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Cesare Gridelli,1 Tianlei Chen,2 Amy Ko,2 Mary E O’Brien,3 Teng Jin Ong,4 Mark A Socinski,5 Pieter E Postmus6 1Division of Medical Oncology, S. G. Moscati Hospital, Avellino, Italy; 2Biostatistics, Celgene Corporation, Summit, NJ, USA; 3Medical Oncology, Royal Marsden Hospital, London, UK; 4Medical Affairs, Celgene Corporation, Summit, NJ, USA; 5Lung Cancer & Esophageal Cancer, Florida Hospital Cancer Institute, Orlando, FL, USA; 6Pulmonary Diseases, Clatterbridge Cancer Center, Liverpool, UK Background: Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Patients and methods: Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. Results: Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Conclusion: nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup. Keywords: taxanes, comorbidities, age, chemotherapy, histology

Michael Thomas,1,2 David R Spigel,3 Robert M Jotte,4 Michael McCleod,5 Mark A Socinski,6 Ray D Page,7 Laurent Gressot,8 Jeanna Knoble,9 Oscar Juan,10 Daniel Morgensztern,11 Dolores Isla,12 Edward S Kim,13 Howard West,14 Amy Ko,15 Teng Jin Ong,15 Nataliya Trunova,15 Cesare Gridelli16 On behalf of ABOUND.sqm investigators 1Department of Thoracic Oncology/Internal Medicine, Thoraxklinik im Universitätsklinikum Heidelberg, 2Translational Lung Research Center Heidelberg, Heidelberg, Germany; 3Sarah Cannon Research Institute, Nashville, TN, 4Department of Medical Oncology/Hematology, Rocky Mountain Cancer Centers, Denver, CO, 5Florida Cancer Specialists, Fort Myers, 6Florida Hospital Cancer Institute, Orlando, FL, 7The Center for Cancer and Blood Disorders, Fort Worth, 8North Cypress Cancer Center, Cypress, TX, 9The Mark H. Zangmeister Center, Columbus, OH, USA; 10Department of Medical Oncology, Hospital Universitari i Politécnic La Fe, Valencia, Spain; 11Department of Medical Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; 12Department of Medical Oncology, University Hospital Lozano Blesa, Zaragoza, Spain; 13Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, 14Thoracic Oncology Program, Swedish Cancer Institute, Seattle, WA, 15Celgene Corporation, Summit, NJ, USA; 16Department of Oncology/Hematology, S.G. Moscati Hospital, Avellino, Italy Background: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. Methods: Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). Results: Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. Conclusion: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders. Keywords: nab-paclitaxel, non-small cell lung cancer, quality of life, response, squamous

Terminal osseous overgrowth is a common complication after trans-diaphyseal amputation in children, leading to pain, soft tissue problems, and recurrent surgical procedures. We report three different cases with post-amputation issues of osseous overgrowth, ulceration, and deformity over the amputation site. The first case involves a 9-year-old boy with a right leg congenital amputation secondary to amniotic band syndrome. The right below-knee stump later experienced recurrent episodes of osseous overgrowth, leading to ulceration. After the prominent tibia was resected and capped with the ipsilateral proximal fibula, a positive outcome was achieved with no more recurrent overgrowth over the right leg stump. The second case involves a 9-year-old girl born with an amniotic constriction band over both legs. Her left leg remained functional after a circumferential Z-plasty, but the right leg was a congenital below-knee amputation. Multiple refashioning surgeries were performed on the right leg due to osseous overgrowth but the patient continued to experience recurrent overgrowth causing pain and difficulty fitting into a prosthesis. We performed osteocartilaginous transfer of the proximal part of the ipsilateral fibula to the right tibial end, successfully preventing the overgrowth of the tibia without any complications. The third case involves an 11-year-old boy with a history of meningococcal septicemia who underwent a right below-knee amputation and left ankle disarticulation due to complications of septic emboli. He experienced a prominent right distal tibia stump, which later developed into valgus deformity as a result of the previous insult to the proximal tibial growth plate. We performed a corrective osteotomy over the proximal right tibia and capped the entire tibia with the ipsilateral fibula as an intramedullary splint for the osteotomy site. Post-operatively, we achieved satisfactory deformity correction and successfully halted the recurrent overgrowth over the right tibia stump. The method of ipsilateral fibula capping is safe and effective in managing the osseous overgrowth complications in trans-diaphyseal amputations among children. Therefore, it is a reasonable option during primary below-knee amputations in children compared to multiple refashioning surgeries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Pon, Ong, Abd Rasid, Abd Rashid and Jamil.)

