Advancements in biologic therapy in eosinophilic asthma.

INTRODUCTION: Asthma encompasses a spectrum of phenotypes often categorized into two groups- type 2 high (T2 high) and type 2 low (T2 low). T2 high includes atopic and eosinophilic presentations whereas T2 low is non-atopic, non-eosinophilic, and oft associated with neutrophilic inflammation. Eosinophilic asthma is often driven by IgE, IL-4, IL-5, and IL-13 and TSLP. This can lead to eosinophilic inflammatory response in the airways which in turn can be used as target for treatment. AREAS COVERED: The article will focus on biologic therapy that is currently being used in eosinophilic asthma management in mainly the adult population including clinical trials and co-morbidities that can be treated using the same biologics. A review on asthma biologics for pediatric population has been reviewed elsewhere. EXPERT OPINION: Biological therapy for asthma targeting the IgE, IL-4, IL-5, IL-13, and TSLP pathways are shown to have benefit for the treatment of eosinophilic asthma, as exemplified in real-world studies. When choosing the right biological agent factors such as phenotype, comorbidities, and cost-effectiveness of the biologic agent must be taken into consideration.

Keeping a track on leptomeningeal disease in non-small cell lung cancer: A single-institution experience with CNSideTM.

Background: Leptomeningeal disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) diagnostic modalities, including cerebrospinal fluid (CSF) cytology, MRI, and clinical evaluation. These hindrances contribute to the poor survival of LMD patients. CNSide is a CLIA-validated test that detects and characterizes CSF-derived tumor cells and cell-free (cf) DNA. We performed a retrospective analysis on the utility of CNSide to analyze CSF obtained from advanced non-small cell lung cancer (aNSCLC) patients with suspected LMD treated at the Huntsman Cancer Institute in Salt Lake City, UT. Methods: CNSide was used to evaluate CSF from 15 patients with aNSCLC. CSF tumor cell quantification was performed throughout treatment for 5 patients. CSF tumor cells and cfDNA were characterized for actionable mutations. Results: In LMD-positive patients, CNSide detected CSF tumor cells in 88% (22/25) samples versus 40% (10/25) for cytology (matched samples). CSF tumor cell numbers tracked response to therapy in 5 patients where CNSide was used to quantify tumor cells throughout treatment. In 75% (9/12) of the patients, genetic alterations were detected in CSF, with the majority representing gene mutations and amplifications with therapeutic potential. The median survival for LMD patients was 16.1 m (5.2-NR). Conclusions: We show that CNSide can supplement the management of LMD in conjunction with SOC methods for the diagnosis, monitoring response to therapy, and identifying actionable mutations unique to the CSF in patients with LMD.

Synergistic Toxicities from Multiple Therapies for Synchronous Malignancies.

Patients may present with multiple malignancies in the setting of particular environmental and occupational exposures. These patients often require combination systemic therapy, which has not yet been studied for concurrent use. While toxicities for specific chemotherapies and immunotherapies may be well known, the possibility of exaggerated toxicity due to combination therapy exists and is understudied. Several trials are underway that may shed further light on how combination therapies affect patient toxicity. This case report outlines the unfortunate development of severe edema and rash, refractory to traditional methods of management, from combining immunotherapy and chemotherapy.

Real-world comparison of survival outcomes with cisplatin versus carboplatin in patients with limited-stage small-cell lung cancer.

