FISH; n=11) were most frequently used in real-world studies and FISH testing most frequently used in clinical trials (n=9/10). METamp definitions varied among clinical trials using ISH/FISH testing (MET to chromosome 7 centromere ratio of ≥1.8 to ≥3.0; or gene copy number [GCN] ≥5 to ≥10) and among trials using NGS (tissue testing: GCN ≥6; liquid biopsy: MET copy number ≥2.1 to >5). Limited to no data were identified on the economic and humanistic burdens, and real-world treatment of METamp NSCLC. Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines. Conclusion: Primary METamp occurs in approximately 5% of NSCLC cases, and secondary METamp in approximately 15% of cases previously treated with an EGFR inhibitor. Variability in testing methods (including ISH/FISH and NGS) and definitions were observed. Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

Initiation and feasibility of a multi-specialty minimally invasive surgical programme using a novel robotic system: A case series.

INTRODUCTION: There are a number of small case series examining new robotic surgical systems, but this is the first large case series assessing the feasibility of the Versius® system from CMR Surgical (1 Evolution Business Park, Cambridge, UK) in a multi-specialty setting. MATERIALS AND METHODS: All patients undergoing Versius®-assisted surgery in a previously robot-naïve centre were consented for collection of data on demographics, pre-, intra-, and postoperative outcomes. Data collection was performed prospectively from the start of the robotic surgical programme. RESULTS: 160 operations were performed over a 19-month period, including 68 colorectal, 60 gynaecology, and 32 general surgery cases. The conversion rate to open surgery was 4.4% for colorectal, and 0% for gynaecology and general surgery. Median length of stay was 6 days for colorectal, 1 day for gynaecology, and 0 days for general surgery. Other outcomes were comparable to existing literature for robotic assisted surgery. CONCLUSION: The Versius® system is safe and feasible for use in a multi-specialty minimally invasive surgery programme, including colorectal, general surgical & gynaecological cases, and operative volume can be safely and easily scaled up in a district general hospital setting without prior robotic surgical experience.

A colorectal straight-to-test cancer pathway with general-practitioner-guided triage improves attainment of the 28-day diagnosis target and increases outpatient clinic capacity.

AIM: This study investigates whether a straight-to-test (STT) colorectal cancer pathway improves attainment of the National Health Service (NHS) England 28-day Faster Diagnosis Standard and the effect of the pathway on reducing face-to-face outpatient clinic appointments. Patient satisfaction and the safety of a novel general practitioner (GP) led patient triage system regarding suitability for colonoscopy are also evaluated. METHODS: This is an observational study of all patients managed via an STT colorectal cancer pathway between 1 September 2019 and 19 March 2020. Comparison is made with all patients referred on the suspected colorectal cancer pathway prior to implementation of the STT pathway from 1 January 2019 to 30 July 2019. Patient satisfaction with the STT pathway was assessed with a telephone-based questionnaire. RESULTS: Attainment of the 28-day diagnosis target for all suspected colorectal cancer referrals improved following the establishment of the STT pathway (88% vs. 82%, P < 0.0001). From a potential total of 548 outpatient colorectal clinic appointments for patients on the STT pathway, 504 (92%) were avoided. In those eligible for the STT pathway, GP assessment of patients suitable for colonoscopy agreed with that of the colorectal department in 93% of cases. Of the 50 patients who undertook the satisfaction survey, 86% were satisfied or very satisfied with the pathway. No patient suffered adverse events as a result of their STT investigations. CONCLUSION: An STT pathway for suspected colorectal cancer referrals with novel GP-led patient triage safely streamlines patients through the suspected colorectal cancer diagnostic pathway and significantly reduces requirement for face-to-face outpatient clinic attendance. This is achieved with high patient satisfaction.

State-Level Immunization Information Systems: Potential for Childhood Immunization Data Linkages.

Objectives Sources of immunization data include state registries or immunization information systems (IIS), medical records, and surveys. Little is known about the quality of these data sources or the feasibility of using IIS data for research. We assessed the feasibility of collecting immunization information for a national children's health study by accessing existing IIS data and comparing the completeness of these data against medical record abstractions (MRA) and parent report. Staff time needed to obtain IIS and MRA data was assessed. Methods We administered a questionnaire to state-level IIS representatives to ascertain availability and completeness of their data for research and gather information about data formats. We evaluated quality of data from IIS, medical records, and reports from parents of 119 National Children's Study participants at three locations. Results IIS data were comparable to MRA data and both were more complete than parental report. Agreement between IIS and MRA data was greater than between parental report and MRA, suggesting IIS and MRA are better sources than parental report. Obtaining IIS data took less staff time than chart review, making IIS data linkage for research a preferred choice. Conclusions IIS survey results indicate data can be obtained by researchers using data linkages. IIS are an accessible and feasible child immunization information source and these registries reduce reliance on parental report or medical record abstraction. Researchers seeking to link IIS data with large multi-site studies should consider acquiring IIS data, but may need strategies to overcome barriers to data completeness and linkage.

Immunoglobulin heavy light chain test quantifies clonal disease in patients with AL amyloidosis and normal serum free light chain ratio.

BACKGROUND: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are used for clonal detection in plasma cell dyscrasias, while serum free light chain (sFLC) testing provides quantitation of clonal disease. Up to 20% of patients with light chain (AL) amyloidosis may present with normal FLC ratio (FLCr). METHODS: We assessed the diagnostic, quantitative and prognostic potential of serum heavy light chain ratio (HLCr) in 199 untreated patients at initial evaluation. RESULTS: An abnormal HLCr was found in 37.2%, abnormal FLCr in 81.9% and positivity by SIFE/UIFE in 94% of patients. HLCr together with SIFE/UIFE identified clonality in 94% patients; the combination with FLCr yielded 100% sensitivity. An HLCr abnormality was significantly over-represented in normal compared to abnormal FLCr group (63.9% versus 31.3%). HLCr did not predict overall survival (OS) (log rank, p = 0.09), while an abnormal FLCr was associated with decreased OS (log rank, p = 0.03). The combined use of both ratios trended toward increased OS in the abnormal HLCr/normal FLCr group (log rank, p = 0.11; Wilcoxon, p = 0.04). On multivariate analysis, HLCr was not predictive of OS, whereas an abnormal FLCr was associated with shorter OS (HR = 1.7, p = 0.04). CONCLUSIONS: The HLC assay has potential as a supplemental test to quantify monoclonal protein in patients with normal FLCr results.

Ingested cylindrical batteries in an incarcerated male: a caustic tale!

A 37-year-old incarcerated man presented to the accident and emergency department following the deliberate ingestion of eight cylindrical batteries. He also admitted to inserting a razor blade wrapped in cling-film into his rectum; in addition, he sustained a self-inflicted laceration to his left antecubital fossa, using the metal casing from a battery. His medical history included a borderline and emotionally unstable personality disorder. He had ingested several batteries 12 months previously and required an emergency laparotomy to retrieve them. On the present admission, as there was no clinical evidence of small bowel obstruction, he was treated conservatively with serial radiographs. Following conservative management, the batteries failed to progress through the gastrointestinal tract, hence a laparotomy was performed and all the batteries were extricated. This paper discusses the management and associated sequelae of patients presenting following the intentional ingestion of a battery.

Adult intussusception presenting as rectal prolapse.

We present a case of an elderly man with what appeared to be an episode of rectal prolapse following straining while defaecating. Laparotomy revealed the prolapse to be an intussusception of large bowel with a villous adenoma as its lead point. Reduction resection was performed with primary anastomosis, and the patient recovered well from the surgery. Rectal prolapse has often been viewed as a benign condition in the elderly, but more thought needs to be put into the diagnosis in patients with risks of malignancy. Prolapse of an intussuscepted bowel segment in adults is an exceedingly rare presentation, often signifying a risk of malignancy. Appropriate investigations and surgical techniques need to be employed in effectively resolving symptoms while minimising the chances of tumour seeding.

Cell-surface and cytokine biomarkers in autoimmune and inflammatory diseases.

Increasing emphasis is being placed on biomarkers as indicators of disease states in patients with autoimmune and inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. Careful description of the expression of cell-surface markers and cytokines produced by T and B lymphocytes can lead to a more complete characterization of disease activity in patient populations, and serve as an indicator of the patient's response to therapy.

Reducing bioaerosol dispersion from wastewater treatment and its land application: a review and analysis.