Background: The quality of warfarin therapy can be determined by the time in the therapeutic range (TTR) of international normalized ratio (INR). The estimated minimum TTR needed to achieve a benefit from warfarin therapy is ≥ 60%., Aim: To determine TTR and the predictors of poor TTR among atrial fibrillation patients who receive warfarin therapy., Methods: A retrospective observational study was conducted at a cardiology referral center in Selangor, Malaysia. A total of 420 patients with atrial fibrillation and under follow-up at the pharmacist led Warfarin Medication Therapeutic Adherence Clinic between January 2014 and December 2018 were included. Patients' clinical data, information related to warfarin therapy, and INR readings were traced through electronic Hospital Information system. A data collection form was used for data collection. The percentage of days when INR was within range was calculated using the Rosendaal method. The poor INR control category was defined as a TTR < 60%. Predictors for poor TTR were further determined by using logistic regression., Results: A total of 420 patients [54.0% male; mean age 65.7 (10.9) years] were included. The calculated mean and median TTR were 60.6% ± 20.6% and 64% (interquartile range 48%-75%), respectively. Of the included patients, 57.6% ( n = 242) were in the good control category and 42.4% ( n = 178) were in the poor control category. The annual calculated mean TTR between the year 2014 and 2018 ranged from 59.7% and 67.3%. A high HAS-BLED score of ≥ 3 was associated with poor TTR (adjusted odds ratio, 2.525; 95% confidence interval: 1.6-3.9, P < 0.001)., Conclusion: In our population, a high HAS-BLED score was associated with poor TTR. This could provide an important insight when initiating an oral anticoagulant for these patients. Patients with a high HAS-BLED score may obtain less benefit from warfarin therapy and should be considered for other available oral anticoagulants for maximum benefit., Competing Interests: Conflict-of-interest statement: The authors have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab -paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab -paclitaxel 100 mg/m 2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. Conclusions: The nab -paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326). EudraCT number: 2014-001105-41., (Copyright © 2021 Morgensztern, Dols, Ponce Aix, Postmus, Bennouna, Fischer, Juan-Vidal, Stewart, Ardizzoni, Bhore, Wolfsteiner, Reck, Talbot, Govindan and Ong.)

