Survival outcomes of patients with HER2/neu-positive breast cancer with germline BRCA mutations.

BACKGROUND: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations. METHODS: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were analyzed by BRCA mutation status. Univariate and multivariable Cox proportional hazards regression models were used to analyze the association between clinical variables and outcomes. RESULTS: Of 1099 patients with HER2/neu-positive BC, 73 (6.6%) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. At a median follow-up of 78.6 months, the 5-year recurrence-free survival rate was 85% in BRCA carriers and 87% in noncarriers (p = .79), and the 5-year overall survival rate was 94% in BRCA carriers and 94% in noncarriers (p = .78). In a multivariable model, BRCA was not associated with recurrence-free survival (hazard ratio, 0.99; 95% confidence interval, 0.51-1.90; p = .96) or overall survival (hazard ratio, 0.83; 95% confidence interval, 0.33-2.07; p = .69). CONCLUSIONS: BRCA1/2 mutations occurred in 6.6% of patients with HER2/neu-positive BC and did not affect survival outcomes. Assessing the potential benefits of new treatment strategies, such as combining anti-HER2/neu therapies with poly(ADP-ribose) polymerase inhibitors, may lead to enhanced outcomes for these patients.

Assessing the effectiveness of MRI, 18F-fluciclovine PET, SUVmax, and PSA in detecting local recurrence of prostate cancer after prostatectomy.

Purpose: The primary objective of this study was to evaluate the discriminatory utility of magnetic resonance imaging (MRI), 18F-fluciclovine positron emission tomography (PET), maximum standardized uptake value (SUVmax), prostate-specific antigen (PSA), and combinations of these diagnostic modalities for detecting local prostate cancer recurrence in the setting of rising PSA after radical prostatectomy. Material and methods: Patients were characterised for clinical features such as Gleason score, PSA at surgery, PSA at follow-up, follow-up MRI result, follow-up PET result, follow-up SUVmax, and follow-up disease status. The utility of diagnostic parameters for detecting disease recurrence at the prostatectomy bed was assessed using receiver operating characteristics (ROC) analysis to determine the area under the curve (AUC) for each model. Sensitivity, specificity, and positive/negative predictive values were also calculated. Optimal cut-off points for continuous variables were determined based on maximum Youden's J statistics. Results: The study found that MRI had the highest concordance (96%), sensitivity (100%), specificity (91%), positive predictive value (93%), and negative predictive value (100%) among the diagnostic modalities. The AUC for MRI was 0.9545, indicating a high discriminatory ability for detecting prostate cancer local recurrence. When combined, PET and SUVmax (cut-off value of 2.85) showed an improved performance compared to using them individually, with an AUC of 0.8925. Conclusions: The analysis suggests that MRI is the most effective imaging modality for detecting local prostate cancer recurrence, with 18F-fluciclovine PET and SUVmax also showing promising combined results. PSA has moderate discriminatory utility at follow-up but can still provide valuable information in detecting prostate cancer recurrence. Further research and recent references are needed to support these findings.

Retrospective Analysis of Imaging Characteristics of Tectal Gliomas.

BACKGROUND AND PURPOSE: Tectal gliomas (TGs) are rare tumors that involve critical locations in the brainstem, including the superior and inferior colliculi and the Sylvian aqueduct. The rarity of these tumors and the lack of large clinical studies have hindered adequate understanding of this disease. We sought to determine the association between imaging characteristics of TG and progression-free survival (PFS). MATERIALS AND METHODS: In this retrospective cohort study, impact of imaging characteristics (contrast enhancement, calcifications, cystic changes, presence of hydrocephalus) on survival was analyzed for 39 patients with TG. We used the Kaplan-Meier survival analysis method for determining the association between imaging characteristics and PFS. Progression-free survival was measured from time of diagnosis to radiographic or pathological disease progression during observation period. Progression was defined as more than 25% increase of the lesion in size, per response assessment in neuro-oncology, together with clinical deterioration and/or a need for intervention. Progression-free survival differences by various imaging characteristics were assessed using the log-rank test and univariable Cox proportional hazard regression. Because most of the studies in the current literature tend to overrepresent pediatric patients, we aimed to determine the association between TG tumors' imaging characteristics and PFS in both adult and pediatric patients. All statistical analyses were performed using STATA version 16.1 (Stata Corp, College Station, Tex). RESULTS: Of the 39 patients, radiographic tumor progression was observed in 15 cases (38.5%). Median PFS for 39 patients during observation was 21.8 years. Tectal gliomas that showed contrast enhancement initially or developed contrast enhancement during surveillance on magnetic resonance imaging had significantly lower PFS than those without (hazard ratio, 3.55; 95% confidence interval, 1.09-11.58; log-rank P value, 0.02). CONCLUSIONS: Analysis of this patient population showed that contrast-enhancing TGs should not be categorically defined as benign lesions. This subgroup of patients should be followed closely for signs of progression.