Wastewater treatment systems and spray irrigation of treated water may spread microorganisms such as bacteria and viruses through dispersion of aerosol particles. A recent review (Brooks, Josephson, Gerba, & Pepper, 2004) identifies appropriate reports. Teltsch and co-authors report findings that suggest effective management controls involve providing buffer zones, irrigating in the daytime and in times of low humidity, reducing microorganism levels in water used for spraying, and testing for multiple types of viruses and bacteria (Teltsch & Katzenelson, 1978; Teltsch, Shuval, & Tadmor, 1980; Teltsch, Kedmi, Bonnet, Borenzstajn-Rotem, & Katzenelson, 1980). Camann, Moore, Harding, and Sorber support these findings. They also note that fecal streptococci are hardier than fecal coliform and appear frequently in background samples, suggesting that this bacterium is a better indicator of background and downwind conditions than are fecal coliform bacteria. In their study, storage prior to spray irrigation reduced microorganism concentrations by 99 percent. Downwind concentrations of sprayed reservoir water were often comparable to background values (Camann, Moore, Harding, & Sorber, 1988). Italian researchers (Brandi, Sisti, & Amagliani, 2000; Carducci, Gemelli, Cantiani, Casini, & Rovini, 1999; Carducci et al., 2000) confirm variable die-away rates of microorganisms, observe a positive association between fecal streptococci and the presence of viruses, and recommend consideration of submerged aeration for sludge digestion at sewage treatment plants. No reports are available that measure dispersion of bioaerosols from wastewater consistently treated to meet contemporary disinfection standards.

Treatment with humanized monoclonal antibodies against CD80 and CD86 combined with sirolimus prolongs renal allograft survival in cynomolgus monkeys.

BACKGROUND: Co-stimulatory blockade has been shown to prolong allograft survival in different transplant models. We investigated the effect of combining humanized anti-CD80 and anti-CD86 monoclonal antibodies (mAb) with sirolimus in cynomolgus monkey renal transplant recipients. METHODS: After renal transplantation, groups of four animals were treated daily with sirolimus, sirolimus and nine weekly doses of mAb, two weekly doses of mAb, or sirolimus and two weekly doses of mAb. RESULTS: Survival was significantly better in monkeys treated with the combination of sirolimus and mAb when compared with treatment with either agent alone (P=0.0067 by log-rank analysis). When combined with sirolimus, nine weekly doses of mAb did not result in an additional survival benefit compared with only two mAb doses (P=0.74). None of the treatment regimens used in this study resulted in development of transplantation tolerance. CONCLUSIONS: Sirolimus can be successfully combined with humanized mAb against CD80 and CD86. Induction with a short course of mAb is effective in prolonging allograft survival in combination with sirolimus.

Mating pattern variability among western toad (Bufo boreas) populations.

Breeding ecology and mating patterns of the western toad, Bufo boreas, were examined in three large explosively breeding populations in the Oregon Cascade Mountains. Two mating patterns occurred variably within and among the three populations. First, a large male mating advantage was observed in two of the three populations when data from all the days of data collection were combined. When each day of breeding was analyzed separately, there was a large male mating advantage on 3 of 5 days at one population, and mating was random on all days at the two other populations. The second mating pattern, positive assortative mating by size, was observed at two of the three populations. This pattern was found on separate days of breeding as well as when data from all days were combined at one population, and on only one day of breeding at the second population.In a survey of anuran amphibian mating patterns, intraspecific variation was found in 13 of 15 species, including the present study of the western toad. Intrapopulation variation in mating patterns among breeding years has been observed in 5 of 8 anurans, whereas within-site, within-year mating pattern variation has only been reported for the western toad. These results strongly suggest that anuran mating patterns are frequently neither species-specific nor population-specific attributes. Variable mating patterns were most commonly observed in explosively-breeding anurans. Explosive breeders may be susceptible to variable mating patterns because they may be more sensitive to fluctuations in environmental conditions, demographic parameters, and the intensities of intrasexual competition and mate choice.

Rana cascadae tadpoles aggregate with siblings: an experimental field study.

Previous laboratory studies have shown that Rana cascadae larvae preferentially associated with siblings over non-siblings in choice tests. This study, conducted during three consecutive summers, tests the hypothesis that R. cascadae larvae aggregate nonrandomly with respect to sibship in natural ponds. Pairs of sibships were reared in separate tanks or together in the same tank in the laboratory. Each sibship within a pair was then stained with neutral red or methylene blue dye and released together in a natural pond. Over a period of several days, aggregations of tadpoles within test ponds were repeatedly captured, censused for sibship composition, and released. In control tests, two groups of tadpoles from the same sibship were dyed different colors and released together. In total, 25 different tests were conducted using tadpoles from 31 sibships and 456 aggregations were sampled. The distribution of color compositions of aggregations in control tests did not differ from an expected random distribution. Color compositions of aggregations in experimental tests differed from controls and from an expected random distribution. Aggregations in these tests tended to be dominated by one of the two colors (sibships). We conclude that R. cascadae tadpoles recognize and prefer to aggregate with siblings in natural field conditions. Circumstances of early rearing (i.e., whether tadpoles were reared with siblings or in mixed sibling/non-sibling groups) had no influence on preferences to associate with siblings, but there was an inverse correlation between group size and sibling association.