INTRODUCTION: Limited-stage small-cell lung cancer (LS-SCLC) is potentially curable with concurrent chemoradiation (CRT). Cisplatin is the preferred platinum for the chemotherapy backbone in national guidelines. Unfortunately, many LS-SCLC patients are elderly, with comorbidities and poor performance status (PS), which preclude the use of cisplatin. Carboplatin may be a suitable alternative. This analysis evaluates the overall survival (OS) and time to next treatment (TTNT) in LS-SCLC patients receiving concurrent CRT by platinum use. MATERIALS AND METHODS: The study included LS-SCLC patients in the Flatiron Health nationwide de-identified electronic health record-derived database who received CRT in 2013-2019 with follow-up through May 2020. TTNT and OS were compared using both unadjusted and inverse propensity-weighted Cox proportional hazards models. RESULTS: This study included patients treated with carboplatin (n = 600) or cisplatin (n = 572) in combination with etoposide and radiation. Cisplatin patients were younger, had a shorter time from diagnosis to radiation, and had less kidney disease. In an unadjusted analysis, median overall survival (mOS) was greater in the cisplatin group than the carboplatin group with mOS of 22.3 months vs. 19.2 months and Hazard Ratio (HR) of 0.83 (p = 0.01). In the inverse propensity-weighted analysis, this difference was no longer significant (HR 0.93, p = 0.37). No differences were seen in TTNT. CONCLUSION: When balancing on key clinical factors, we observed no statistical difference in OS or TTNT by platinum choice in real-world LS-SCLC patients treated with CRT.  Although observational, the results from this large data set are consistent with the hypothesis that either cisplatin or carboplatin is an appropriate therapy regardless of health status.

RNA-sequencing attest increased sperm motility in bovine spermatozoa treated with ethanolic extract of Putranjiva roxburghii.

In the course of time, scientific communities have a growing interest in understanding ethano medicines. The Putranjiva roxburghii, a native plant of the Indian Subcontinent is described as a "Child amulet tree" in Ayurveda. Based on the fact that this herbal medicine has an indispensable component of integrative medicine, the present study was planned to assess the effect of ethanolic dried extract of Putranjiva seeds on the motility of X and Y-bearing bovine spermatozoa. The in-vitro effect of seed extract diluted in S-TALP medium on bull semen has been evaluated by Computer Assisted Semen Analysis (CASA) shows a marked increase in the motility of spermatozoa. Motile and non-motile spermatozoa have been separated by glass wool column from the control as well as treated group. The X and Y-bearing sperm quantification have been carried out by droplet digital polymerase chain reaction (ddPCR). The extract didn't exert any differential effect on the motility and viability of X and Y chromosome-bearing spermatozoa. The transcriptome profiling (RNA-Seq) identified 93 differentially expressed genes between the extract treated and control group. It unveils the up-regulation of CATSPER, AKAP3, SPAG, ADAM1B, ADAM2 and ADAM32 genes that are involved in increasing sperm motility. Transcriptome profile also unveil the expression of ZAR1, CYP17A1, APPL2, HOXB4 and SP9 genes involved with embryonic development processes in Putranjiva extract-treated motile spermatozoa. The results envisaged the medicinal value of Putranjiva herb on increased fertility due to combinatory effect like increased sperm motility and favourableness on embryogenesis. The study ruled out the possibility of herbs having any biased effect on the selection of either male or female-bearing spermatozoa in the bull. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03452-4.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

A Real-World Analysis of the Use of Systemic Therapy in Malignant Pleural Mesothelioma and the Differential Impacts on Overall Survival by Practice Pattern.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive malignancy that affects older adults with frequent comorbidities, making real-world treatment decisions challenging. This study compares the overall survival (OS) of patients with MPM by physician's choice of first-line (1L) platinum chemotherapy (PC), second-line (2L) immunotherapy versus chemotherapy, and by receipt of maintenance therapy (MT). METHODS: The study included patients diagnosed with advanced MPM in the Flatiron Health electronic health record-derived database who initiated PC with pemetrexed in the 1L setting between 2011 and 2019. Patients in the 2L therapy analysis received single-agent chemotherapy versus immunotherapy after the progression of disease from our 1L cohort. Patients in the MT cohort were identified on the basis of continued receipt of pemetrexed with or without bevacizumab after dropping PC at prespecified intervals. The OS of patients by choice of 1L PC, 2L immunotherapy versus chemotherapy, and receipt of MT was summarized by means of Kaplan-Meier survival estimates and compared in the context of propensity score matching weighted analyses. RESULTS: In propensity score matching weighting analysis from 2065 patients with MPM, there was no evidence of an OS difference by choice of 1L PC (hazard ratio [HR] = 1.08, 95% confidence interval [CI]: 0.89-1.31, p = 0.43), suggestive evidence of an OS difference by choice of 2L immunotherapy versus chemotherapy (HR = 0.68, 95% CI: 0.42-1.08; p = 0.10), and no evidence of an OS difference by receipt of MT (HR = 0.92, 95% CI: 0.72-1.16, p = 0.46). CONCLUSIONS: Using real-world, propensity score-matched weighted analysis of MPM, we found there was no difference in OS by choice of 1L PC, 2L immunotherapy or chemotherapy, or by receipt of MT.

Adoption of Patient-Generated Health Data in Oncology: A Report From the NCCN EHR Oncology Advisory Group.

BACKGROUND: Collecting, monitoring, and responding to patient-generated health data (PGHD) are associated with improved quality of life and patient satisfaction, and possibly with improved patient survival in oncology. However, the current state of adoption, types of PGHD collected, and degree of integration into electronic health records (EHRs) is unknown. METHODS: The NCCN EHR Oncology Advisory Group formed a Patient-Reported Outcomes (PRO) Workgroup to perform an assessment and provide recommendations for cancer centers, researchers, and EHR vendors to advance the collection and use of PGHD in oncology. The issues were evaluated via a survey of NCCN Member Institutions. Questions were designed to assess the current state of PGHD collection, including how, what, and where PGHD are collected. Additionally, detailed questions about governance and data integration into EHRs were asked. RESULTS: Of 28 Member Institutions surveyed, 23 responded. The collection and use of PGHD is widespread among NCCN Members Institutions (96%). Most centers (90%) embed at least some PGHD into the EHR, although challenges remain, as evidenced by 88% of respondents reporting the use of instruments not integrated. Forty-seven percent of respondents are leveraging PGHD for process automation and adherence to best evidence. Content type and integration touchpoints vary among the members, as well as governance maturity. CONCLUSIONS: The reported variability regarding PGHD suggests that it may not yet have reached its full potential for oncology care delivery. As the adoption of PGHD in oncology continues to expand, opportunities exist to enhance their utility. Among the recommendations for cancer centers is establishment of a governance process that includes patients. Researchers should consider determining which PGHD instruments confer the highest value. It is recommended that EHR vendors collaborate with cancer centers to develop solutions for the collection, interpretation, visualization, and use of PGHD.

Real World Characterization of Advanced Non-Small Cell Lung Cancer in Never Smokers by Actionable Mutation Status.

BACKGROUND: Non-small cell lung cancer (NSCLC) in never-smokers (NS) is vastly different from those with a smoking history in terms of etiology, driver mutations, and immunotherapy responsiveness. This study compares the real-world overall survival (OS) of NSCLC patients by smoking history and mutation status. METHODS: The study included 30,310 advanced or metastatic NSCLC patients in the Flatiron Health EHR-derived database who received biomarker testing results (EGFR, ALK, ROS1, and BRAF), and initiated therapy between 2011 and 2017, with follow up through June 2018. OS by smoking and driver mutation groups was summarized via Kaplan-Meier survival estimates, and compared in the context of a multivariate Cox proportional hazard model. RESULTS: OS differed by smoking and driver-mutation categories (adjusted and stratified P< .001). The median OS for wild-type (WT) smoking patients was 9.6 months, for mutated (MT) smokers was 19.4 months (adjusted and stratified hazard ratio [HR] relative to WT smokers 0.65; 95% CI 0.60-0.71), for WT NS was 15.1 months (HR 0.78; 95% CI 0.73-0.83 relative to WT smokers), and for MT NS was 25.5 months (HR 0.52; 95% CI 0.48-0.58 relative to WT smokers). CONCLUSION: NS with NSCLC survived longer than those with smoking history, in both groups of WT and mutation-positive patients. Findings highlight that in NSCLC patients, a history of never smoking may have similar effect on hazard of death as the presence of an actionable mutation. Taken together, differences in heredity, mutations, and biologic history suggest that NS lung cancer is a distinct clinical entity and must be managed accordingly.

