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Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose We evaluated a previously published risk model (Novant model) to identify patients at risk for healthcare facility–onset Clostridioides difficile infection (HCFO-CDI) at 2 hospitals within a large health system and compared its predictive value to that of a new model developed based on local findings. Methods We conducted a retrospective case-control study including adult patients admitted from July 1, 2016, to July 1, 2018. Patients with HCFO-CDI who received systemic antibiotics were included as cases and were matched 1 to 1 with controls (who received systemic antibiotics without developing HCFO-CDI). We extracted chart data on patient risk factors for CDI, including those identified in prior studies and those included in the Novant model. We applied the Novant model to our patient population to assess the model’s utility and generated a local model using logistic regression–based prediction scores. A receiver operating characteristic area under the curve (ROC-AUC) score was determined for each model. Results We included 362 patients, with 161 controls and 161 cases. The Novant model had a ROC-AUC of 0.62 in our population. Our local model using risk factors identifiable at hospital admission included hospitalization within 90 days of admission (adjusted odds ratio [OR], 3.52; 95% confidence interval [CI], 2.06-6.04), hematologic malignancy (adjusted OR, 12.87; 95% CI, 3.70-44.80), and solid tumor malignancy (adjusted OR, 4.76; 95% CI, 1.27-17.80) as HCFO-CDI predictors and had a ROC-AUC score of 0.74. Conclusion The Novant model evaluating risk factors identifiable at admission poorly predicted HCFO-CDI in our population, while our local model was a fair predictor. These findings highlight the need for institutions to review local risk factors to adjust modeling for their patient population.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Background Atypical meningiomas (AMs) are meningiomas that have a higher rate of recurrence than grade I meningioma. Due to the higher risk of recurrence, adjuvant radiotherapy (RT) after resection of AM has been employed. At our institution, some neurosurgeons employ adjuvant RT on all primarily resected AMs, while others employ watchful waiting with serial imaging. Objective To study the effect of adjuvant RT on newly resected AMs. Methods A retrospective review of all AMs primarily resected at our institution from 1996 to 2018 was completed. Data on patient demographics, radiographic findings, use of adjuvant RT, time of follow-up, and recurrences were collected. Adjuvant RT was defined as RT that occurred within 6 mo of initial resection. Results A total of 162 patients met the inclusion criteria. Gross total resection was achieved in 73% of cases. Average time until recurrence in the cohort was 37 mo. A total of 108 patients had adjuvant RT, while 54 patients did not. On multivariate survival analysis, sex, Simpson grade resection, and use of adjuvant RT were independent predictors of recurrence. Mean time to recurrence in patients who received adjuvant RT was 43.7 mo versus 34.7 mo for those who did not receive adjuvant RT. Conclusion This study includes the largest retrospective cohort of patients who have received adjuvant RT after primary resection of AM. Our results suggest that the use of adjuvant RT is independently associated with a lower chance of recurrence. These data suggest that practitioners can consider the use of adjuvant RT for newly resected AMs, regardless of Simpson grade resection.

Purpose: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR–tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx. Patients and Methods: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation. Results: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment. Conclusions: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.

Background To the authors' knowledge, race-based differences in efficacy for the treatment of patients with advanced non-small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real-world differences in outcome in a diverse patient population. Methods The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single-agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia. Primary efficacy comparison between Black patients and White patients was performed using bivariate and multivariate analyses for overall survival (OS) and progression-free survival (PFS). Results Data from 257 patients were analyzed. The median age of the patients was 69 years; 50.6% of the patients were female, 63.4% were White, 29.5% were Black, and 7.1% of the patients were of "other" race. ICB was the first-line treatment in 51 patients (19.9%), the second-line treatment in 161 patients (62.6%), and the third-line treatment in 33 patients (12.9%). The most commonly used agents were nivolumab (49.0%), pembrolizumab (25.2%), and atezolizumab (21.3%). No differences with regard to OS (P = .839) and PFS (P = .235) were noted between Black and White patients. The sample overall response rate was 20.6% (15.2% in Black patients and 23.1% in White patients). No differences with regard to OS (P = .081) and PFS (P = .176) were observed between female and male patients. The rate of immune-related adverse events was found to be similar in Black and White patients (20.0% vs 29.9%; P = .148). On multivariate analysis, race was not found to be significantly associated with OS or PFS. Conclusions Real-world analysis of the authors' institutional experience demonstrated similar efficacy and tolerability of ICB in Black versus White patients with advanced NSCLC. Larger multi-institutional studies including other US minority populations would make the findings of the current study more generalizable.

Background Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration NCT01218555

Purpose The primary objective of the study described here was to compare rates of patient adherence to anticancer medications filled at an internal health system specialty pharmacy (HSSP) vs external specialty pharmacies. The primary outcome was the medication possession ratio (MPR), and the secondary outcomes included proportion of days covered (PDC), and time to treatment (TTT). Methods A retrospective chart review was conducted to compare the MPR, PDC, and TTT for patients who received oral anticancer therapy using prescriptions claim data. A t test or Wilcoxon test was used to explore the effect of demographic and other factors on adherence and TTT. A multiple regression model with backward elimination was used to analyze significant factors to identify covariates significantly associated with the outcomes. Results Of the 300 patients screened for study inclusion, 204 patients whose records had complete MPR and PDC data and 164 whose records had TTT data were included in the analysis. There were significant between-group differences in mean MPR and mean PDC with patient use of the HSSP vs external pharmacies (1.00 vs 0.75 [P < 0.001] and 0.95 vs 0.7 [P < 0.001], respectively). Pharmacy type (P = 0.024) and tumor type (P = 0.048) were significantly associated with TTT. Conclusion The multiple regression analysis indicated that oncology patients who filled their anticancer medication precriptions at an internal HSSP at an academic medical center had significantly higher adherence, as measured by MPR and PDC, and quicker TTT than those who filled their prescriptions at an external specialty pharmacy.

