Role of Peripheral Parenteral Nutrition Composition on Clinical Outcomes in Patients Undergoing Gastrectomy or Colectomy: A Phase III Indian Clinical Trial.

Aims and background: Various types of parenteral nutritional products exist, each with specific formulations designed to meet the diverse nutritional needs of patient's post-abdominal surgery. Here, two different parenteral nutrition (PN) solutions BFLUID and NUTRIFLEX PERI are compared in terms of therapeutic efficacy and safety profile. Materials and methods: A prospective, multi-center, randomized, parallel-group, non-inferiority Phase III clinical trial compared two PN solutions namely BFLUID (N = 78) and NUTRIFLEX PERI (N = 72) in 150 patients undergoing gastrectomy or colectomy. Primary endpoints included length of hospital stay while secondary endpoints included assessment and comparison of length of ICU/HDU stay, assessment of incidents of infections and mortality, change in blood levels of vitamin B1, change in nutritional parameters, thrombophlebitis, pain at the injection site, and recording of adverse events (AEs). Results: There was no significant difference in terms of length of hospital stay, length of ICU/HDU stay as well as changes in nutritional parameters from baseline and change in blood levels of vitamin B1 from baseline. Both study groups exhibited comparability in terms of AEs, pain at the injection site, and the incidence of phlebitis. There was no significant difference in the number and severity of adverse events reported in both groups. Additionally, no signs of infection were observed in patients from either group. Conclusion: The trial successfully demonstrated the non-inferiority of BFLUID to NUTRIFLEX PERI. Moreover, the results indicated that PN enriched with high levels of branched-chain amino acids (BCAAs), essential amino acids (EAAs), and thiamine is both safe and efficacious for adult patients undergoing gastrectomy or colectomy. How to cite this article: Goyal A, Pathak A, BS Madhu, Soni H, Bhatt K, Raju KVVN, et al. Role of Peripheral Parenteral Nutrition Composition on Clinical Outcomes in Patients Undergoing Gastrectomy or Colectomy: A Phase III Indian Clinical Trial. Indian J Crit Care Med 2024;28(9):871-878.

US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

PURPOSE: The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test. PATIENTS AND METHODS: Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region. RESULTS: A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3). CONCLUSION: Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

Refining shape and size of silver nanoparticles using ion irradiation for enhanced and homogeneous SERS activity.

We present green synthesis of silver nanoparticles in water using unirradiated and Ag 15 + ion irradiated phytoextracts of Bergenia Ciliata leaf, Eupatorium adenophorum leaf, Rhododendron arboreum leaf and flower. The use of different plant extracts and their subsequent ion irradiation allow for successful refinement of nanoparticle size and morphology. Due to changes in reducing and capping agents the nanoparticle surface functionalization also varies which not only controls the morphology but also allows for surface oxidation and aggregation processes. In this work, we have synthesized silver nanoparticles which exhibit sizes in the range from 13 to 24 nm and having shapes like spherical, quasispherical, trigonal, hexagonal, cylindrical, dendritic assemblies, and porous nanoparticles. Owing to changes in the size and shape of the nanoparticles, their direct bandgap (2.05 eV - 2.48 eV) and local surface plasmon resonance (420 nm - 490 nm) could also be tuned. These nanoparticles are examined as SERS substrates, where their enhancement factors, limit of detection for methylene blue, and SERS substrate homogeneity have been tested. It has been observed the nanoparticles synthesized using unirradiated plant extracts present an enhancement factor of 10 6 with a limit of detection 10 - 8 M. Whereas nanoparticles with refined morphology and shapes upon irradiation present high enhancement factors of >10 7 and detection limit down to 10 - 9 M. In addition, uniformity in Raman spectra over the SERS substrates has been obtained for selected Ag NPs substrates synthesized using irradiated extracts with minimum relative standard deviation in enhancement factor < 12%.

US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

Autophagy indicators in oral squamous cell carcinoma.

Autophagy plays an important role in maintaining cellular homeostasis. Dysregulation of autophagy has been linked to a number of diseases, including cancer. We retrospectively evaluated immunohistochemical expression of the autophagy markers LC3B and p62 and the autophagy regulator mTOR as an indicator of autophagy in 100 surgically resected primary oral squamous cell carcinoma (OSCC) samples and sought associations with various clinicopathological factors. The expression of all three proteins was significantly higher in malignant squamous cells than in benign squamous cells in the free mucosal margin adjacent to the OSCC. Male sex, higher tumour (T) stage, node (N) stage and tumour, node, metastasis (TNM) stage were significantly associated with high marker expression; age and histological grade showed no significant association. LC3B, p62 and mTOR expression were positively correlated with one another in OSCCs, and the correlation was significant for LC3B and mTOR as well as for LC3B and p62. Disease-free survival showed an inverse correlation with high mTOR expression. Our data suggest that autophagy inhibitors and mTOR inhibitors may have a therapeutic role in the treatment of OSCCs.

FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Regulatory implications of ctDNA in immuno-oncology for solid tumors.

In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.

A review on mechanisms of resistance to PARP inhibitors.

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology, US Food and Drug Administration Public Workshop-Workshop Proceedings.