Comparative effectiveness of second-line ipilimumab vs. nivolumab in combination with ipilimumab in patients with advanced melanoma who received frontline anti-PD-1 antibodies.

INTRODUCTION: Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab. METHODS: A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis. RESULTS: A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab (n = 22) or ipilimumab in combination with nivolumab (n = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p = 0.81. CONCLUSIONS: In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.

Understanding functional implication of ß-casein gene variants in four cattle breeds characterized using AmpliSeq approach.

Here, we designed a custom panel targeting whole ß-casein gene SNPs of zebu and taurine cattle breeds to identify variants and applicability in dairy cattle genotyping. We sequenced two libraries consisting of different pools of primer sets from 95 individuals on the Illumina MiSeq. Consequently, over 92% target regions were amplified and 71 SNPs were available after quality filtering. Only three intronic variants were novel while majority of the identified variants were catalogued in dbSNP as known variants. Identified missense SNPs lead to variant A1/A2, B, F and A3, located in exon 7 only. For confirmation, A1/A2 locus was genotyped using PCR-RFLP. Variant B was observed in all animals, either in homozygous or in heterozygous form. Variants A1, F and A3 predicted to have a deleterious effect on protein function by decreasing the structural stability. Additionally, SIFT score revealed that the A1 variant might affect the protein function.

Prognostic Significance of Patient-Reported Outcomes in Cancer.

PURPOSE: Performance status (PS), an established prognostic surrogate of cancer survival, is a physician-synthesized metric of patient symptoms and mobility that is prone to bias and subjectivity. The National Cancer Institute (NCI) Patient-Reported Outcomes Measurement Information System-Cancer (PROMIS-Ca) Bank, a patient-centric patient-reported outcome (PRO) evaluation of physical function (PF), fatigue, depression, anxiety, and pain, shares subject matter with PS and, therefore, may also be prognostic while eliminating physician interpretation. METHODS: Patients at Huntsman Cancer Institute were assessed using the NCI PROMIS-Ca Bank. Using tablets at routine office visits, PF, fatigue, depression, anxiety, and pain scores were collected from patients with advanced melanoma, non-small-cell lung cancer, colorectal cancer, and breast cancer. A PRO score collected at a single time point within 6 months of metastatic diagnosis for each patient was merged with curated clinical outcome data. The association of PROs, overall survival (OS), and hospitalization-free survival (HFS) were assessed in multivariable analysis that included sex and cancer type. RESULTS: Two hundred eighty-two complete sets of patient data were available for analysis. All 5 PRO domains were strongly prognostic of OS and HFS. While the PRO domains were interrelated with moderate to strong correlations (0.40-0.79), multivariable regression suggested that PF was most strongly associated with the clinical outcomes of OS (P < .001) and HFS (P < .001). CONCLUSION: NCI PROMIS-Ca PROs may be prognostic of both cancer survival and likelihood of hospitalization. Future prospective studies are needed for all major prognostic factors to fully understand the independent prognostic value of PROs.

Comparative-effectiveness of pembrolizumab vs. nivolumab for patients with metastatic melanoma.