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.

Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4+ T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-γ production by activated CD4+ T cells. Additionally, IFN-γ stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4+ T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation. One Sentence Summary Blockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+ T cell and CXCR3-dependent manner.

Gain of chromosome 1q (+1q) is commonly identified in multiple myeloma and has been associated with inferior outcomes. However, the prognostic implication of +1q has not been evaluated in the setting of standard triplet regimens. We retrospectively analyzed 201 consecutive patients with newly diagnosed myeloma who received induction with lenalidomide, bortezomib, and dexamethasone (RVD) and were tested for +1q at diagnosis by fluorescent in-situ hybridization. Patients with +1q (n = 94), compared to those without +1q (n = 107), had shorter median progression-free survival (PFS) (41.9 months vs 65.1 months, p = 0.002, HR = 1.90) and overall survival (median not reached (NR) for either arm, p = 0.003, HR 2.69). In subgroup analyses, patients with co-occurring +1q and t(4;14), t(14;16) or del(17p) or with 4 or more copies of 1q had significantly worse PFS (25.1 months and 34.6 months, p p = 0.0063, respectively), whereas patients with three copies and no other high-risk cytogenetic abnormalities had no significant difference in PFS. These data suggest that when treated with RVD induction, patients with +1q should be considered at very high risk for early progression in multiple myeloma when ≥4 copies are detected or in the context of other high-risk cytogenetic abnormalities.

Background Increased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC. Patients and Methods Patients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition. Results Fifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET. Conclusion These results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy.

Patients with large prostate glands are underrepresented in clinical trials incorporating brachytherapy due to concerns for excessive toxicity. We sought to compare health-related quality of life (HRQOL) outcomes between small (60 cc) and large (≥60 cc) prostates treated with high-dose-rate brachytherapy (HDR-B).One hundred thirty patients at Emory University were treated with HDR-B monotherapy (n = 75) or HDR-B in combination with external beam radiation therapy (n = 55). American Urologic Association Symptom Score (AUASS) and expanded prostate cancer index composite for clinical practice (EPIC-CP) scores were recorded. A linear mixed model was performed dichotomizing prostate volume (60 and ≥ 60 cc) with AUASS, individual EPIC-CP domains (urinary incontinence, urinary irritation/obstruction [UIO], bowel function, sexual function, and vitality/hormonal function), and overall EPIC-CP HRQOL scores.Median followup was 22.6 months (range 2.2-55.8). The median gland volume for the entire cohort (n = 130),60 cc cohort (n = 104), and ≥60 cc cohort (n = 26) was 44 cc, 41.1 cc, and 68.0 cc, respectively. There were no baseline differences in HRQOL scores between cohorts. At 2 months, AUASS and UIO scores increased similarly between cohorts (AUASS p = 0.807; UIO p = 0.539), then decreased (longitudinal effect p0.001 and p = 0.005, respectively) to remain not significantly different at 12 months (AUASS p = 0.595; UIO p = 0.673). Overall, prostate volume was not significantly associated with change in AUASS (p = 0.403), urinary incontinence (p = 0.322), UIO symptoms (p = 0.779), bowel symptoms (p = 0.757), vitality/hormonal symptoms (p = 0.503), or overall HRQOL (p = 0.382).In appropriately selected patients, HDR-B appears well tolerated in patients with ≥60 cc prostate glands without an increase in patient-reported toxicity. Volume should not be a strict contraindication in those with adequate baseline function.

Background There is conflicting evidence regarding the role of peritumoral lymphatic vessel density (LVD) and blood microvessel density (MVD) in the metastasis and prognosis of head and neck squamous cell carcinoma (HNSCC). Existing studies are limited to one or two head and neck subsites and/or small sample sizes. A larger study incorporating multiple sub‐sites is needed to address the role of peritumoral LVD and MVD in HNSCC metastasis and prognosis. Methods Tissue samples from 200 HNSCC cases were stained simultaneously using immunohistochemistry (IHC) for markers of peritumoral LVD (lymphatic vessel marker D240) and MVD (blood vessel marker CD31). Of the stained slides, 166 and 167 were evaluable for LVD and MVD, respectively. The results were then correlated with clinicopathologic features and patient outcomes. Results Patients with metastatic disease were more likely to have high peritumoral MVD. Through multivariable analyses, MVD was not significantly related to DFS and OS, while low LVD was related to higher risk of disease progression and poor survival. Conclusions Peritumoral MVD was found to be positively associated with metastasis, while LVD was found to be inversely related to both metastasis and progression of HNSCC. These findings may suggest a prognostic role of both peritumoral LVD and MVD in patients with HNSCC.