PURPOSE: Next-generation sequencing (NGS) oncology panels are becoming integral in hospital and academic settings to guide patient treatment and enrollment in clinical trials. Although NGS technologies have revolutionized decision-making for cancer therapeutics, physicians may face many challenges in parsing and prioritizing NGS-based test results to determine the best course of treatment for individual patients. On January 29, 2018, the US Food and Drug Administration held a public workshop entitled, "Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology." Here, we discuss the presentations and discussion highlights across the four sessions of the workshop. METHODS: The goal of the public workshop was to engage stakeholders and solicit input from experts in precision oncology to discuss the integration of complex NGS data into patient management and regulatory innovation within the precision oncology community. The US Food and Drug Administration gathered representatives from academia, industry, patient advocacy, government, and professional organizations for a series of presentations followed by panel discussions. After the workshop, the transcript and speaker presentation slides were reviewed and summarized for manuscript preparation. RESULTS: Speakers and panelists provided diverse perspectives on the integration of NGS technology into patient care for oncology and on the complexities that surround data interpretation and sharing. Discussions highlighted the challenges with standardization for variant classification while expressing the utility of consensus recommendations among stakeholders in oncology for driving innovation in the era of precision medicine. CONCLUSION: As precision medicine advances, clear communication within the field of precision oncology will be key to creating an environment that facilitates the generation and sharing of data that have value to patients.

Management of Lymphomas: Consensus Document 2018 by an Indian Expert Group.

The clinical course of lymphoma depends on the indolent or aggressive nature of the disease. Hence, the optimal management of lymphoma needs a correct diagnosis and classification as B cell, T-cell or natural killer (NK)/T-cell as well as indolent or high-grade type lymphoma. The current consensus statement, developed by experts in the field across India, is intended to help healthcare professionals manage lymphomas in adults over 18 years of age. However, it should be noted that the information provided may not be appropriate to all patients and individual patient circumstances may dictate alternative approaches. The consensus statement discusses the diagnosis, staging and prognosis applicable to all subtypes of lymphoma, and detailed treatment regimens for specific entities of lymphoma including diffuse large B-cell lymphoma, Hodgkin's lymphoma, follicular lymphoma, T-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Burkitt's lymphoma, and anaplastic large cell lymphoma.

Femtosecond Laser-Induced, Nanoparticle-Embedded Periodic Surface Structures on Crystalline Silicon for Reproducible and Multi-utility SERS Platforms.

Fabrication of reproducible and versatile surface-enhanced Raman scattering (SERS) substrates is crucial for real-time applications such as explosive detection for human safety and biological imaging for cancer diagnosis. However, it still remains a challenging task, even after several methodologies were developed by various research groups, primarily due to (a) a lack of consistency in detection of a variety of molecules (b) cost-effectiveness of the SERS substrates prepared, and (c) byzantine preparation procedures, etc. Herein, we establish a procedure for preparing reproducible SERS-active substrates comprised of laser-induced nanoparticle-embedded periodic surface structures (LINEPSS) and metallization of silicon (Si) LINEPSS. LINEPSS were fabricated using the technique of femtosecond laser ablation of Si in acetone. The versatile SERS-active substrates were then achieved by two ways, including the drop casting of silver (Ag)/gold (Au) nanoparticles (NPs) on Si LINEPSS and Ag plating on the Si LINEPSS structures. By controlling the LINEPSS grating periodicity, the effect of plasmonic nanoparticles/plasmonic plating on the Si NPs embedded periodic surface structures enormously improved the SPR strength, resulting in the consistent and superior Raman enhancements. The reproducible SERS signals were achieved by detecting the molecules of Methylene Blue (MB), 2,4-dinitrotoluene (DNT), and 5-amino-3-nitro-l,2,4-triazole (ANTA). The SERS signal strength is determined by the grating periodicity, which, in turn, is determined by the input laser fluence. The SERS-active platform with grating periodicity of 130 ± 10 nm and 150 ± 5 nm exhibited strong Raman enhancements of ∼108 for MB and ∼107 for ANTA molecules, respectively, and these platforms are demonstrated to be capable, even for multiple usages.

Mosaic chromosome Y loss and testicular germ cell tumor risk.

Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. Cohort studies investigating mLOY and mortality have reported contradictory results. Previous work found that a 1.6 Mb deletion of the AZFc region on the Y chromosome (the 'gr/gr' deletion) is associated with both male infertility and increased risk of testicular germ cell tumors (TGCT). We investigated whether mosaic loss across the entire Y chromosome was associated with TGCT. We obtained blood- and buccal-derived DNA from two case-control studies: the NCI Familial Testicular Cancer Study (cases=172; controls=163) and the NCI US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (cases=506; controls=611). We used 15 quantitative polymerase chain reactions spanning the Y chromosome to assess mLOY. Multivariate logistic regression models adjusted for study batch effects detected no significant overall relationship between mean chromosome Y target-to-reference (T/R) ratio and TGCT (odds ratio=0.34, 95% confidence interval=0.10-1.17, P=0.09). When restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls (0.993 vs 1.014, P-value=0.01). Our study suggests that mLOY, as measured by 15 probes spanning the Y chromosome, could be associated with familial TGCT, but larger studies are required to confirm this observation.

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family.

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia.

Rare inactivating PDE11A variants associated with testicular germ cell tumors.

Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort.

BACKGROUND: Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. METHODS: We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. RESULTS: Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR = 11.9; 95% CI, 5.1-23.4; excess absolute risk = 7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR = 13.4; 95% CI, 1.6-48.6). CONCLUSIONS: Our data are the first to indicate that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. IMPACT: Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies.