Factors Associated with Total Laryngectomy Utilization in Patients with cT4a Laryngeal Cancer.

BACKGROUND: Despite recommendations for upfront total laryngectomy (TL), many patients with cT4a laryngeal cancer (LC) instead undergo definitive chemoradiation, which is associated with inferior survival. Sociodemographic and oncologic characteristics associated with TL utilization in this population are understudied. METHODS: This retrospective cohort study utilized hospital registry data from the National Cancer Database to analyze patients diagnosed with cT4a LC from 2004 to 2017. Patients were stratified by receipt of TL, and patient and facility characteristics were compared between the two groups. Logistic regression analyses and Cox proportional hazards methodology were performed to determine variables associated with receipt of TL and with overall survival (OS), respectively. OS was estimated using the Kaplan-Meier method and compared between treatment groups using log-rank testing. TL usage over time was assessed. RESULTS: There were 11,149 patients identified. TL utilization increased from 36% in 2004 to 55% in 2017. Treatment at an academic/research program (OR 3.06) or integrated network cancer program (OR 1.50), male sex (OR 1.19), and Medicaid insurance (OR 1.31) were associated with increased likelihood of undergoing TL on multivariate analysis (MVA), whereas age > 61 (OR 0.81), Charlson-Deyo comorbidity score ≥ 3 (OR 0.74), and clinically positive regional nodes (OR 0.78 [cN1], OR 0.67 [cN2], OR 0.21 [cN3]) were associated with decreased likelihood. Those undergoing TL with post-operative radiotherapy (+/- chemotherapy) had better survival than those receiving chemoradiation (median OS 121 vs. 97 months; p = 0.003), and TL + PORT was associated with lower risk of death compared to chemoradiation on MVA (HR 0.72; p = 0.024). CONCLUSIONS: Usage of TL for cT4a LC is increasing over time but remains below 60%. Patients seeking care at academic/research centers are significantly more likely to undergo TL, highlighting the importance of decreasing barriers to accessing these centers. Increased focus should be placed on understanding and addressing the additional patient-, physician-, and system-level factors that lead to decreased utilization of surgery.

Disparities in Survival Outcomes among Racial/Ethnic Minorities with Head and Neck Squamous Cell Cancer in the United States.

BACKGROUND: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood. PATIENTS AND METHODS: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000-2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan-Meier product limit estimates and the log-rank test to evaluate the differences between strata. RESULTS: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03-1.15, p = 0.002). CONCLUSIONS: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors.

Disparities in survival outcomes among Black patients with HPV-associated oropharyngeal cancer.

Patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) have a favorable prognosis and excellent overall survival (OS), and studies have demonstrated these findings in cohorts of predominantly White patients. Racial/ethnic (R/E) minorities, particularly Black patients, with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared with White patients. In this study, we aimed to determine if Black patients with HPV-OPSCC have a similar favorable prognosis to the White population. This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database from 2010 to 2016. We identified patients with Stage I-IV HPV- OPSCC who were treated with radiation, surgery, chemotherapy, or a combination of modalities. Patient outcomes were stratified by R/E groups including White Versus Black patients. The main outcome in this study was OS. Analyses for proportions of categorical variables were performed using a χ2  or Fisher's exact test. Univariate and multivariate time-to-event survival analyses were performed using Kaplan-Meier product limit estimates and log-rank test to test the differences between strata. A Cox proportional hazards regression model was used to assess the association between covariates and risk of death (OS). We identified 9256 OPSCC patients who met inclusion criteria and were treated between 2010 and 2016, of which 7912 were White (85.5%) and 1344 were Black (14.5%). A total of 1727 were HPV-OPSCC, of which 1598 were White (92.5%) and 129 (7.5%) were Black. By race, the 5-year OS for White versus Black OPSCC patients was 42% versus 23%, respectively (log-rank, p < 0.0001). Among HPV-positive OPSCC patients, the 5-year OS for White versus Black patients was 65% versus 39% (log-rank, p < 0.0001). Among HPV-negative patients, the 5-year OS for White versus Black patients was 36% versus 13% (log-rank, p < 0.0001). On multivariate analysis, after accounting for age, sex, insurance status, income, Charlson-Deyo score, receipt of surgery, distance from facility, and total treatment time, Black race trended toward, but was not associated with worse survival. Hazard ratio (HR:1.24, 95% confidence interval [CI] 0.85-1.81, p = 0.255). This national cohort study of OPSCC patients demonstrates that Black patients with HPV-OPSCC have a poor prognosis and OS similar to HPV-negative White patients. This may be partly due to socioeconomic barriers such as insurance and income. Further work is needed to better understand the specific drivers of inferior survival outcomes in this specific patient population.

List Prices for Proton Radiation Therapy.

PURPOSE: Some patients elect for self-pay proton radiation therapy (PT) in the United States, but price transparency is a significant concern. The U.S. government recently declared that hospitals must provide a comprehensive list of "standard" charges for all services. Yet, the proportion of compliant proton centers is unknown, as is the extent to which prices vary nationally. METHODS AND MATERIALS: We obtained online chargemasters from U.S. proton centers. Technical charges for per fraction delivery of PT of varying complexity were obtained by billing code (77520, 77522, 77523, 77525) and keyword searches. Prices were adjusted for cost-of-living differences using the Medicare geographic cost price index. The relationship between prices for each PT billing code and cost of living was assessed. The interrelationship in cost between codes was examined. The effect of geographic region and other key variables on pricing was explored. RESULTS: Thirty-six proton centers were identified. Twenty-eight (78%) had accessible chargemasters with 20 (56%) listing at least one PT charge. The median prices for billing codes 77520, 77522, 77523, 77525 were $4707, $4712, $5904, and $6690, respectively, with a trend toward greater cost for more complex therapy (77523, 77525; P = .056). Large ranges ($16,863, $16,059, $18,414, $22,143) resulted in ratios of maximum/minimum prices of 5 to 10x. Only prices for code 77522 were associated with cost of living (P = .039). Across institutions, prices for all 4 codes were positively interrelated (all P < .0001). Prices differed between regions (P < .0001) but not by National Cancer Institute designation. CONCLUSIONS: List prices for PT differ dramatically between institutions and regions without obvious explanation, raising the concerning possibility that such variation is largely arbitrary. Policy solutions that promote rationalized pricing would greatly benefit this patient population.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

INTRODUCTION: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. METHODS AND MATERIALS: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. RESULTS: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. CONCLUSIONS: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. METHODS AND MATERIALS: From 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs). RESULTS: The 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting. CONCLUSION: In contemporary chest RT-based clinical trials, reported CVD rates were lower than expected population rates.

Cost Comparison From a Patient Perspective for Intracranial Stereotactic Radiation Therapy.

PURPOSE: Historically, opaque health care pricing in the US has prevented patients from identifying opportunities to lower costs. Attempting to promote price transparency, the US government recently mandated that hospitals publish prices for all services in a document called a chargemaster. Patients often travel to tertiary centers for intracranial stereotactic radiation therapy (SRT), but cost comparison is complicated by multiple delivery systems and fractionation schemes. We hypothesized that prices published in chargemasters vary widely between SRT techniques and institutions. METHODS AND MATERIALS: We obtained chargemasters published online by National Cancer Institute-designated clinical centers. Technical charges for Gamma Knife single-fraction stereotactic radiosurgery (GK), single-fraction linear-accelerator stereotactic radiation surgery (SRS), and 3-fraction fractionated stereotactic radiation therapy (FSRT) were obtained from chargemasters by billing code and keyword searches. Prices were adjusted by the Medicare geographic cost price index (GPCI). Pairwise comparisons were conducted to compare prices between modalities and geographic regions. Relationships with cost index were examined using Spearman correlations, as was the price interrelationship between modalities across institutions. RESULTS: Of 62 chargemasters obtained, 58 listed SRT prices. Median prices were $49,529 for GK, $31,834 for FSRT, and $22,915 for SRS. Prices varied widely, with large ranges corresponding to 2 to 9 times the magnitude of median prices (GK, $111,298; FSRT, $312,480; and SRS, $104,396). Adjusting for GPCI, GK (P = .0003) and FSRT (P = .001) were more expensive than SRS, and no difference in price was noted between regions. The FSRT price was positively correlated with GPCI (P = .033), but prices for the other techniques were not. Modality prices were all positively correlated (all P < .001), meaning that institutions with prices greater than the median price for SRS were similarly expensive for GK and FSRT. CONCLUSIONS: Published prices for SRT vary by delivery system, fractionation, and institution without a clear explanation. Obtaining personalized price estimates may offer cost savings for patients. Policy changes encouraging reliable access to insurer-negotiated cost estimates for SRT are needed.

Characterization of Esophageal and Sphincter Reflexes across Maturation in Dysphagic Infants with Oral Feeding Success vs Infants requiring Gastrostomy.

To test the hypothesis that esophageal and sphincteric sensory-motor reflexes are distinct across maturation in infants with dysphagia receiving gastrostomy-tube (G-tube). This is a retrospective review of 29 dysphagic infants (N = 15 study requiring gastrostomy, N = 14 age matched control achieving oral feeds) that underwent longitudinal pharyngeal-esophageal manometry at 42.3 (37-50.2) weeks postmenstrual age (PMA) and 48.9 (43.3-57.9) weeks PMA. Graded stimuli (0.1-5 mL) of varying media (air, water, and apple juice) tested esophageal peristaltic reflex, upper esophageal sphincter contractile reflex (UESCR), and lower esophageal sphincter relaxation reflex (LESRR). Comparisons were performed between study and controls and across maturation (time-1 vs time-2). Data represented as mean ± SE or OR (95% CI). Across maturation (time-1 vs time-2): Study infants did not exhibit significant differences across in peristaltic, UES, or LES reflexes (all p > 0.05). In contrast, controls exhibited increased UES resting pressure (13 ± 3 vs 17 ± 3 mmHg, p = 0.001), LES resting pressure (22 ± 3 vs 25 ± 3 mmHg, p < 0.009), LES nadir pressure (0.5 ± 1 vs 4.3 ± 1 mmHg, p = 0.001), and esophago-deglutition responses [2.5 (1.23-4.88), p = 0.04], and decreased secondary peristalsis [0.44 (0.31-0.61), p = 0.001], UESCR [0.4 (0.25-0.65), p = 0.001], LESRR [0.4 (0.24-0.75), p = 0.01], and symptoms [0.6 (0.45-0.83), p = 0.005]. Among infants with dysphagia, esophageal provocation induced peristaltic reflex, UESCR, and LESRR advance with longitudinal maturation when infants are oral-fed successfully, but not in those who received gastrostomy. Underlying mechanisms may be related to esophageal sensitivity, afferent or efferent transmission, and coordination of upstream excitation and downstream inhibition, which can be potential therapeutic targets for improving feeding capabilities after gastrostomy placement in infants with dysphagia.

Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown. METHODS: From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS). RESULTS: Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies. CONCLUSIONS: Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.

Antibody Conjugation of Fluorescent Nanodiamonds for Targeted Innate Immune Cell Activation.

BACKGROUND: fluorescent nanodiamonds (FND) are nontoxic, infinitely photostable nanoparticles that emit near-infrared fluorescence and have a modifiable surface allowing for the generation of protein-FND conjugates. FND-mediated immune cell targeting may serve as a strategy to visualize immune cells and promote immune cell activation. METHODS: uncoated-FND (uFND) were fabricated, coated with glycidol (gFND), and conjugated with immunoglobulin G (IgG-gFND). In vitro studies were performed using a breast cancer/natural killer/monocyte co-culture system, and in vivo studies were performed using a breast cancer mouse model. RESULTS: in vitro studies demonstrated the targeted immune cell uptake of IgG-gFND, resulting in significant immune cell activation and no compromise in immune cell viability. IgG-gFND remained at the tumor site following intratumoral injection compared to uFND which migrated to the liver and kidneys. CONCLUSION: antibody-conjugated FND may serve as immune drug delivery vehicles with "track and trace capabilities" to promote directed antitumor activity and minimize systemic toxicities.

Postoperative Stereotactic Body Radiotherapy for Spinal Metastasis and Predictors of Local Control.

BACKGROUND: Spine surgery is indicated for select patients with mechanical instability, pain, and/or malignant epidural spinal cord compression, with or without neurological compromise. Stereotactic body radiotherapy (SBRT) is an option for durable local control (LC) for metastatic spine disease. OBJECTIVE: To determine factors associated with LC and progression-free survival (PFS) for patients receiving postoperative stereotactic spine radiosurgery. METHODS: We analyzed consecutive patients from 2013 to 2019 treated with surgical intervention followed by SBRT. Surgical interventions included laminectomy and vertebrectomy. SBRT included patients treated with 1 to 5 fractions of radiosurgery. We analyzed LC, PFS, overall survival (OS), and toxicity. Univariate and multivariate analyses were performed. RESULTS: A total of 63 patients were treated with a median follow-up of 12.5 mo. Approximately 75% of patients underwent vertebrectomy and 25% underwent laminectomy. One-year cumulative incidence of local failure was 19%. LC was significantly improved for patients receiving radiosurgery ≤40 d from surgery compared to that for patients receiving radiosurgery ≥40 d from surgery, 94% vs 75%, respectively, at 1 yr (P = .03). Patients who received preoperative embolization had improved LC with 1-yr LC of 88% vs 76% for those who did not receive preoperative embolization (P = .037). Significant predictors for LC on multivariate analysis were time from surgery to radiosurgery, higher radiotherapy dose, and preoperative embolization. The 1-yr PFS and OS was 56% and 60%, respectively. CONCLUSION: Postoperative radiosurgery has excellent and durable LC for spine metastasis. An important consideration when planning postoperative radiosurgery is minimizing delay from surgery to radiosurgery. Preoperative embolization and higher radiotherapy dose were associated with improved LC warranting further study.

Bone grafting history affects soft tissue healing following implant placement.

BACKGROUND: This study aimed to determine and compare soft tissue healing outcomes following implant placement in grafted (GG) and non-grafted bone (NGG). METHODS: Patients receiving single implant in a tooth-bound maxillary non-molar site were recruited. Clinical healing was documented. Volume and content of wound fluid (WF; at 3, 6, and 9 days) were compared with adjacent gingival crevicular fluid (GCF; at baseline, 1, and 4 months). Buccal flap blood perfusion recovery and changes in bone thickness were recorded. Linear mixed model regression analysis and generalized estimating equations with Bonferroni adjustments were conducted for repeated measures. RESULTS: Twenty-five patients (49 ± 4 years; 13 males; nine NGG) completed the study. Soft tissue closure was slower in GG (P < 0.01). Differential response in WF/GCF protein concentrations was detected for ACTH (increased in GG only) and insulin, leptin, osteocalcin (decreased in NGG only) at day 6 (P ≤0.04), with no inter-group differences at any time(P > 0.05). Blood perfusion rate decreased immediately postoperatively (P < 0.01, GG) followed by 3-day hyperemia (P > 0.05 both groups). The recovery to baseline values was almost complete for NGG whereas GG stayed ischemic even at 4 months (P = 0.05). Buccal bone thickness changes were significant in GG sites (P ≤ 0.05). CONCLUSION: History of bone grafting alters the clinical, physiological, and molecular healing response of overlying soft tissues after implant placement surgery.

Neoadjuvant-modified FOLFIRINOX vs nab-paclitaxel plus gemcitabine for borderline resectable or locally advanced pancreatic cancer patients who achieved surgical resection.

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G.

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

BACKGROUND: Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown. OBJECTIVES: The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials. METHODS: From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed. RESULTS: Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22). CONCLUSIONS: Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Wound Fluid Cytokine Profile Following Bone Regeneration Procedures.

Clinical parameters available to evaluate early healing phases of bone regeneration procedures are limited. This study explores wound fluid (WF) content for molecular markers to differentiate wound healing responses in the early postoperative period after bone graft placement. Fifteen patients (50 ± 5 years old; 8 men) scheduled to receive tooth extraction and bone graft placement at maxillary nonmolar single-tooth sites were recruited. Primary wound closure was not intended at time of surgery. Gingival crevicular fluid from adjacent teeth or WF from surgical wound edges were collected (30 seconds) at baseline, at 3, 6, and 9 days, and at 1 and 4 months. Multiplex protein assay was used to determine concentration of various wound healing mediators. Immediately after surgery, 87% of surgical sites exhibited open wound. At day 9, mean wound exposure was 4.8 ± 0.4 mm. At 1 month, all wounds were clinically closed. The WF tripled in volume at day 3 and day 6 (P ≤ .05), compared with baseline gingival crevicular fluid, and gradually decreased as wounds closed. The WF concentrations of interleukin (IL)-6, placental growth factor, plasminogen activator inhibitor 1, insulin-like growth factor binding protein 1, and soluble cluster determinant 40 ligand were increased during early healing days, generally with peak concentration at day 6 (P ≤ .004). Conversely, WF concentrations of IL-18 and epidermal growth factor were decreased after surgery, generally not reaching baseline values until wound closure (P ≤ .008). In general, WF cytokine expression kinetics were concordant with wound closure dynamics (P ≤ .04). These results suggest that WF molecular markers such as IL-6, and to a lesser extent placental growth factor and IL-18, might help differentiate wound healing responses after bone regeneration procedures.

Usefulness of Integrating Heart Failure Risk Factors Into Impairment of Global Longitudinal Strain to Predict Anthracycline-Related Cardiac Dysfunction.

The prediction of cancer therapeutics-related cardiac dysfunction (CTRCD) is an essential aspect of care for individuals who receive potentially cardiotoxic oncologic treatments. Certain clinical risk factors have been described for incident CTRCD, and measurement of left ventricular (LV) longitudinal strain by speckle tracking 2-dimensional echocardiography (2DE) is the best-validated myocardial mechanical imaging assessment to detect subtle changes in LV function during cancer treatment. However, the direct integration of clinical and imaging risk factors to predict CTRCD has not yet been extensively examined. This was a retrospective study of 183 women with breast cancer aged 50.9 ± 10.8 years who received treatment with anthracyclines (doxorubicin dose of 422 ± 69 mg/m2, with 41.2% of subjects also receiving trastuzumab) and underwent 2DE at clinically determined intervals. CTRCD was diagnosed when LV ejection fraction dropped ≥10% to a subnormal (<53%) value by 2DE. Left ventricular global longitudinal strain (LV-GLS) was assessed offline. The risk prediction tool based only on clinical factors previously described by Ezaz et al was applied to our cohort and accurately stratified these subjects into low-, intermediate-, and high-risk groups, with incident CTRCD in 7.4%, 26.9%, and 54.6%, respectively (chi-square = 20.7, p <0.0001). We developed novel multivariate models to predict CTRCD using (1) demographic variables only (c = 0.8674), (2) echocardiographic (peak LV-GLS) variables only (c = 0.8440), or (3) a combination of demographic and echocardiographic variables, with the combined model exhibiting superior receiver-operating characteristics (c = 0.9629). In conclusion, estimation of CTRCD risk should integrate all available data, including both clinical variables and an imaging assessment.

Gingival Perfusion and Tissue Biomarkers During Early Healing of Postextraction Regenerative Procedures: A Prospective Case Series.

BACKGROUND: Postextraction alveolar bone loss, mostly affecting the buccal plate, occurs despite regenerative procedures. To better understand possible determinants, this prospective case series assesses gingival blood perfusion and tissue molecular responses in relation to postextraction regenerative outcomes. METHODS: Adults scheduled to receive bone grafting in maxillary, non-molar, single-tooth extraction sites were recruited. Clinical documentation included the following: 1) probing depth (PD); 2) keratinized tissue width (KT); 3) tissue biotype (TB); and 4) plaque level. Wound closure was clinically evaluated. Gingival blood perfusion was measured by laser Doppler flowmetry (LDF). Wound fluid (WF) and gingival biopsies were analyzed for protein levels and gene expression, respectively, of relevant molecular markers. Bone healing outcomes were determined radiographically (cone-beam computed tomography). Healing was followed for 4 months. RESULTS: Data from 15 patients are reported. Postoperatively, neither complications nor changes in PD, KT, or TB were observed. LDF revealed decreased perfusion followed by hyperemia that persisted for 1 month (P ≤0.05). WF levels of angiopoietin-2, interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor peaked on day 6 (P ≤0.05) and decreased thereafter. Only IL-8 and TNF-α exhibited increased gene expression. Linear bone changes were negligible. Volumetric bone changes were minimal but statistically significant, with more bone loss when membrane was used (P = 0.05). CONCLUSIONS: Gingival blood perfusion after postextraction bone regenerative procedures follows an ischemia-reperfusion model. Transient increases in angiogenic factor levels and prolonged hyperemia characterize the soft tissue response. These soft tissue responses do not determine radiographic bone changes.

Impact of the Addition of Digital Breast Tomosynthesis (DBT) to Standard 2D Digital Screening Mammography on the Rates of Patient Recall, Cancer Detection, and Recommendations for Short-term Follow-up.

RATIONALE AND OBJECTIVES: The addition of digital breast tomosynthesis (DBT) to digital screening mammography (DM) has been shown to decrease recall rates and improve cancer detection rates, but there is a lack of data regarding the impact of DBT on rates of short-term follow-up. We assessed possible changes in performance measures with the introduction of DBT at our facility. MATERIALS AND METHODS: In our observational study, databases were used to compare rates of recall, short-term follow-up, biopsy, and cancer detection between women undergoing DM without (n = 10,477) and women undergoing DM with (n = 2304) the addition of DBT. Regression analysis was performed to determine associations with patient age, breast density, and availability of comparison examinations. RESULTS: The addition of DBT resulted in significantly lower recall rates (16%-14%, P = .017), higher rates of biopsy (12.7%-19.1%, P < .01), and increased detection of ductal carcinoma in situ, with a difference of 2.3 cases per 1000 screens (P = .044). A 33% increase in cancer detection rates was observed with DBT, which did not reach statistical significance. Short-term follow-up of probably benign findings was 80% higher in the DBT group (odds ratio = 1.80, 95% confidence interval = 1.38-2.36, P < .001). CONCLUSIONS: To our knowledge, we are the first to study the impact of DBT on rates of short-term follow-up, and observed an 80% increase over the DM group. Further research is needed to determine the malignancy rate of Breast Imaging Reporting and Data System 3 lesions detected with DBT, and establish appropriate follow-up to maximize cancer detection while minimizing expense and patient anxiety.

The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma.

The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-α alone had little effect on cell viability in vitro. However, the combination of ixazomib with IFN-α significantly enhanced ixazomib's ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-α also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-α-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-α-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-α for the treatment of advanced BRAF V600E mutant melanoma.

The Effect of Platform Switching on Periimplant Crevicular Fluid Content During Early Wound Healing.

PURPOSE: The objective of this study was to investigate the soft tissue response and periimplant crevicular fluid (PICF) content around platform-switched (PS) and platform-matched (PM) implants during early healing. MATERIALS AND METHODS: Nonsmokers treatment planned to receive a single implant in 2 quadrants were recruited. Two-stage implant placement protocol with 1 PM and 1 PS implant was implemented. Periimplant probing depths (PDs), modified sulcus bleeding index, and plaque indices were recorded, and PICF was collected at 1, 2, 4, and 6 weeks after abutment connection. RESULTS: PD readings were higher at week 1 than at week 6 for both groups (P = 0.0005). PD was statistically deeper in PM than in PS at week 1 (P = 0.03). There was a time-dependent decrease in total PICF volume for both groups. This decrease was statistically significant for PS (P = 0.0005), with no differences between the 2 groups at any time (P > 0.05). The decrease observed in both PM and PS for PICF interleukin 6 and macrophage inflammatory protein-1ß, and in PS for tumor necrosis factor-α (TNF-α) was statistically significant (P ≤ 0.03). TNF-α was statistically higher in PS than in PM at week 1 (P = 0.005). CONCLUSION: Within the limits of this study, it seems that periimplant soft tissue response around PM and PS implants is mostly similar during the early healing period.