Introduction: Despite improvements in the treatment of advanced non-small cell lung cancer (NSCLC), certain patient populations remain underrepresented in clinical trials. Many patients have benefited from platinum doublets, including nab -paclitaxel-based regimens, but there are patients with comorbidities who particularly require careful balancing of efficacy and safety. Clinical trial data are limited for patients who are elderly or have renal impairment, diabetes, or impaired performance status., Methods: To better understand outcomes in these patient populations, we performed a pooled analysis using data from the ABOUND clinical trial program (ABOUND.SQM, ABOUND.PS2, ABOUND.70+) and the key phase III trial of nab -paclitaxel/carboplatin in advanced NSCLC. The populations included in this pooled analysis consisted of elderly patients (≥ 70 years) and patients with renal impairment (eGFR < 60 ml/min/1.73 m 2 ), diabetes, or poor performance status (ECOG PS 2)., Results: Median progression-free survival (PFS) ranged from 4.1 months in patients with ECOG PS 2 (95% CI, 2.04-5.09 months) to 7.7 months in patients with diabetes (95% CI, 5.88-10.12 months). PFS for elderly patients and patients with renal impairment was 6.9 months each (95% CI, 6.01-7.98 months and 4.47-9.79 months, respectively). Median overall survival (OS) was 18.2 months (95% CI, 10.94-28.22 months), 17.4 months (95% CI, 14.59-20.14 months), and 16.1 months (95% CI, 14.09-18.50 months) in patients with renal impairment, patients with diabetes, and elderly patients, respectively. Patients with ECOG PS 2 exhibited the shortest median OS: 5.6 months (95% CI, 3.98-11.37 months). Overall response rates were 56.9%, 54.6%, 45.9%, and 29.4% in patients with diabetes, elderly patients, patients with renal impairment, and patients with ECOG PS 2, respectively. Most treatment-related adverse events were hematologic. The most common grade 3/4 hematologic adverse events in patients with renal impairment, elderly patients, patients with diabetes, and patients with poor performance status included neutropenia, anemia, and thrombocytopenia., Conclusions: Although survival data in patients with ECOG PS 2 were notably inferior to the other cohorts, our findings are consistent with those previously reported in the population-specific studies of the ABOUND trials and lend additional support for the use of nab -paclitaxel-based regimens in historically understudied and vulnerable populations., Competing Interests: CJL: Consultant/advisory fees, Celgene Corporation; other consulting fees: AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Novartis, Pfizer, Takeda, Hospira, Merck, Boehringer Ingelheim. AG: Honoraria for Advisory Board, AstraZeneca; other fees, ICON Plc, CRO. CG: Advisory Board and Speakers’ Bureau member, MSD, Bristol Myers Squibb, Roche, AstraZeneca. DM: Advisory/Consultant, AbbVie, Bristol Myers Squibb, PharmaMar, Takeda. DS: Consulting or advisory role and research funding, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Genentech/Roche, Lilly, Novartis, Pfizer; research funding, Merck, University of Texas Southwestern Medical Center—Simmons Cancer Center. MT: Grants, Celgene Corporation, Bristol Myers Squibb, Roche, AstraZeneca; consulting fees, Celgene Corporation, AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche. JW: Grants, Celgene Corporation; consulting fees, Celgene Corporation. RP: Employment, Bristol Myers Squibb. RB: Employment, Bristol Myers Squibb. MW: Consulting fees, Bristol Myers Squibb. TJO: Employment, Bristol Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Celgene, a wholly owned subsidiary of Bristol Myers Squibb. The funder had the following involvement with the study: study design, data collection and data analysis., (Copyright © 2021 Langer, Gajra, Gridelli, Konduri, Morgensztern, Spigel, Talbot, Thomas, Weiss, Pilot, Bhore, Wolfsteiner, Ong and Socinski.)

Background: We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non-small-cell lung cancer., Patients and Methods: Patients with treatment-naive squamous non-small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m 2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m 2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS)., Results: Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator's discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC)., Conclusions: The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Assess safety and efficacy of nivolumab plus nab -paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial., Patients and Methods: Fifty chemotherapy-naive patients received nab -paclitaxel 125 mg/m 2 plus gemcitabine 1,000 mg/m 2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc ., Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67 + CD8 + /CD4 + cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67 + CD8 + T-cell values were higher in responders than in nonresponders., Conclusions: The safety profile of nivolumab plus nab -paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation., (©2020 American Association for Cancer Research.)

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab -paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [ nab -paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [ nab -paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

Background: Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer., Methods: This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m 2 plus gemcitabine 1000 mg/m 2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete., Findings: Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients., Interpretation: The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings., Funding: Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether treatment of overactive bladder (OAB), one comorbidity of nocturia, could reduce waking to void and improve other co-existing symptoms., Methods: A prospective cohort study was conducted at Royal Melbourne Hospital. Participants received 12 weeks of standard treatment, including lifestyle interventions and pharmacotherapy. Outcome measures were nocturia episodes, severity of urinary urgency/incontinence, sleep quality, daytime somnolence, anxiety and depression scores, quality of life and change in blood pressure., Results: Twenty participants completed the study. Nocturia frequency improved by one void per night. Overactive Bladder Symptom Score, sleep quality, first uninterrupted sleep time and systolic blood pressures improved. There were no significant changes in daytime somnolence, mood or quality of life., Conclusions: In this pilot study, nocturia and other co-morbid dysfunctions appeared to improve when the severity of OAB was reduced. Treatment of OAB co-morbid with nocturia reduces urinary symptoms and may improve sleep parameters and positively impact return to health., (© 2019 AJA Inc.)

Introduction: Multicenter, phase I study of concurrent and delayed nivolumab plus nab -paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received nab -paclitaxel 100 mg/m 2 (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. Results: All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. Conclusions: The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with nab -paclitaxel/carboplatin for the treatment of advanced NSCLC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02309177., (Copyright © 2019 Goldman, Waterhouse, George, O'Dwyer, Bhore, Banerjee, Lyons, Louis, Ong and Kelly.)

Background: A partial response according to the Response Evaluation Criteria in Solid Tumors includes a wide range of changes in tumor size. This study evaluated whether further specification of tumor reduction based on the depth of response (DpR) would provide a more precise association with outcomes for patients with non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy., Methods: A retrospective analysis was performed for the randomized phase 3 CA031 trial in patients with NSCLC treated with carboplatin in combination with nab-paclitaxel or solvent-based paclitaxel. Quartiles according to the maximum tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%; quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4], >75%) and were compared with those patients with no tumor reduction (NTR). The primary objective was to evaluate the association between DpR and overall survival (OS)., Results: Of the 1052 patients enrolled in the CA031 trial, 959 (91%) were evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%) who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%) who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and 23.5 months, respectively. The maximum DpR on treatment was an independent predictor of improved OS in comparison with patients with NTR; the hazard ratio decreased from 0.43 in Q1 to 0.16 in Q4., Conclusions: DpR was strongly associated with OS in patients with NSCLC receiving first-line platinum-based therapy. Additional studies may help to define the role of DpR in solid tumors., (© 2019 American Cancer Society.)

Background: First-line nab-paclitaxel/carboplatin was associated with a significantly improved overall response rate (primary endpoint) versus paclitaxel/carboplatin in a phase III trial of advanced non-small-cell lung cancer (NSCLC). We report the results of an analysis evaluating the correlation of response and the time to response with survival and quality-adjusted outcomes., Patients and Methods: Using a landmark approach, progression-free survival (PFS), overall survival (OS), and quality-adjusted time without symptoms or toxicity (Q-TWiST) were compared between patients with a confirmed partial or complete response at or before 6 weeks (≤ 6-week responders) and those without (≤ 6-week nonresponders). The outcomes were also analyzed in two 12-week landmark analyses: ≤ 12-week responders versus ≤ 12-week nonresponders and early responders (≤ 6 weeks) versus late responders (6-12 weeks) versus ≤ 12-week nonresponders., Results: The median OS and PFS for the ≤ 6-week responders versus ≤ 6-week nonresponders were 14.5 versus 10.3 months (P < .001) and 5.5 versus 4.5 months (P = .002), respectively. The ≤ 6-week responders gained 2.1 months of mean Q-TWiST. The median OS and PFS for the ≤ 12-week responders versus ≤ 12-week nonresponders were 16.3 versus 8.4 months and 5.3 versus 2.8 months (both P < .001), respectively, and the ≤ 12-week responders gained 3.2 months of mean Q-TWiST. The median OS was 13.1, 16.6, and 8.4 months (P < .001), the median PFS was 4.1, 6.7, and 2.8 months (P < .001), and the mean Q-TWiST was 10.2, 11.7, and 7.8 months for the early responders, late responders, and ≤ 12-week nonresponders, respectively. Both early and late responders had significantly longer Q-TWiST compared with the ≤ 12-week nonresponders (difference, +2.4 and +3.9 months, respectively; P < .05)., Conclusion: These results underscore response as an important surrogate for assessment of long-term treatment outcomes in advanced NSCLC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab -paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2., Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab -paclitaxel 100 mg/m 2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab -paclitaxel monotherapy (100 mg/m 2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs)., Results: 11/40 treated patients (27.5%; 95% CI, 14.60-43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab -paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99-7.00) and 7.7 (95% CI, 4.93-13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%)., Conclusion: This nab -paclitaxel-based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab -paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab -paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab -paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P  = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44-1.19; P  = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30-0.76; P  < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02-2.78; P  = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade ≥ 2 PN or grade ≥ 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab -paclitaxel/carboplatin in elderly patients with advanced NSCLC.

Background: Patients may not raise nocturia as a concern as they mistakenly consider the symptom to be a normal part of ageing. Nocturia is associated with significant morbidity and is likely to be a marker of poor health., Objective: This paper provides questions to guide diagnosis, evaluation and individualised treatment of nocturia., Discussion: Nocturia results from the interplay between nocturnal polyuria, reduced bladder storage and sleep disruption. Changes in the function of the urinary bladder, kidneys, brain and cardiovascular system, and hormone status underlie the development and progression of nocturia. Medications commonly prescribed to older people can affect development or resolution of nocturia. The bother caused to a patient by waking to void relates to disturbance of slow-wave sleep, the physical act of getting out of bed and resulting chronic fatigue. An assessment process that identifies relevant and co-existing causes of an individual's nocturia will facilitate a targeted approach to treatment.

Introduction: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC)., Methods: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening., Results: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib., Conclusions: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients., Methods: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ⩾60 and ⩾70 years as cut points., Results: Among patients aged ⩾60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2-2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ⩾70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL., Conclusion: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC.

Aim: Emergency department (ED) doctors are under time pressure to expedite decision-making. This task would seem more difficult in older patients who present atypically, have multiple comorbidities and require more diagnostic tests. This study aimed to investigate the rate of appropriate initial diagnosis of older ED patients admitted under medical units, and whether time was a factor., Methods: Retrospective review of all patients admitted under medical units from ED over a one-month period was conducted., Results: Four hundred ninety-three records were reviewed. Mean time to ED review was 87 minutes, and to medical registrar review, 409 minutes. Overall rate of appropriate initial diagnosis made by ED was 85.8%, with significantly lower rate detected in older patients. Overall rate for medical registrar was 94.5%., Conclusions: Admitted older ED patients received lower rates of appropriate initial diagnosis. Time may be a contributing factor to this lower rate. Length of stay was prolonged if initial diagnosis was inappropriate., (© 2014 ACOTA.)

Purpose: This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer (NSCLC)., Patients and Methods: Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m(2) per day on days 1 and 8) and cisplatin (75 mg/m(2) on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP)., Results: The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed., Conclusion: This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.

Design: Interventional case report., Methods: In an institutional practice setting, two women, aged 25 and 45, developed acute myopia after starting topiramate for epilepsy. One patient also developed bilateral angle closure glaucoma., Results: Topiramate was discontinued. Anterior chamber shallowing was noted in both patients at presentation. Ultrasonography showed ciliochoroidal effusion. Baseline measurements of anterior chamber depth and lens thickness were obtained., Conclusions: Topiramate may be associated with ciliochoroidal effusion with forward displacement of the lens-iris diaphragm and anterior chamber shallowing, resulting in acute myopia and angle-closure glaucoma. Increased lens thickness contributes only minimally (9%-16%) to anterior chamber shallowing.

Tin is present in low concentrations in most canned foods and beverages, the highest levels being found in products packaged in unlacquered or partially lacquered tinplate cans. A limited number of case-reports of acute gastrointestinal disorders after consumption of food containing 100-500 mg/kg tin have been reported, but these reports suffer many insufficiencies. Controlled clinical studies on acute effects of tin migrated from packaging suggest a threshold concentration for adverse effects (AEs) of >730 mg/kg. Two separate randomised, single-centre, double-blind, crossover studies, enabling comparison of the tolerability of tin added as tin(II) chloride at concentrations of <0.5, 161, 264 and 529 mg/kg in 250 ml tomato juice in 20 volunteers (Study 1) and tin migrated from packaging at concentrations of <0.5, 201 and 267 mg/kg in 250 ml tomato soup in 24 volunteers (Study 2) were carried out. Distribution studies were conducted to get insight in the acute AEs of low molecular weight (<1000 Da) tin species in the soluble fraction of food products. Results show that the chemical form of tin and not the elemental concentration per se determines the severity of AEs. A clear dose-response relationship was only observed when tin was added as tin(II) chloride in tomato juice. No clinically significant AEs were reported in Study 2 and comparison of the incidence of tin-related AEs showed no difference between the dose levels (including control). Tin species of low molecular weight in supernatant represented 31-32% of total tin in canned tomato soup versus 56-61% in juice freshly spiked with tin(II) chloride. Differences in the incidence of AEs following administration of tomato juice with 161 and 264 mg of tin per kg and tomato soup with 201 and 267 mg of tin per kg likely results from differences in the concentration of low molecular weight tin species and in the nature of tin complexes formed. The results of this work demonstrate that tin levels up to 267 mg/kg in canned food cause no AEs in healthy adults and support the currently proposed tin levels of 200 mg/kg and 250 mg/kg for canned beverages and canned foods, respectively, as safe levels for adults in the general population.