Background: Pembrolizumab (P) and nivolumab (N) are commonly used therapies for advanced melanoma. However, their effectiveness has never been directly compared, leaving little guidance for clinicians to select the best therapy. Therefore, we sought to retrospectively compare the overall survival of patients with metastatic melanoma treated with front line P or N in the real-world setting.Material and methods: This study included patients with advanced melanoma, diagnosed between 1 January 2011 and 31 July 2018, treated with frontline P or N who were included in a nationwide, longitudinal de-identified electronic health record (EHR)-derived database. Overall survival (OS) was estimated for each treatment group using Kaplan-Meier curves with a log-rank test. Comparison of OS was estimated using an inverse probability weighting model to reduce bias between the groups. The model was adjusted using age, sex, ECOG, LDH (elevated or not), BRAF (mutated or not), Kit (mutated or not), NRAS (mutated or not), PD-L1 expression (0% or greater), Body Mass Index, and primary site.Results: 888 patients with advanced disease who received treatment with frontline P (n = 486) or N (n = 402) were identified. Median OS for all patients treated with P was 22.6 months (m) and was 23.9 m for those treated with N (p = 0.91). In the inverse probability weight analysis there was no difference in survival between patients treated with P or N 1.06 (95% CI 0.84-1.33).Concluding Statement: In our retrospective, real-world analysis of patients with advanced melanoma, no statistical difference in OS was noted between patients treated with frontline P compared to N. This supports the current practice of choosing either P or N based on patient and provider preference.

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Nivolumab-induced hypothyoidism with consequent hypothyroid related myopathy.

PURPOSE: Nivolumab is a fully human IgG4 programmed death 1 immune checkpoint inhibitor (ICI) antibody that has anti-tumor activity by selectively blocking the interaction of the programmed death 1 receptor with its two known programmed death ligands PD-L1 and PD-L2. In doing so, this immune checkpoint inhibitor removes the negative signal stifling T cell activation and proliferation within the tumor microenvironment and demonstrates favorable antitumor activity. CASE REPORT: We report an interesting case of immune checkpoint inhibitor-induced primary hypothyroidism with associated hypothyroid myopathy in a young patient with surgically resected stage IIIB melanoma receiving adjuvant nivolumab. He presented 12 weeks into therapy with severe myalgias, arthralgias, and intermittent disequilibrium of unclear etiology. Laboratory evaluation demonstrated a significant elevation in thyroid stimulating hormone and creatine kinase with an undetectable free T4 with standard laboratory measurement. With thyroid hormone replacement therapy alone, he had rapid improvement in his musculoskeletal symptoms and laboratory parameters over a three-week period. DISCUSSION: This case emphasizes the serious nature of endocrine immune-related adverse events in patients receiving immune checkpoint inhibitors. Additionally, it highlights that unlike most other immune-related adverse events, endocrine immune-related adverse events can generally be managed with adequate hormone replacement alone with swift improvements in symptoms. This allows patients to continue immune checkpoint inhibitors safely without immunosuppression which may dampen the anti-tumor activity of these agents. CONCLUSION: This case highlights the importance of early recognition and the appropriate management of endocrine immune-related adverse events to maximize patient safety and good outcomes.

Red Tide: Overview and Clinical Manifestations.

Harmful algal blooms occur when toxin-producing algae grow rapidly. These occur worldwide and have significant impacts on aquatic ecosystems and on human health. Specifically, the toxic blooms of Karenia brevis in Florida may affect humans via inhalation or ingestion. On retrospective reviews, health care costs appear to rise during these outbreaks because of respiratory and gastrointestinal manifestations. Treatment for exposure is supportive care, though traditional inhalers may help with respiratory complications.

Combination of Local Ablative Therapy and Continuation of Immune Checkpoint Inhibitor (ICI) Therapy Provides Durable Treatment Response Past Oligometastatic Progression in NSCLC: A Case Report.

Adenosquamous carcinoma is a rare type of non-small cell lung cancer associated with advanced disease and poor prognosis. There is limited data for the management of mixed histology disease in elderly or frail patients. A 79-year-old woman with no smoking history presented with a right upper lobe lung mass on chest x-ray. Biopsy of the mass demonstrated an EGFR-amplified, PD-L1 positive adenosquamous lung cancer. The mass was surgically resected but the patient was not a candidate for adjuvant chemotherapy. The patient later developed a metastatic paraspinal lesion that was successfully managed with SBRT. Approximately six months later, the patient developed adrenal metastases and pembrolizumab was initiated. After three cycles of systemic therapy, she developed subcutaneous lesions in her back and chest wall, which were managed with palliative resection. Scans demonstrate stable disease and continued responsiveness to pembrolizumab over one year from the most recent local ablative therapy. This case illustrates the potential role of local ablative therapy for oligometastatic progression, as it may confer significant benefit in elderly patients or those with a more indolent disease course. Additionally, we have demonstrated that continuing immunotherapy past progression is reasonable in patients with no viable alternate therapy options, as delayed responses may occur.

Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.

BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi. METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.

Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up.

BACKGROUND: The natural histories of, and treatment options for, epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancers (NSCLCs) are distinctly different from those of lung cancer that lacks actionable mutations. Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that has been approved in other malignancies. OBJECTIVE: A phase I trial of ipilimumab plus targeted therapy with either erlotinib or crizotinib was performed to assess the safety of the combination in patients with EGFR-mutated or ALK-rearranged advanced NSCLC. METHODS: Patients with EGFR-mutated or ALK-rearranged NSCLC on a stable dose of erlotinib or crizotinib for > 28 days were eligible for the study. Patients were treated with ipilimumab 3 mg/kg for four cycles plus erlotinib or crizotinib. RESULTS: Treatment of the EGFR cohort resulted in dose-limiting toxicity in three of eight patients, with grade 3 diarrhea. The protocol was amended to reduce the ipilimumab dose to 1 mg/kg. Excessive toxicity resulted in the study being closed after 14 patients. Four of 11 EGFR-mutated patients ultimately developed grade 3 colitis. Of three ALK-rearranged patients, one developed hypophysitis and another grade 2 pneumonitis. For 11 EGFR-mutated patients, progression-free survival (PFS) from the start of ipilimumab was 17.9 months. Erlotinib treatment began a median 7.7 months before ipilimumab; therefore, erlotinib PFS was 27.8 months. Median overall survival (OS) has not been reached but will be > 42.3 months from erlotinib initiation. For three ALK-rearranged patients, ipilimumab PFS was 24.1 months. Median OS has not been reached but will be at least 47.2 months from the initiation of crizotinib. CONCLUSION: Erlotinib plus ipilimumab caused excessive short-term gastrointestinal toxicity leading to early study closure. However, PFS and OS were notable; therefore, targeted therapies with immunotherapy in NSCLC merit further study. Clinicaltrials.gov registration number: NCT01998126.

Total and Free 25-Hydroxy-Vitamin D and Bacterial Vaginosis in Pregnant African American Women.

Objective: This study sought to investigate associations between serum total and free 25(OH)D and bacterial vaginosis (BV) in early and later pregnancy among US black women to provide insight into the most clinically relevant measure of vitamin D status among pregnant black women with respect to risk for BV as well as insights into critical time points for measuring and/or addressing vitamin D status in pregnancy. Methods: Data and biospecimens were derived from a subsample (N = 137) of women from the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort, for whom data related to vitamin D status (serum assays for total and free 25(OH)D) and Nugent score of Gram stained vaginal specimens in early (8-14 weeks) and later (24-30 weeks) were available. We compared total and free 25(OH)D concentrations for women according to Nugent score category (normal flora, intermediate flora, and BV) and assessed the odds of BV according to measures of vitamin D status. Results: Thirty-seven (27%) women had adequate vitamin D status at baseline, whereas 70 (51%) had insufficient vitamin D and 30 (22%) were vitamin D deficient; there were not significant differences in the proportion of women with adequate, insufficient, or deficient vitamin D according to Nugent score category. However, the odds of BV later in pregnancy were significantly higher for women who experienced a smaller rise in total 25(OH)D and free 25(OH)D from 8-14 through 24-30 weeks gestation. Conclusion: The change in measures of vitamin D status from early to later pregnancy is associated with the occurrence of BV in pregnancy. Further research is needed to examine the association between the change in vitamin D status over pregnancy and the occurrence of BV and other measures of vaginal microbial composition as well as to identify factors that influence change in vitamin D status over pregnancy.