Contrast Enhancement Patterns in Pediatric Glioblastomas.

BACKGROUND AND PURPOSE: Brain tumors are the most common cause of cancer-related deaths among the pediatric population. Among these, pediatric glioblastomas (GBMs) comprise 2.9% of all central nervous system tumors and have a poor prognosis. The purpose of this study is to determine whether the imaging findings can be a prognostic factor for survival in children with GBMs. MATERIALS AND METHODS: The imaging studies and clinical data from 64 pediatric patients with pathology-proven GBMs were evaluated. Contrast enhancement patterns were classified into focal, ring-like, and diffuse, based on preoperative postcontrast T1-weighted magnetic resonance images. We used the Kaplan-Meier method and Cox proportional hazard regression to evaluate the prognostic value of imaging findings. RESULTS: Patients with ring-enhanced GBMs who underwent gross total resection or subtotal resection were found to have a significantly shorter progression-free survival ( P = 0.03) comparing with other enhancing and nonenhancing glioblastomas. CONCLUSIONS: In this study, we analyzed survival factors in children with pediatric glioblastomas. In the group of patients who underwent gross total resection or subtotal resection, those patients with focal-enhanced GBMs had significantly longer progression-free survival ( P = 0.03) than did those with other types of enhancing GBMs (diffuse and ring-like).

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.

HER2 testing in breast cancers: comparison of assays and interpretation using ASCO/CAP 2013 and 2018 guidelines.

PURPOSE: HER2 overexpression and gene amplification are routinely tested by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. In addition, HER2 mRNA expression is also tested by the Oncotype DX assay. Discordance between laboratories among the different assays remains a problem. To improve the routine HER2 reporting, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) updated their guidelines in 2018. Our study will compare concordance of HER2 status by IHC and FISH using ASCO/CAP 2013 and 2018 guidelines with Oncotype DX. METHODS: We retrospectively reviewed 657 estrogen receptor positive primary breast cancer cases with available Oncotype DX tests between 2011 and 2018. Medical records were reviewed for HER2 results by IHC, FISH, and Oncotype DX. The HER2 results by different assays and between 2013 and 2018 guidelines were compared. RESULTS: Of the 657 cases, 280 were tested by IHC, FISH, and Oncotype DX. HER2-equivocal cases by IHC 2013 guidelines were all negative (67/67, 100%) by FISH 2018 guidelines and by Oncotype DX. HER2-equivocal cases by FISH 2013 guidelines were all negative (16/16, 100%) by FISH 2018 guidelines, while 15/16 (93.8%) negative and 1/16 (6.2%) equivocal by Oncotype DX. The HER2-equivocal and HER2-negative groups were similar in age, gender, histology, grade, and Ki67 score. CONCLUSIONS: HER2 concordance was highest between Oncotype DX (99.6%) and FISH per 2018 guidelines. This suggests that the ASCO/CAP 2018 guidelines improved the accurate stratification of HER2-equivocal cases.

Immune evasion phenotype is common in Richter transformation diffuse large B-cell lymphoma variant.