Ophthalmic artery hypoperfusion is a relatively uncommon clinical entity. This study illustrates the posterior segment findings of ophthalmic artery hypoperfusion in a series of nine patients. Colour photographs and relevant fluorescein angiograms highlighting the findings are shown. The retinal manifestations of ophthalmic artery hypoperfusion in this series of patients include midperipheral haemorrhages, dilated retinal veins, optic disk collaterals, optic disk neo-vascularization, cotton wool spots, grey intraretinal lesions, fundus pallor, optic disk swelling and choroidal infarcts. Recognition of the ophthalmic changes in this condition may lead to detection of carotid artery disease, the surgical and medical treatment of which has important bearing on patient management.

Unlabelled: This study aimed to define the differences in lung function between British Caucasian and rural eastern Indian children, and to test the hypothesis that nutrition could account for such "ethnic" variation. To exclude confounders, a rural Indian setting was identified and children were screened for respiratory illness before lung function and nutritional characteristics were measured. Regression equations for this population have already been published. In this study, the lung function differences between rural eastern Indian (n=391) and mean predicted lung function for Caucasian children were characterized, matched for height and sex. In addition, stepwise multiple regression models were fitted to investigate the relative associations of lung function differences with body mass index (BMI), occipitofrontal circumference and age. Although the largest differences in the forced expiratory volume in 1 s (FEV1) [girls 28.7 (27.3-30.1), boys 23.4 (22.2-24.6)] and forced vital capacity [girls 27.9 (26.4-29.4), boys 30.7 (29.6-31.9)] [values as mean difference in % predicted (95% confidence intervals)] ever reported between two populations were observed, differences in peak expiratory flow rate (PEFR) were small. BMI was strongly associated with inter-racial differences for FEV1 for both sexes (boys beta = -0.227, girls beta = -0.353. p < 0.001) and PEFR for girls (beta = -0.200, p < or = 0.05) (beta = standardized coefficient)., Conclusion: Preventable nutritional factors may play a causal role in determining the FEV1 differences between rural Indian and Caucasian children. As peak FEV1 in youth influences respiratory morbidity in later life, it is important to define specific nutrient deficiencies that may relate to poor FEV1 growth in these children.

We have assessed the consistency of measurement of femoral head circumference using 3 standard measuring instruments used in hemiarthroplasty of the hip. Fifty femoral heads were independently sized by ten independent observers using a caliper, a half circular measuring template, each allowing measurement to the nearest millimeter. We found significantly greater variance of the results using the half-circular templates (p=0.001) and the calipers (p=0. 011) compared with the full circular measuring templates. Measurement with calipers underestimated femoral head size by 0.72 mm compared with full circular measuring templates (p=0.02). Insertion of an undersized hemiarthroplasty head is a cause of increased point loading of the acetabulum and may result in increased rates of acetabular erosion. The use of full circular measurement templates is recommended as the most consistent method for head sizing in hemiarthroplasty of the hip.

This paper has, given some idea of our concepts of the processes involved in the transport of Cu across cell membranes in the liver, which we have summarised in Fig 1. Cu(II)His2 is reduced to Cu(I). This is transported across the membrane, re-oxidised, either before or after binding to glutathione (Freedman et al., 1989) or HAH1 (Klomp et al., 1997), binds to SAHH, and donates Cu(II) to the ATPase. It is very interesting that cells which are very diverse from an evolutionary point of view still use very similar methods to handle the metal. Whether regulation of transport is also the sam remains to be seen. We would guess that, although there will be strong similarities, there will also be very significant differences, reflecting the different environments seen by different tissues in mammalian cells and given the different requirements of the tissues.

