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A cross-sectional prospective cohort study including 1026 heifers administered tulathromycin due to high risk of clinical signs of bovine respiratory disease (BRD), measured poor association between BRD clinical outcomes and results of bacterial culture and tulathromycin susceptibility from BRD isolates of deep nasopharyngeal swabs (DNS) and adequate association with viral polymerase chain reaction (PCR) results from nasal swabs. Isolation rates from DNS collected on day-0 and at 1 st BRD-treatment respectively were: Mannheimia haemolytica (10.9% & 34.1%); Pasteurella multocida (10.4% & 7.4%); Mycoplasma bovis (1.0% & 36.6%); and Histophilus somni (0.7% & 6.3%). Prevalence of BRD viral nucleic acid on nasal swabs collected exclusively at 1 st BRD-treatment were: bovine parainfluenza virus type-3 (bPIV-3) 34.1%; bovine viral diarrhea virus (BVDV) 26.3%; bovine herpes virus type-1 (BHV-1) 10.8%; and bovine respiratory syncytial virus (BRSV) 54.1%. Increased relative risk, at 95% confidence intervals, of 1 st BRD-treatment failure was associated with positive viral PCR results: BVDV 1.39 (1.17–1.66), bPIV-3 1.26 (1.06–1.51), BHV-1 1.52 (1.25–1.83), and BRSV 1.35 (1.11–1.63) from nasal swabs collected at 1 st BRD-treatment and culture of M . haemolytica 1.23 (1.00–1.51) from DNS collected at day-0. However, in this population of high-risk feeder heifers, the predictive values of susceptible and resistant isolates had inadequate association with BRD clinical outcome. These results indicate, that using tulathromycin susceptibility testing of isolates of M . haemolytica or P . multocida from DNS collected on arrival or at 1 st BRD-treatment to evaluate tulathromycin clinical efficacy, is unreliable.

Abstract Growth-promoting implants are broadly used in the feedlot industry to improve growth performance and to increase production efficiencies. With cattle being fed longer and to heavier weights, there is demand for extended-release implants that payout for at least 200 d. Our objective was to evaluate feedlot growth of Synovex ONE Grower, a moderate potency (150 mg trenbolone acetate [TBA] and 21 mg estradiol benzoate [EB]), extended-release, growth-promoting implant for 200 d. At four locations (Texas, Idaho, California, and Nebraska), 200 steers (n = 800; d 0 body weight [BW] = 320.2 ± 9.5 kg) and 200 heifers (n = 800; d 0 BW = 311.5 ± 9.5 kg) were blocked by BW and randomized to 1 of 2 treatments: 1) Control, empty subcutaneous needle inserted and extracted from the middle third of one ear; 2) ONE Grower, 150 mg TBA and 21 mg EB extended-release implant administered in middle third of one ear. Treatments were commingled within pen of the same sex (n = 4/site; 2/sex/site) in a split plot design replicated across four sites. Cattle were fed finishing ration ad libitum common to each geographical region at least once daily and were observed for any abnormal health events twice daily. Treatments were administered on d 0. Mid-study implant site evaluations were performed on d 35 or 41. Initial BW was recorded on d 0 and final BW was recorded on d 200 to 204. Cattle were harvested from d 201 to 231; however, carcass data were not collected due to slaughter facility complications brought on by the COVID-19 pandemic. Data were analyzed using the PROC MIXED and PROC GLIMMIX procedures of SAS (Version 9.4, SAS Institute, Cary, NC; P < 0.05), and animal was the experimental unit. There were no treatment × sex interactions (P ≥ 0.052) for any variable. Final BW on d 200 was greater (P < 0.01) for steers and heifers implanted with ONE Grower compared to Control; ONE Grower improved final BW by 5.7% for steers and 3.9% for heifers. Overall average daily gain (ADG) from d 0 to 200 was greater (P < 0.01) for ONE Grower steers and heifers compared to Control with an increase in ADG of 13.1% for steers and 8.9% for heifers. For cattle implanted with ONE Grower, implant retention rates at d 35 or 41 were 95.7% and 96.3% for steers and heifers, respectively. There was no difference (P ≥ 0.32) in percentage deads, removals, or bullers (steers) between treatments. Synovex ONE Grower improved final BW and ADG in feedlot steers and heifers fed for at least 200 d.

Abstract A cross-sectional prospective cohort study to correlate BRD clinical outcomes for tulathromycin metaphylaxis/treatment for bovine respiratory disease (BRD) with the results of bacterial culture and tulathromycin susceptibility from isolates of deep nasopharyngeal swabs (DNS) as well as viral polymerase chain reaction (PCR) results from nasal swabs revealed poor correlation of bacterial culture and tulathromycin susceptibility with response to tulathromycin metaphylaxis or treatment. 1031 heifers, assumed to be at high-risk (>40% expected BRD morbidity rates), were procured and transported to a research feedlot in Texas. Isolation rates from DNS collected on arrival and at first treatment respectively were: Mannheimia haemolytica (10.9% & 34.1%); Pasteurella multocida (10.4% & 7.4%); Mycoplasma bovis (1.0% & 36.6%); and Histophilus somni (0.7% & 6.3%). Prevalence of BRD viral nucleic acid on nasal swabs collected at first treatment were: PI-3V (34.1%); BVDV (26.3%); BoHV-1 (10.8%); and BRSV (54.1%). Increased relative risk of treatment failure was associated with positive viral PCR results, PI-3V (1.2644), BVDV (1.3917), BHV-1 (1.5156), and BRSV (1.3474) from nasal swabs collected at first pull and culture of M. haemolytica (1.2284) from DNS collected at arrival; however, no other statistically predictable risk of treatment outcomes were measured from DNS for bacterial isolation or tulathromycin susceptibility for M. haemolytica or P. multocida at arrival or first treatment. Predictive values of bacterial culture and tulathromycin susceptibility were substantially lower than the 85% level expected with susceptibility testing. These results indicate tulathromycin susceptibility testing of isolates of M. haemolytica or P. multocida from DNS collected on arrival or at first pull unreliably predict clinical efficacy of tulathromycin for BRD control or treatment most likely due to impacts of unpredictable risk factors and other viral and/or bacterial BRD comorbidities. * Abbreviations BA Blood agar BHV-1 Bovine Herpes virus type 1 BQA Beef Quality Assurance BRD bovine respiratory disease BRSV Bovine Respiratory Syncytial virus BVDV Bovine Viral Diarrhea virus CAS clinical appearance score CLSI Clinical and Laboratory Standards Institute DNS deep nasopharyngeal swab HFA Hayflick’s agar H. somni Histophilus somni M. bovis Mycoplasma bovis M. haemolytica Mannheimia haemolytica MHB Mueller Hinton broth MIC minimum inhibitory concentration Multiplex PCR BVDV, BRSV, BHV-1, PI-3V NPV Negative Predictive Value PCR polymerase chain reaction PI-3V Bovine Parainfluenza virus type 3 PMI Post Metaphylaxis Interval P. multocida Pasteurella multocida PPV Positive Predictive Value PTI Post Treatment Interval RRTF relative risk for treatment failure TFR treatment failure rate TSR treatment success rate

Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.

In a pilot study, two doses of neoadjuvant nivolumab administered to patients with resectable lung cancer resulted in a major pathological response in 45% and amplified T-cell clones specific for tumor antigens.

Purpose.—To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker. Methods.—The American Society of Clinical Oncology and the College of American Pathologists (CAP) convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations. Results.—Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy. Recommendations.—The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than 6 HER2 gene copies per nucleus, or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or a FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.

BackgroundWe conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.MethodsPatients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.ResultsWhile the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.ConclusionsThough treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Purpose.—To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods.—The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results.—Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria. Recommendations.—The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.

Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd–3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.

Purpose.—To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods.—The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results.—Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. Recommendations.—The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.