Among various Phase I clinical trial designs, rule-based standard 3 + 3 designs are the most widely utilized for their simplicity and robustness. It is necessary to define crucial operating characteristics of a Phase I clinical trial before it starts. Based on the assumed probability of dose limiting toxicity (DLT) at each tested dose level, Lin and Shih elaborated formulas to calculate the five key operating characteristics of Phase I clinical trials using the two subtypes of standard 3 + 3 designs (with vs without dose de-escalation): probability of each dose level being chosen as the maximum tolerated dose (MTD); expected number of patients treated at each dose level; expected number of patients experiencing DLT at each dose level; target toxicity level (TTL) (expected probability of DLT at MTD); expected total number of patients experiencing DLT. Understanding these formulas requires advanced statistical knowledge and the formulas are too complicated to be used directly. To facilitate their application, we have developed stand-alone interactive software for convenient calculation of these key operating characteristics. The calculated results are presented in tables and plots that can be saved and easily edited for further use. Some examples of calculation using the software are presented and discussed. Keywords: Standard 3+3 design, Statistical software, Operating characteristics, Cancer phase I clinical trials, Maximum tolerated dose, Dose limiting toxicity

Objective To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC. Materials and Methods Cell growth, apoptosis and signaling changes in HNSCC cells following tipifarnib exposure in vitro were assessed by SRB, colony formation assay, annexin V staining and Western blot, respectively. A patient-derived xenograft (PDX) animal model was adopted to evaluate the efficacy of tipifarnib in vivo with and without cetuximab. Results Treatment of wild-type H-Ras HNSCC cell lines in vitro with tipifarnib reduced cell growth and increased levels of defarnesylated H-Ras in a dose-dependent manner. In a PDX mouse model, treatment with single-agent tipifarnib led to only near-significant growth inhibition. The addition of cetuximab resulted in increased anti-proliferative effect both in culture and in PDX models, which was also mirrored by Western blot and apoptosis assay results. Conclusion Tipifarnib has only a moderate ability to slow tumor growth as a single agent in HNSCC with wild type H-Ras, despite specifically inhibiting the farnesyltransferase upon which the function of H-Ras depends. The combination of cetuximab and tipifarnib appears to enhance the anti-proliferative effect of single-agent tipifarnib and marginally enhance that of single agent cetuximab. These findings deserve further evaluation.

The effect of oral microbial composition on periodontal health and on systemic health has been, and is being established. The oral microbiome, in turn, can be altered by local and systemic diseases and conditions. Gastroesophageal reflux disease (GERD), has been associated with increased acidity in the oral cavity resulting in dental erosion, and controversially a reduced risk of periodontal disease. We hypothesized that presence of GERD was linked to a modified microbial profile in untreated GERD patients and that the use of proton pump inhibitor (PPI) drugs: potent disruptors of gut microbiome, in GERD patients might result in a salivary microbiome that is further distinct. Untreated GERD patients showed multiple differences in salivary microbiome as compared to healthy controls. Taxa found at lower levels related to the presence of GERD not treated by PPI included: Prevotella melaninogenica, Prevotella pallens, Leptotrichia, and Solobacterium moorei and thirteen others. In contrast, GERD patients chronically using PPI showed minimal differences in salivary taxa compared to healthy controls not using PPI.

Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC. Correlations of FGFR3 Weighted Index (WI) with p16 status and mp53 WI as well as its association with disease-free survival (DFS) and overall survival (OS) were evaluated. FGFR3 expression was detected in 61% and 70% of cases in cohorts 1 and 2, respectively. FGFR3 level was significantly higher in p16-negative tumors in both cohorts (p

Background Although many patients with follicular lymphoma (FL) undergo routine radiographic surveillance during their first remission, no consensus exists on the modality, duration, frequency, or need for routine imaging studies. The authors retrospectively examined the effect of surveillance imaging on relapse detection and overall survival (OS) in patients with FL. Methods Patients with newly diagnosed FL who had a response to induction therapy were identified from the Lymphoid Malignancies Enterprise Architecture Database (LEAD) at Emory University and from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic. Patients were evaluated for both relapse and method of relapse detection (ie, clinical concerns vs radiologic detection through surveillance imaging in an asymptomatic patient). Results Of 148 patients in the LEAD cohort, 55 (37%) relapsed, and the majority (n = 35; 64%) of relapses were detected clinically. In the MER cohort, 63 of 177 relapses (54%) were detected clinically. There was no significant difference in OS from the date of diagnosis between the 2 methods of relapse detection in the LEAD (hazard ratio [HR], 0.61; 95% CI, 0.13-2.94; P = .54) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Similarly, there was no significant difference in OS from the date of relapse between the 2 methods of relapse detection in the LEAD (HR, 0.47; 95% CI, 0.10-2.27; P = .35) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Conclusions These findings suggest a limited role for routine surveillance imaging in patients with FL who complete front-line therapy. Future studies should evaluate which patients may benefit from a more aggressive surveillance approach and should explore novel methods of relapse detection.

Introduction The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established. Methods We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples. Results We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene set enrichment analysis for differentially expressed genes between the SCLC survival outliers (top and bottom deciles) matched for clinically relevant prognostic factors revealed substantial up-regulation of interferon-γ response genes in long-term survivors. The SCLC-Y subtype was associated with high expression of interferon-γ response genes, highest weighted score on a validated 18-gene T-cell–inflamed gene expression profile score, and high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited-stage versus extensive-stage SCLC (30.6% versus 8.5%; p = 0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation data sets from the SCLC cell lines and tumor samples. Conclusions SCLC subtyping using transcriptional signaling holds clinical relevance with the inflamed phenotype associated with the SCLC-Y subset.

Purpose Radiosurgery and fractionated intensity modulated radiation therapy (IMRT) are effective treatment modalities for meningiomas and schwannomas. Although fractionated IMRT yields favorable tumor control, daily treatments for 5 to 6 weeks can be burdensome for patients and health care systems. Thus, hypofractionated radiation may be a reasonable alternative. The purpose of this study was to review the results of patients with benign meningiomas or schwannomas treated at our institution with moderately hypofractionated IMRT. Methods and Materials After institutional review board approval, patients treated at a single academic institution between 2008 and 2018 with a primary diagnosis of either meningioma or schwannoma and who received 30 Gy at 3 Gy per fraction were identified. Patient and tumor characteristics, as well as follow-up documentation, were reviewed. Tumor progression was determined by reviewing patient imaging and provider notations. Results From 2008 to 2018, 70 patients with either meningioma or schwannoma were treated to 30 Gy. The median patient age was 73 years (range, 43-92 years). At the median follow up of 3.2 years, the local control was 92.9%. Two patients (2.9%) had disease progression, which occurred at 9.6 and 6.6 years after treatment. One patient developed asymptomatic radiographic changes consistent with radiation necrosis, which resolved without intervention. All patients completed the prescribed course without interruption. The mean tumor volume was 18.9 cm3, median volume was 36.6 cm3 (range, 3.4-245.5 cm3), and tumor volume was not associated with recurrence risk. Both tumors with progression were schwannomas. Conclusions Hypofractionated radiation with 30 Gy at 3 Gy per fraction is an effective, convenient, and well-tolerated alternative for patients with benign meningiomas or schwannomas. Modest hypofractionation provided durable control for a wide range of tumor volumes and should be considered for patients with a limited life expectancy or those unable to receive a more extended fractionated radiation therapy course.

Background The ability to accurately monitor response to treatment in patients with metastatic castration resistant prostate cancer (mCRPC) on chemotherapy has been a challenge. Conventional methods of therapy response assessment have limitations and molecular imaging has been explored as an important alternative. We set out t o determine if anti-1-amino-3-anti-1-amino-3-[18F]-fluorocyclobutane-1-carboxylic acid ([18F]fluciclovine) positron emission tomography/computed tomography (PET/CT) changes reflect response to docetaxel chemotherapy in mCRPC. Results Seven patients with mCRPC were enrolled. Each patient was scheduled to have [18F]fluciclovine PET/CT at baseline, and after 1 and 6 cycles of chemotherapy. Uptake parameters were recorded in the prostate/bed and up to 10 metastatic lesions. Decrease in uptake of ≥30% was considered response (R); appearance of new lesions or >30% increase in uptake was progressive disease (PD); and change of < 30% uptake was stable disease (SD). Prostate specific antigen (PSA) was obtained at baseline and before each cycle. Bone scintigraphy and CT were acquired at baseline and after the 6th cycle. Assessment of response was based on Prostate Cancer Clinical Trial Working Group 3 recommendations. Correlation between [18F]fluciclovine uptake and time to PSA progression was also determined. All patients completed the 1 st and 2 nd [18F]fluciclovine PET/CT, while 4/7 patients completed all 3 scans. PET response correlated with PSA response in 3/7 (42.9%) patients and 3/4 (75%) patients after 1 and 6 cycles of docetaxel, respectively. Bone scan and CT correlated with PSA response in 1/4 (25%) patients. Mean SUVmax and SUVmean were significantly higher in patients with progressive disease versus non-progressive disease after 6 cycles of docetaxel (p

The goal of the present work is to present a novel methodology for the extraction of MBF, MFR and RFR along coronary arteries by means of multimodality image fusion of dynamic PET and CCTA images. FFR is the reference standard to identify flow-limiting lesions, but its invasiveness limits broad application. New noninvasive methodologies are warranted to stratify patients and guide treatment. A group of 16 low-risk CAD subjects who underwent both 13NH3 PET and CCTA were analyzed. Image fusion techniques were employed to align the studies and CCTA-derived anatomy used to identify coronaries trajectories. MBF was calculated by means of a 1-tissue compartmental model for the standard vascular territories and along patient-specific vessel paths from the base to the apex of the heart. Low-risk ranges for MBF. MFR and RFR for LAD, LCX and rPDA were computed for the entire cohort and separated by gender. Computed low-risk ranges were used to assess a prospective patient with suspected CAD. Our vessel-specific functional indexes and 3D displays offer promise to more closely replicate what is commonly performed during a catheterization session and have the potential of providing effective noninvasive tools for the identification of flow-limiting lesions and image-guided therapy.

Background Myeloma occurs disproportionately in African Americans, with disparities in outcomes potentially caused by access to care, cytogenetics, and immunity. A gap in knowledge of immune function dissimilarities between African Americans and whites exists. Data for other diseases suggest innate differences in immunity and inflammatory markers, with potential implications for therapeutic monoclonal antibodies reliant on secondary immune activation for activity. Methods Patients receiving daratumumab or elotuzumab, lenalidomide, and dexamethasone were retrospectively studied with a primary endpoint of response at 2 (daratumumab) or 4 months (elotuzumab). Secondary endpoints included stable disease or better at the same points, treatment duration, time to best response, and adverse events. Results Eighty patients were included; baseline characteristics were balanced with the exception of the stage at diagnosis, which was more advanced in African Americans. No statistically significant difference in response was seen: 37.9% in whites versus 11.8% in African Americans with daratumumab (P = .090) and 60% in whites versus 44% in African Americans with elotuzumab (P = .462). There were no differences in the duration of treatment, the time to best response, or adverse events. Common potential immune-related adverse events in both arms were fatigue (39%), back pain (30%), and infusion reactions (40%). Anemia was significantly associated with a response to daratumumab (P = .02); no patients without anemia responded at 2 months, whereas 34.4% of patients with anemia did. Conclusions No significant difference in response, duration of treatment, or time to response was seen by race, although a trend toward greater early response rates in whites was observed. In these cohorts, as in other analyses, African American patients tended to present with later stage disease.

OBJECTIVES This study examined the pattern of use and factors predicting prolonged prescription opioid medications among cancer patients following treatment with curative intent. MATERIALS AND METHODS Patients diagnosed with cancer over a 3-year period at a large urban safety-net hospital were included. Univariate and multivariate analyses was used to identify factors associated with continued opioid use. RESULTS Of the 199 patients included in the study, 38% continued to receive an opioid prescription well beyond the acute diagnosis and treatment phase. Mean age was 60.3 years, with a female preponderance (63%). Surgical resection only (31.6%) and the combination of surgery, chemotherapy, and radiation (19.7%) were the commonest treatment modalities. Pain-related comorbidities predating cancer diagnosis were reported in 53.3% of the patients, and about 33% were also on pain-modifying medications (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.92-6.77; Fisher exact test P

This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic localization. Abundant staining for both IL-6 and pSTAT3 was evident in tumor-rich regions of each specimen. IL-6 correlated with cytoplasmic pSTAT3 but not nuclear or total pSTAT3 in this cohort of OPSCC tumors, regardless of p16 status (r = 0.682, p

Patients often receive axillary ultrasound-biopsy (AUS-B) before clinical evaluation. One positive biopsy in the absence of palpable disease rarely indicates additional nodal involvement, but it eliminates patients from being managed by the American College of Surgeons Oncology Group Z0011 trial criteria. To determine which patients may benefit from AUS-B, we analyzed whether characteristics on AUS were associated with large-volume axillary disease and, thus, the need for axillary lymph node (LN) dissection. A retrospective review identified patients who met Z0011 criteria and underwent AUS. Clinicopathologic and ultrasound characteristics were compared between patients with ≤2 versus ≥3 positive LNs. Two hundred and seven patients with cT1-2N0 tumors underwent preoperative AUS and breast-conserving surgery. On multivariate analysis, three AUS combinations were associated with ≥3 positive LNs: cortical thickness (CT) > 4 mm + loss of fatty hilum + round shape (P = 0.0218), CT > 4 mm + loss of fatty hilum (P = 0.0211), and CT > 4 mm + round shape (P = 0.0155). Preoperative axillary LN biopsy in patients with a single abnormal LN characteristic on AUS may be unnecessary because a positive finding will eliminate management according to Z0011 criteria. Cortical thickness >4 mm combined with any other abnormal characteristic was associated with ≥3 positive LNs, supporting the performance of AUS-B in this population.

Background Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT. Methods This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg/day), pasireotide (600 μg twice daily), and SIRT (SIR-Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long-acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose-limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers-angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin-like growth factor binding protein 1, insulin-like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2-were assessed. The Norfolk Quality of Life-Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL). Results Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well-differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver-only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment-related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression-free survival and overall survival were 18.6 and 46.3 months, respectively. Conclusions The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. Cancer 2018;124:1992-2000. © 2018 American Cancer Society.

The incidence, survival, and propensity for nodal metastasis in early-stage gastric signet ring cell carcinoma have not been defined in the United States. These data are critical determinants for treatment allocation. Cases of gastric signet ring cell carcinoma were extracted from the national SEER database for the years 2004–2013. Age-standardized incidence was derived. Survival was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify predictors of nodal metastasis. Exclusion criteria included neoadjuvant radiotherapy and lack of histologic or nodal data. A total of 10,624 cases were initially identified. The analysis cohort included 506 cases with early T-stage N0M0 disease following exclusions. The incidence was 0.094 per 100,000 person-years. The 5-year survival rate was 82.8%. Tumor stage (p

Background: The impact of age-, gender-, and race-based differences on safety and efficacy in phase I clinical trials has not been well studied. Methods: We analyzed data from phase I clinical trials evaluating targeted biologic agents in patients with advanced solid malignancies. Race and gender distribution of enrolled patients was compared to the referral population demographics at the city, metro, and state levels. The association between age, gender, and race with type, frequency, and severity of treatment-emergent toxicities and clinical benefit was assessed using univariate and multivariable models. Results: Data from 117 eligible patients – Blacks/Caucasians/Others (27/85/5); male/female (66/51) – were obtained. Blacks were younger than Caucasian patients (median age of 56 vs. 62 years, p = 0.004). Nausea/vomiting was more frequent in female patients (43 vs. 24%, p = 0.03), while hematologic toxicity was more likely in Whites. While median time on treatment was comparable (113 vs. 91; p = 0.840), the median overall survival was significantly shorter for Blacks versus Caucasians (7.4 vs. 11.4 months; p = 0.0227). Black race (HR 2.11; 95% CI 1.24–3.60; p = 0.006) and older age (HR 1.03; 95% CI 1.00–1.06; p = 0.029) were associated with an increased risk of death. Conclusions: Age-, gender-, and race-based disparities were observed with specific toxicity and survival outcomes on phase I clinical trials of anticancer agents.

Objectives: The Cancer Genome Atlas (TCGA) reported a FAT1 mutation rate of 23% in head and neck squamous cell carcinoma (HNSCC), which was higher in human papilloma virus (HPV)-negative cancer. Wild-type FAT1 exhibits a tumor suppressor activity, and the majority of mutated FAT1 genes are inactivated by missense or truncation, leading to altered or terminated gene products. However, the roles of FAT1 mutants in HNSCC oncogenesis and progression remain poorly understood. Methods: We investigated the landscape of altered protein and gene expression associated with FAT1 mutation, which predicted clinical outcomes of 329 HNSCC patients. The relationships of FAT1 mutation with clinical information from HNSCC datasets of TCGA were tested using Chi-Square or Fisher's exact test. The association of FAT1 mutation with more than 200 proteins or phosphorylated sites detected by Reverse Phase Protein Arrays (RPPA) was revealed using Student's T-test. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan Meier method, Log-rank tests, and COX model. Hierarchical clustering classified HNSCC subgroups, and the underlying signaling pathways and regulatory networks were revealed by Ingenuity Pathway Analysis (IPA). Results: Clinically, the prevalence of FAT1 mutation was significantly associated with HPV(-), female, or older patients, and enriched in the oral cavity and larynx/hypopharynx primary tumor sites. FAT1 mutation was significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, CAVEOLIN1 and VEGFR2, while twelve proteins were upregulated in patients with wild type FAT1, including immune check point molecule PD1. Poorer OS or PFS was observed in patients with FAT1 mutation and/or altered HER3_pY1289, IRS1, CYCLINE2, RET_pY905, P16INK4A, CMYC, MTORpS2448, or CAVEOLIN. IPA revealed dominant ERBB/neuregulin pathways, and protein signature panels divulged the heterogeneity of patient subgroups and predicted PFS. Alteration of FAT1 appears to involve mostly HPV-unrelated HNSCC and may contribute to the resistance to EGFR-targeted therapy and immunotherapy. Summary: We revealed dozens of actionable proteins associated with FAT1 mutation, which provide important insight into possible prospective clinical investigation with therapeutic relevance. (Supported by grants from a pilot Winship Invests Grant of Emory University Winship Cancer Institute to GZC and NFS; and NIDCD/NIH intramural projects Z01-DC-00016, 73, 74 to ZC, and partially by the University of Illinois Cancer Center Biostatistics Shared Resource Core). Citation Format: Zhuo Georgia Chen, Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, Nabil F. Saba, Zhong Chen. Identification of proteins associated with FAT1 mutations which potentially contribute to oncogenesis and progression of head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 321.

Objectives Stereotactic body radiation therapy (SBRT) is now the standard of care in medically inoperable stage I NSCLC, yielding high rates of local control. It is unknown whether SBRT can be safely utilized in the locally advanced NSCLC setting. This multi-institution phase I study evaluated the safety of 44 Gy of conventionally fractionated thoracic radiation with concurrent chemotherapy plus dose-escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary end point of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost. Methods Inclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor 8 cm or smaller, and N1 or N2 lymph nodes 5 cm or smaller. Tumors were staged with positron emission tomography/computed tomography (CT), and four-dimensional CT simulation was used for radiation planning. The treatment schema was 44 Gy of thoracic radiation (2 Gy/d) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy had been delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved mediastinal lymph nodes. Consolidation chemotherapy was given at the discretion of the treating medical oncologist. Four SBRT boost dose cohorts were tested: cohort 1 (9 Gy × 2), cohort 2 (10 Gy × 5), cohort 3 (6 Gy × 5), and cohort 4 (7 Gy × 5). Patients were treated in cohorts of three patients, and the Bayesian escalation with overdose control method was used to determine the MTD of the SBRT boost. Dose-limiting toxicities (DLTs) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment. Results The study enrolled 19 patients from November 2012 to December 2016. There were four screen failures, and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). DLT developed in one patient in dose cohort 3 (n = 3) and in 2 patients in dose cohort 4 (n = 3). The calculated MTD was 6 Gy × 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients at this dose level. Thus, the calculated MTD was 6 Gy × 5; however, 10 Gy × 2 is thought to be a reasonable dose as well, given that no grade 5 toxicities occurred with that dose. Conclusions The MTD of a SBRT boost combined with 44 Gy of thoracic chemoradiation was 6 Gy × 5. A SBRT boost dose of 10 Gy × 2 could be considered safer, with no grade 3 or higher toxicities observed at this dose level during the follow-up period in this study.

Patient adherence with positive airway pressure (PAP) therapy is a significant clinical problem in obstructive sleep apnea treatment. Personality traits may be a factor for non-adherence. The aim of this study is to investigate the relationship between PAP therapy adherence and patient personality traits. Patients were screened and recruited during their visit to a sleep clinic. Baseline data were collected from each patient’s electronic chart. Behavioral inhibition system/behavioral activation system (BIS/BAS) scales, short measure of five-factor model personality traits (mini-IPIP), positive and negative affect score (PANAS), and appetitive motivation scores (AMS) tests were used to measure personality traits. Data from the PAP device were obtained following a minimum of an initial 30 days, with adherence defined as >4 h/night on 70% of nights. Univariate and multivariate logistic regression and Pearson correlation tests were used to analyze the data. A total of 400 patients were recruited. Three hundred twenty-one patients had all the data and were included in the study. Behavioral activation system–fun seeking (BAS-FS) and, to a certain extent, negative affect were significantly associated with adherence. Intellect/imagination was marginally significant. Additionally, older age (>65 years), profession, PAP type, side effects, efficiency, apnea–hypopnea index (AHI), and residual AHI showed significant associations with patient adherence with PAP therapy. Multivariate analysis revealed that BAS-FS was still a significant predictor of adherence even after adjusting for other covariates. BAS-FS, negative affect, and intellect/imagination are significant factors for adherence to PAP therapy in obstructive sleep apnea patients.

Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients’ responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non–small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1–targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses to PD-1–targeted therapies.

BACKGROUND To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with “reduced frequency” molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482–88. © 2017 American Cancer Society.

Tobacco exposure is an established risk factor for pancreatic cancer and chronic pancreatitis; however, its role in pancreatic insufficiency is not clear.This controlled, cross-sectional study examined smokers and nonsmokers with no history of pancreatic disease. Histories and validated inventories of alcohol and tobacco use were obtained, and pancreatic insufficiency was assessed using the fecal elastase-1 assay.Of 7854 patients approached, 226 were interviewed and 200 enrolled. The rates of pancreatic insufficiency [18% (18/100)] and severe pancreatic insufficiency [10% (10/100)] were significantly higher in smokers than in controls [6% (6/100), P = 0.009 and 1% (1/100), P = 0.010, respectively]. On multivariate logistic regression, the risk of pancreatic insufficiency in smokers was significantly increased [odds ratio, 4.34 (1.37-13.75); P = 0.012], controlling for alcohol use and relevant covariates. Tobacco exposure was associated with the highest odds ratio for pancreatic insufficiency. Alcohol consumption was strongly associated with tobacco exposure (P0.001), but not with pancreatic insufficiency by multivariate analysis (P = 0.792).This study suggests that tobacco exposure is independently associated with pancreatic exocrine insufficiency in patients without a prior diagnosis of pancreatic disease. Tobacco exposure seems to have greater detrimental effects on pancreatic function than alcohol in this population.

Survival rates for children with Down syndrome (DS) and acute myeloid leukemia (AML) are high; however, little is known regarding the health-related quality of life (HR-QOL) of these survivors. Individuals who survived ≥5 years following diagnosis of childhood AML were invited to complete parent or patient-report surveys measuring HR-QOL and chronic health conditions. In total, 26 individuals with DS had a median age at diagnosis of 1.8 years (range, 0.77 to 10.9 y) and median age at interview of 15 years (range, 8.3 to 27.6 y). Participants with DS and AML were compared with AML survivors without DS whose caregiver completed a HR-QOL survey (CHQ-PF50). In total, 77% of survivors with DS reported ≥1 chronic health condition compared with 50% of AML survivors without DS (P=0.07). Mean physical and psychosocial QOL scores for children with DS and AML were statistically lower than the population mean, though not discrepant from AML survivors without DS. Although the overall prevalence of chronic health conditions in survivors with DS is higher than in survivors without DS, prior studies of children with DS have reported similarly high rates of chronic health conditions, suggesting that AML therapy may not substantially increase this risk.

We explored the influence of FACBC (fluciclovine) PET/CT on the decision to offer radiotherapy and radiotherapy treatment field recommendations in postprostatectomy patients with recurrent prostate cancer.After obtaining institutional review board approval and informed consent, 87 patients with detectable prostate-specific antigen (PSA) levels were recruited into a prospective clinical trial. After an initial provider-determined radiotherapy plan based on conventional imaging, 44 of 87 patients were randomized to additionally undergo fluciclovine PET/CT. Pre- and post-fluciclovine radiotherapy decisions were compared and changes were noted. Statistical significance of these decision changes was determined.Two of 44 patients in the experimental arm dropped out before fluciclovine scanning. Thirty-four (81.0%) of 42 had positive results on fluciclovine. Overall radiotherapy decision was changed in 17 (40.5%) of 42. Mean PSA, original Gleason score, and prostatectomy-PET interval did not differ significantly between patients with and without radiotherapy decision changes. Two (4.8%) of 42 had the decision for radiotherapy withdrawn due to positive extrapelvic findings. Radiotherapy field decision was changed in 15 (35.7%) of 42. Eleven (73.3%) of 15 had fields changed from prostate bed only to both prostate bed and pelvis, while 4 (26.7%) of 15 had fields changed from both prostate bed and pelvis to prostate bed only. Changes in overall radiotherapy decision and field were statistically significant (P0.0001). However, the change in the decision to offer radiotherapy or not was not statistically significant (P = 0.15).Fluciclovine PET/CT significantly changed radiotherapy management decisions in postprostatectomy patients with recurrent prostate cancer. Further work in determining differences in PSA-free survival is ongoing.

To evaluate the comparative outcome and cost of vascular plugs versus coils for internal iliac artery embolization prior to endovascular aortic aneurysm repair. A search was performed for internal iliac artery embolization studies in adult patients from January 2005 to July 2018. Inclusion criteria included embolization of unilateral or bilateral IIAs with either coils or plug(s) prior to endovascular aortic repair. Meta-analysis was performed using a fixed effects model with the inverse variance-weighted average method to determine pooled differences in surgical time, fluoroscopy time, radiation exposure, number of devices used, cost of devices, and post-embolization buttock claudication. Heterogeneity was assessed using the Chi-square statistic. Pooled outcomes were compared, and quality assessments were evaluated using the Newcastle–Ottawa scale. Six studies met inclusion criteria. One hundred and eighty-one patients were included in the study, of which 87 were in the plug group and 94 in the coil group. Vascular plug use led to 35.32 min shorter surgery time (p

Background High epicardial adipose tissue (EAT) attenuation (Hounsfield units [ HUs] ) on computed tomography is considered a marker of inflammation and is associated with an increased risk of cardiovascular events. Statins reduce the volume of EAT , but it is unknown whether they affect EAT HUs . Methods and Results We reviewed the chest computed tomographic scans of 420 postmenopausal women randomized to either 80 mg of atorvastatin or 40 mg of pravastatin daily and rescanned after 1 year to measure change in coronary artery calcium score. EAT HUs were measured near the proximal right coronary artery and remote from any area of coronary artery calcium. Computed tomographic images were also queried for subcutaneous adipose tissue (SubQ) attenuation ( HUs ) change over time. The mean patients’ age was 65±6 years. The baseline EAT HU value was higher than the SubQ HU value (−89.4±24.0 HU versus −123.3±30.4 HU ; P EAT HU value decreased significantly in the entire cohort (−5.4±29.7 HU [−6% change]; P HU and −4.55+28 HU ; P =0.55). EAT HU change was not associated with change in total cholesterol, low‐density lipoprotein cholesterol, coronary artery calcium, and EAT volume (all P =not significant). Change in high‐density lipoprotein cholesterol was marginally associated with EAT HU change ( P =0.07). Statin treatment did not induce a change in SubQ HUs . Conclusions Statins induced a decrease in EAT HUs over time, independent of intensity of low‐density lipoprotein cholesterol lowering. The positive effect on EAT and the neutral effect on SubQ suggest that statins induced a decrease in metabolic activity in EAT by reduction in cellularity, vascularity, or inflammation. The clinical significance of the observed change in EAT HUs remains to be demonstrated.

Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation.Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used.Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively.The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

BackgroundImmune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.MethodsPatients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.ResultsEighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.ConclusionsThe D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration numberNCT02701400.

Purpose A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

Background Standard adjuvant treatment for pancreatic adenocarcinoma (PDAC) is gemcitabine [Gem(CONKO-001: Gem vs. placebo DFS:13.4 vs. 6.7 mo; P

BACKGROUND Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

The purpose of this study was to examine structured template use among emergency radiologists, and if this influences audio dictation time, radiology report length, or total radiologist study time. Retrospective data collection of consecutive occurrences of seven common imaging examinations interpreted by a dedicated emergency radiology division over a 2-month period yielded 3449 reports. Templates had been in place for >3 years. For each examination, we documented the individual audio dictation time (ADT), total words, and total time the radiologist spent on a study from report creation until final signing. In 81.2 % (n = 2772) of all cases, a basic template was used. In 2.8 % (n = 78) of these template-use cases, the radiologist removed key elements from the structured template. Of the 3417 reports with complete data, mean ADT was 37.3 s, mean word length was 132.3 (of which, on average, 64 were dictated), and total radiologist time per study (TRT) was 349.7 s. Study type was significantly associated with ADT, total words, and TRT (p

// Zhongliang Hu 1, 2, * , Guoqing Qian 1, * , Susan Muller 3 , Jing Xu 4 , Nabil F. Saba 1 , Sungjin Kim 5 , Zhengjia Chen 5, 6 , Ning Jiang 1 , Dongsheng Wang 1 , Hongzheng Zhang 1 , Kristin Lane 7 , Clifford Hoyt 7 , Dong M. Shin 1 , Zhuo Georgia Chen 1 1 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA 2 Department of Pathology, Xiangya Hospital, Department of Pathology, Xiangya Medical School, Central South University, Changsha, Hunan, China 3 Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA 4 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China 5 Biostatistics and Bioinformatics Shared Resource at Winship Cancer Institute, Emory University, Atlanta, GA, USA 6 Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA, USA 7 Caliper/Perkin Elmer Life Sciences and Technology, Hopkinton, MA, USA * These authors are contributed equally to this work Correspondence to: Zhuo Georgia Chen, email: gzchen@emory.edu Keywords: multiplexed quantum dot, head and neck squamous cell carcinoma, EGFR, E-cadherin Received: September 18, 2015 Accepted: April 22, 2016 Published: May 09, 2016 ABSTRACT Purpose: To predict lymph node metastasis and prognosis in head and neck squamous cell carcinoma (HNSCC). Results: The combination of membranous E-cadherin and membranous epidermal growth factor receptor (EGFR) quantified by QD technology with age, gender, and grade had greater predictive power than any of the single biomarkers or the two combined biomarkers quantified by conventional immunohistochemistry (IHC). The predictive power of this model was validated in another independent sample set; the predictive sensitivity of this model for LNM was 87.5%, with specificity up to 97.4%, and accuracy 92.9%. Furthermore, a higher membranous E-cadherin level was significantly correlated with better overall and disease-free survival (OS, DFS; P = 0.002, 0.033, respectively), while lower cytoplasmic vimentin and membranous EGFR levels were significantly correlated with better OS ( P = 0.016 and 0.021, respectively). The combined biomarkers showed a stronger prognostic value for OS and DFS than any of the single biomarkers. Methods: Multiplexed quantum dots (QDs) were used to simultaneously label E-cadherin, vimentin, and EGFR with β-actin as an internal control. Primary tissue samples from 97 HNSCC patients, 49 with and 48 without LNM were included in the training set. Levels of membranous E-cadherin, cytoplasmic vimentin, and membranous EGFR were quantified by InForm software and correlated with clinical characteristics. Conclusions: Multiplexed subcellular QD quantification of EGFR and E-cadherin is a potential strategy for the prediction of LNM, DFS, and OS of HNSCC patients.

BACKGROUND In considering treatment allocation for patients with early esophageal adenocarcinoma, the incidence of lymph node metastasis is a critical determinant; however, this has not been well defined or stratified by the relevant clinical predictors of lymph node spread. METHODS Data from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute were abstracted from 2004 to 2010 for patients with early-stage esophageal adenocarcinoma. The incidence of lymph node involvement for patients with Tis, T1a, and T1b tumors was examined and was stratified by predictors of spread. RESULTS A total of 13,996 patients with esophageal adenocarcinoma were evaluated. Excluding those with advanced, metastatic, and/or invasive (T2-T4) disease, 715 patients with Tis, T1a, and T1b tumors were included. On multivariate analysis, tumor grade (odds ratio [OR], 2.76; 95% confidence interval [95% CI], 1.58-4.82 [P

In the general population and in hemodialysis patients epicardial adipose tissue (EAT) has been associated with increased mortality and cardiovascular events. Weight loss and lipid lowering therapies reduced EAT in the general population. It is unknown whether sevelamer, a phosphate (Pi) binder that lowers cholesterol and reduces inflammation in dialysis patients also affects EAT progression. Post-hoc analysis of a randomized trial of sevelamer (SVL) versus calcium-based Pi binders (CPiB) in incident hemodialysis patients. EAT was measured on cardiac computed tomography scans performed at enrollment, 6, 12 and 18 months from baseline. Of 109 patients, 54 received SVL and 55 CPiB; the median LDL change was −16.4 % (IQR: −67.5, 142.3 %) and 12.1 % (IQR: −51.9, 193.8 %) with SVL and CPiB respectively (p