Background: In animal models, nutritional deficiency leads to profound qualitative changes in the lung beyond an effect on organ size. Although lung growth is non-isotropic, predictive values for spirometric lung function in children are corrected for height alone. Prediction of lung function should consider isotropic growth and nutritional status concurrently., Aim: To establish whether nutritional status influences lung function following the exclusion of the effect of isotropic growth., Methods: Nutritional status (weight, body mass index, mid-upper arm circumference, and subscapular and triceps skinfold thicknesses) was assessed, and lung function (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow rate (PEFR) was measured in 391 healthy school age children with normal respiratory history and examination in a rural setting in West Bengal, India., Results: Lung function normalised for sitting height and stature correlated significantly with indices of nutrition in both sexes. Adding weight as an independent variable to sitting height, new reference prediction equations for FEV1, FVC, and PEFR were calculated., Conclusions: Nutritional differences influence qualitative aspects of lung development in childhood beyond simple isotropic lung growth. Prediction of lung function must take account of these differences if change as a result of disease is to be accurately measured. The identification and correction of relevant dietary deficiencies might help to improve lung function in children.

The Wilson disease adenosinetriphosphatase (ATPase; ATP7B) is believed to bind copper as Cu(I). We provide evidence to suggest that the ATPase actually transports Cu as Cu(II). When the copper is presented to rat liver microsomes as Cu(I), virtually all uptake is ATP independent. If the copper is presented as copper oxalate [Cu(II)], total uptake is reduced to approximately 10% of Cu(I) levels, but ATP-dependent uptake rises, both as a proportion of total uptake and in absolute terms. The reducing agent vitamin C and the Cu(I) chelator bathocuproine both override the effect of oxalate. The data indicate that there are two transporters in the microsomes, an ATP-independent Cu(I) transporter and an ATP-dependent Cu(II) pump. The activity of the Cu(I) transporter correlates most strongly with alkaline phosphatase, suggesting that it is derived from plasma membrane contamination. Cu(II) ATP-dependent transport correlates only with beta-1, 4-galactosyltransferase, which indicates that it is located in the Golgi apparatus.

TIPSS was successfully performed in a 10-year-old female cystic fibrosis (CF) patient with bleeding gastric varices due to portal hypertension; precipitation of portosystemic encephalopathy later unveiled the presence of a latent colonic stricture associated with high potency pancreatic enzymes. The unusual sequence of events resulting from the co-existence of two CF pathologies are described, and the implications of treatment discussed.

In freshly isolated fetal guinea pig type II pneumocytes, zinc uptake is time and temperature dependent. Two pathways of uptake exist, resulting in a rapid phase that reaches a steady state within 30 s and a slower linear phase that does not attain a steady state within 60 min. Both processes exhibit saturation kinetics. The rapid phase has a maximal zinc uptake of 60.7 +/- 9.3 pmol.10(6) cells-1.30 s-1 and an apparent affinity (Kt) of 13.7 +/- 5.4 microM. The maximum velocity of uptake (Vmax) of the slower phase is 24.6 +/- 1.9 pmol.10(6) cells-1.min-1 with a Kt of 22.0 +/- 3.6 microM. Epinephrine, terbutaline, dibutyryl adenosine 3',5'-cyclic monophosphate, and dexamethasone have no significant effect on zinc uptake, while arachidonic acid (AA) stimulates. Dose-response data of AA-stimulated zinc uptake gives an apparent K0.5 of 0.42 +/- 0.01 microM and a Hill coefficient of 1. The maximal uptake in the rapid phase is significantly increased to 146.8 +/- 12.4 pmol.10(6) cells-1.30 s-1 and in the slow phase, the Vmax for zinc uptake is also significantly increased to 33.0 +/- 1.8 pmol.10(6) cells-1.min-1 by 10 microM AA. However, the Kt values in both processes remain unchanged after AA stimulation. The effect is not mediated by either leukotrienes or prostaglandins but can be mimicked by other unsaturated fatty acids.