Immune checkpoint inhibitors (PD-1 inhibitors) have shown clinical activity in Richter transformation-diffuse large B-cell lymphoma variant (RT-DLBCL), thus providing for a novel therapeutic approach. The study group consists of 64 patients with RT-DLBCL. Expression of PD-1, PD-L1, CD30, and microsatellite instability (MSI) status (hMLH1, hMSH2, hMSH6, PMS1) was assessed using immunohistochemistry. EBV-encoded RNA (EBER) was evaluated using colorimetric in situ hybridization. PD-1 and PD-L1 expression levels were categorized on the basis of tumor cell expression as follows: negative (< 5%), positive to low-positive (5-50%), or high-positive (> 50%). An "immune evasion phenotype" (IEP) was defined as RT-DLBCL cases having high-positive expression of PD-1 and/or PD-L1 on tumor cells. The level of PD1-positive tumor-infiltrating lymphocytes (TILs) was estimated as a fraction of total lymphocytes and categorized as negative/low vs. brisk (> 20%). 28/64 (43.7%) patients were characterized as IEP+ RT-DLBCL. A brisk level of PD1+ TILs was significantly more common in IEP1+ compared with IEP- tumors (17/28, 60.7% vs. 5/34, 14.7%; p = 0.001). In addition, CD30 expression was significantly more common in IEP+ compared with IEP- RT-DLBCL (6/20, 30% vs. 1/27, 3.7%; p = 0.0320). Two (2/36; 5.5%) cases were positive for EBER, both IEP+. There was no significant difference between the two groups in terms of age, sex, or time to transformation. Assessment of mismatch repair proteins demonstrated absence of microsatellite instability (MSI) in all cases (18/18; 100%). Notably, patients with brisk PD1+ TILs had a significantly better OS compared to those with a negative/low infiltrate (p = 0.0285).

Adherence to 5-alpha reductase inhibitor therapy for benign prostatic hyperplasia: clinical and economic outcomes.

OBJECTIVE: Our goal was to quantify relationships between adherence to 5-alpha reductase inhibitors (5-ARIs), the risk of acute urinary retention (AUR) and prostate surgery, and medical costs related to patients with benign prostatic hyperplasia (BPH). METHODS: Claims recorded over a period of 6.5 years in a nationwide managed care database were analyzed. We conducted time-to-event multivariate analysis to evaluate relationships between adherence (medication possession ratio [MPR] thresholds of 70% or higher, 75% or higher, and 80% or higher), persistence (length of therapy), and the risk of AUR and surgery. We compared mean monthly BPH-related medical costs in patients with MPRs at or above thresholds and those with MPRs below thresholds and determined changes in BPH-related costs associated with 30-day increments of therapy. RESULTS: In AUR analyses (N = 17,293), meeting or exceeding MPR thresholds was associated with a reduced likelihood of AUR for 70% (hazard ratio [HR], 0.380), 75% (HR, 0.613), and 80% (HR, 0.519) (P < 0.05 for all). In prostate surgery analyses (N = 17,739), the likelihood of surgery was reduced with MPR thresholds of 70% or above (HR, 0.294), 75% or above (HR, 0.542), and 80% or above (HR, 0.436) (P < 0.05 for all). A longer duration of therapy was associated with a reduced likelihood of AUR (HR, 0.860) and surgery (HR, 0.884) (P < 0.05 for both). In both populations, adherence and persistence were also associated with significantly decreased BPH-related medical costs. CONCLUSION: In patients with BPH who received 5-ARI therapy, greater adherence and persistence were associated with significantly reduced risks of AUR and prostate surgery and with significantly lower medical costs. Maximizing adherence may enable patients to realize the potential long-term benefits of 5ARIs.

Temporal Trends in Outcomes in Patients With Adrenocortical Carcinoma: A Multidisciplinary Referral-center Experience.

CONTEXT: Reporting temporal trends in adrenocortical carcinoma (ACC) helps guide management strategies. OBJECTIVE: This work aimed to report the trends in disease burden and clinical outcomes over time that cannot be adequately captured from individual clinical trials. METHODS: A retrospective study was held of ACC patients seen at a referral cancer center between February 1998 and August 2019. Clinical outcomes were compared between an early cohort (February 1998-June 2007) and a late cohort (July 2007-August 2019). RESULTS: A total of 621 patients included with a median age at diagnosis of 49.3 years (range, 0.5-86.6 years). There were 285 (45.9%) patients with hormonal overproduction. More patients in the late cohort had stage IV disease compared to the early cohort (36.8% vs 23.1%; P < .0001). Resection of the primary tumor was performed in 502 patients (80.8%). Complete resection (R0) was more common in the late cohort (165 [60.2%]) than in the early cohort (100 [44.6%]; P = .0005). Of 475 patients with metastatic disease (stage IV or recurrent metastatic disease), 352 (74.1%) received mitotane, 320 (67.4%) received chemotherapy, and 53 (11.2%) received immunotherapy. In the early cohort, 70 (33%) received 2 or more lines of therapy, whereas in the late cohort, 127 (48%) received 2 or more lines of therapy. The 5-year overall survival (OS) rates were 65%, 58%, 45%, and 10% for stage I, II, III, and IV disease, respectively, whereas the 2-year OS rates in patients with stage IV disease was 24% in the early cohort and 46% in the late cohort (P = .01). CONCLUSION: ACC clinical outcomes improved over the past 2 decades as more patients had complete resection or received more lines of systemic therapy.

Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network.

Bevacizumab significantly extends progression-free survival (PFS) and overall survival (OS) times when combined with initial chemotherapy and continued as monotherapy until disease progression or unacceptable toxicity in patients with nonsquamous non-small cell lung cancer (NSCLC). In clinical practice, bevacizumab is sometimes discontinued after completion of chemotherapy. This retrospective analysis of the US Oncology network's electronic medical records evaluated the association between PFS and OS times and bevacizumab monotherapy to progression (BTP) among patients with advanced NSCLC. Patients treated from July 2006 through June 2008 were analyzed as two cohorts based on whether or not they received BTP after completion of first-line chemotherapy plus bevacizumab. Hazard ratios for PFS and OS were estimated using Cox proportional hazards, adjusting for relevant treatment and patient characteristics. To account for survivorship bias, landmark analyses were conducted at 18, 21, and 26 weeks from initial therapy to examine residual PFS and OS times, defined as the time from the landmark to disease progression or death. From the total 498 nonsquamous NSCLC patients, 403 received first-line chemotherapy plus bevacizumab: 154 received BTP, 249 did not. Longer PFS and OS times were observed in patients who received BTP than in those who received no BTP (median OS, 20.9 months versus 10.2 months; median PFS, 10.3 months versus 6.5 months). BTP was associated with a longer residual OS time at all specified landmarks and longer residual PFS time at week 18 than with no BTP. In conclusion, this retrospective analysis provides supportive evidence that continued vascular endothelial growth factor suppression in advanced nonsquamous NSCLC patients is associated with favorable clinical outcomes.

Cost-effectiveness of white blood cell growth factor use among a large nationwide cohort of elderly non-Hodgkin's lymphoma patients treated with chemotherapy.

OBJECTIVE: To determine the cost-effectiveness (as measured as cost per life-year saved) of white blood cell growth factor or colony-stimulating factor (CSF) use among a large cohort of elderly non-Hodgkin's lymphoma (NHL) patients in a real-world setting. METHODS: We identified 13,203 NHL patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database who received the diagnosis from 1992 to 2002 and who received chemotherapy within 12 months of diagnosis. Benefit (effectiveness) of CSF use (primary and secondary prophylaxis) was measured as observed improvement in overall survival. Costs for each patient were calculated by adding the cumulative reimbursement amounts from Medicare claims. Cost-effectiveness was estimated by modeling the joint influence of CSF use on both costs and effectiveness using a propensity-score net monetary benefit approach. RESULTS: Primary prophylactic CSF use was cost-effective at lower willingness-to-pay thresholds, whereas at higher thresholds, not providing prophylactic CSF became the cost-effective strategy. For secondary prophylactic CSF use among patients experiencing neutropenia, fever, and/or infection, the opposite trend was observed. For low willingness-to-pay thresholds (<$20,000 per life-year gained), not administering CSF was the cost-effective strategy, whereas CSF use became cost-effective as willingness to pay increased (from $100,000+ per life-year gained). CONCLUSION: To our knowledge, this is the first large population-based study to empirically measure the cost-effectiveness of CSF among NHL patients treated with chemotherapy. CSF use as primary or secondary prophylaxis may be a cost-effective strategy depending on society's (or payers') willingness to pay for improvements in outcomes.

Metastatic Risk Factors Associated with Class 1A Uveal Melanoma Patients.

In uveal melanoma (UM), gene expression profiling (GEP) is commonly used to classify metastatic risk into three groups (Class 1A, 1B, and 2). Class 1A patients have a lower metastatic risk of 2% at 5 years compared to other groups. We aimed to describe clinical features associated with the development of metastasis in this low-risk group. This single-center IRB-approved retrospective case series review included all UM patients between February 2006 and March 2019 with an archived or fresh specimen classified as Class 1A. Cox regression and receiver operating characteristics analyses were used to identify factors associated with metastasis development and OS. Among 73 UM patients with Class 1A, the 5-year cumulative incidence of local recurrence and distant metastasis was 4.2% and 17.0%, respectively. Stage III disease (HR 20.7; 95% confidence interval (95% CI) 1.4-300.6; p = 0.0264) was found to be independently associated with metastatic recurrence, while primary therapy was associated with OS (enucleation vs. brachytherapy, HR 13.5; 95% CI 1.3-147.6; p = 0.0348). Combined clinical decision-making utilizing factors such as GEP class, American Joint Committee on Cancer (AJCC) stage, and COMS size could have a significant clinical impact by improving risk stratification and adapting follow-up intervals in UM Class 1A patients.

Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study.

PURPOSE: Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. PATIENTS AND METHODS: We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. RESULTS: Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. CONCLUSION: The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma, with deep and sustained confirmed responses.

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT. METHODS: A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed. RESULTS: Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01). CONCLUSIONS: ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

Progression of the Radiologic Severity Index is associated with increased mortality and healthcare resource utilisation in acute leukaemia patients with pneumonia.

Background: Pneumonia is a major cause of mortality and morbidity, but the development of new antimicrobials is lacking. Radiological assessment of pneumonia severity may serve as an effective intermediate endpoint to reduce barriers to successful completion of antimicrobial trials. We sought to determine whether the Radiologic Severity Index (RSI) correlated with mortality and healthcare resource utilisation in patients with acute leukaemia undergoing induction chemotherapy. Methods: We measured RSI (range 0-72) on all chest radiographs performed within 33 days of induction chemotherapy in 165 haematological malignancy patients with pneumonia. Peak RSI was defined as the highest RSI score within 33 days of induction. We used extended Cox proportional hazards models to measure the association of time-varying RSI with all-cause mortality within the first 33 days after induction chemotherapy, and logistic regression or generalised models to measure the association of RSI with total daily cost and healthcare resource utilisation. Results: After adjustment for clinical variables, each one-point increase in RSI was associated with a 7% increase in all-cause 33-day mortality (HR 1.07, 95% CI 1.05 to 1.09, p<0.0001). Peak RSI values of 37.5 or higher were associated with 86% higher daily direct costs (p<0.0001), more days in intensive care unit (9.9 vs 4.8 days, p=0.001) and higher odds for mechanical ventilation (OR 12.1, p<0.0001). Conclusions: Greater radiological severity as measured by RSI was associated with increased mortality and morbidity in acute leukaemia patients with pneumonia. RSI is a promising intermediate marker of pneumonia severity and is well suited for use in antimicrobial trials.

PD-L1/PD1 Expression, Composition of Tumor-Associated Immune Infiltrate, and HPV Status in Conjunctival Squamous Cell Carcinoma.

Purpose: Conjunctival squamous cell carcinoma (SCC), a type of ocular surface neoplasia, is primarily treated by surgical resection and topical immuno- or chemotherapy. Metastatic disease may be treated with systemic chemo- or immunotherapy, albeit with variable response. The purpose of this study was to determine whether immune checkpoint blockade might be considered in the management of conjunctival SCC. Methods: In this retrospective study, we evaluated tumor programmed death-ligand 1 (PD-L1) expression, high-risk human papillomavirus (HPV) status, and immunohistochemical expression of cluster of differentiation 3 (CD3), cluster of differentiation 8 (CD8), and programmed death 1 (PD1) in tumor-associated immune infiltrate in a series of 31 conjunctival SCCs. Results: PD-L1 expression in ≥1% of tumor cells was noted in 14 conjunctival SCCs (47%) and was more prevalent in invasive than in situ SCC and among tumors with higher American Joint Committee on Cancer (AJCC) T category (≥T3 versus ≤T2). The density of CD3-positive T cells was higher in primary than recurrent tumors and higher in invasive than in situ tumors. Density of CD3-positive and CD8-positive T cells was higher in higher AJCC stage tumors. Density of CD8-positive T cells was higher in HPV-positive than HPV-negative tumors. PD-L1 expression correlated with a higher density of CD3-, CD8-, and PD1-positive cells in the tumor-associated immune infiltrate but not with HPV status. Conclusions: Our findings demonstrate that PD-L1 is expressed in almost half of conjunctival SCCs. The density of tumor-associated immune cells correlated with invasive SCC, stage, and HPV status in conjunctival SCC. Our findings support further studies to establish the potential application of immune checkpoint blockade in the management of conjunctival SCC.

Clinical Herpes Zoster in Antarctica as a Model for Spaceflight.

INTRODUCTION: Antarctica is a useful analog for spaceflight, as both environments are remote, isolated, and with limited resources. While previous studies have demonstrated increased asymptomatic viral shedding in both the Antarctic and spaceflight environments, clinical manifestations of reactivated viral disease have been less frequently identified. We sought to identify the incidence of clinical herpes zoster from viral reactivation in the Antarctic winter-over population. METHODS: Medical records from the 2014 winter season were reviewed for the incidence of zoster in U.S. Antarctic personnel and then compared to the age-matched U.S. RESULTS: Five cases of clinical herpes zoster occurred in the Antarctic Station population of 204 persons, for an incidence of 33.3 per 1000 person-years vs. 3.2 per 1000 person-years in the general population. Four cases were in persons under age 40, yielding an incidence of 106.7 per 1000 person-years in persons ages 30-39 compared to an incidence of 2.0 per 1000 person-years in the same U.S. age group. DISCUSSION: Immune suppression due to the stressful Antarctic environment may have contributed to the increased incidence of herpes zoster in U.S. Antarctic personnel during the winter of 2014. Working and living in isolated, confined, and extreme environments can cause immune suppression, reactivating latent viruses and increasing viral shedding and symptomatic disease. Such changes have been observed in other austere environments, including spaceflight, suggesting that clinical manifestations of viral reactivation may be seen in future spaceflight.Reyes DP, Brinley AA, Blue RS, Gruschkus SK, Allen AT, Parazynski SE. Clinical herpes zoster in Antarctica as a model for spaceflight. Aerosp Med Hum Perform. 2017; 88(8):784-788.

Adverse drug events among patients receiving postsurgical opioids in a large health system: risk factors and outcomes.

PURPOSE: Results of a study of postsurgical opioid-related adverse drug events (ORADEs) within a large health system are reported. METHODS: In a retrospective cohort study, data from the information database of an 11-hospital Texas health system were analyzed to (1) describe postsurgical opioid use among adult patients undergoing elective or emergency surgery over a one-year period, (2) identify ORADE risk factors and associated costs, and (3) compare clinical and economic outcomes in patients who experienced ORADEs and those who did not. Multivariate logistic regression was used to identify ORADE risk factors. Propensity score-matched comparisons of outcomes in patients with and without ORADEs were conducted. RESULTS: Among 6,285 patients in the study population, 6,274 (99.8%) received postsurgical opioids; 11.5% of those patients experienced an ORADE. ORADE risk factors included age (≥65 years), male sex, prior opioid use, chronic obstructive pulmonary disease, cardiac dysrhythmias, regional enteritis, diverticulitis, and ulcerative colitis. Patients with multiple risk factors had higher mean hospitalization costs ($21,073) relative to patients with one risk factor ($14,110) or no risk factor ($11,433) and accounted for a disproportionately large share of overall costs; patients who experienced ORADEs were more likely to be cost and length of stay (LOS) outliers. CONCLUSION: Analysis of information from a large database demonstrated that opioid-treated postsurgical inpatients who had multiple risk factors for ORADEs were more likely to have higher mean costs, greater readmission rates, and longer LOS than patients with fewer risk factors.

Development and validation of a risk score to identify patients at high risk for opioid-related adverse drug events.

BACKGROUND: Opioid-related adverse drug events (ORADEs) are common causes of hospitalization and increased health care costs. OBJECTIVES: To (a) estimate rates of specific adverse drug events (ADEs) among gastrointestinal (GI) surgery patients receiving postoperative opioids; (b) examine the utility of a risk-scoring model in categorizing patients at high risk of experiencing ORADEs; and (c) quantify potential clinical/economic benefits of targeting high-risk GI surgical patients for opioid-sparing regimens in terms of hospitalization cost, length of stay (LOS), and 30-day readmission rates. METHODS: Using a retrospective design based on an administrative database, patients with an inpatient surgical procedure between January 1, 2010, and December 31, 2010, were included. GI surgical patients aged greater than 18 years followed from admission through 30 days postdischarge were characterized as high or low risk using clinical/demographic characteristics and were evaluated for several outcomes. Using multivariate logistic regression, the ORADE incidence, total hospitalization cost, LOS, and 30-day readmissions were compared for high-risk and low-risk patients. RESULTS: In 87.8% (n = 3,235) of the surgical population, there was a strong concordance between risk assignment and ORADE incidence. Among the remaining 12.2% (n = 449) of patients, 5.5% (n = 202) were low risk with an ORADE, and 6.7% (n = 247) were high risk without an ORADE. Overall, 20.6% (n = 344) of high-risk patients experienced ≥1 ORADE (mean cost: $31,988; LOS: 12.1 days) compared with only 5.3% (n = 107) of low-risk patients (mean cost: $25,216; LOS: 8.0 days). High-risk patients had higher hospitalization costs and longer LOS than low-risk patients, respectively (mean cost: $19,234 vs. $13,036; mean LOS: 6.8 days vs. 3.3 days). These differences correspond to 47.0% higher costs for high-risk patients and an LOS approximately twice as long compared with low-risk patients. CONCLUSIONS: Patient clinical/demographic characteristics influence the risk of developing ORADEs. Risk assessment tools can effectively identify high-risk patients, thereby enabling interventions that can reduce ORADEs, decrease hospital costs, and improve postsurgical experiences for patients.

Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes.

STUDY OBJECTIVE: To determine the prevalence of postsurgical opioid use in the inpatient setting, to ascertain the frequency of and risk factors for opioid-related adverse drug events (ORADEs) among patients who received opioids, and to evaluate the impact of ORADEs on clinical and economic outcomes. DESIGN: Retrospective cohort study using administrative data. SETTING: Hospital system encompassing 26 hospitals in the southeastern United States. PATIENTS: A total of 37,031 patients aged 18 years or older who underwent a common surgical procedure between January 1, 2009, and December 31, 2010. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated for receipt of postsurgical opioids. Outcomes among opioid users included ORADE rates, hospital length of stay, total hospitalization costs, 30-day readmission rates, outlier status, and inpatient mortality. Factors associated with ORADEs were evaluated; length of stay, costs, readmissions, and mortality were compared between patients experiencing and not experiencing ORADEs by using propensity score matching on age, race-ethnicity, sex, presurgery opioid use, and comorbidities. Length of stay and cost rate ratios were generated by using negative binomial regression and generalized linear models. Odds ratios for 30-day readmissions and inpatient mortality were generated by using logistic regression. Among all surgical patients, 36,529 (98.6%) of patients received opioids, of whom 4955 (13.6%) experienced an ORADE. Increased risk of ORADEs was associated with age 65 years or older, male sex, obesity, presurgery opioid use, and higher score on Charlson Comorbidity Index. Patients with an ORADE had a 55% longer length of stay, 47% higher costs of care, 36% increased risk of 30-day readmission, and 3.4 times higher risk of inpatient mortality than did patients who did not experience an ORADE. CONCLUSION: Opioid use was ubiquitous among hospitalized patients who underwent common surgical procedures. The observed negative outcomes of ORADEs and their impact on patients and the health care system should be considered when evaluating the balance between effectively managing postsurgical pain while minimizing the risk of ORADEs.