Global Health Education Revamped: Implementation of a Cross-Cultural Virtual Elective Through Continuous Improvement Methods.

Introduction: Virtual platforms can increase access to global health (GH) education and cross-cultural communication. The Cleveland-Cusco Connection (CCC) is a virtual GH elective between medical schools in the USA and Peru. This elective was held annually from 2020 to 2023, with monthly virtual sessions held in English and Spanish to facilitate bidirectional learning about healthcare systems, culture, and barriers to care in both nations. Using student surveys throughout the electives, we report the outcomes, barriers, and changes of the CCC over 3 years. Methods: We administered pre- and post-elective surveys to students in the elective in their native languages. We evaluated self-reported non-native language skills, health systems, GH knowledge, and cultural sensitivity. We also surveyed students about course efficacy in achieving learning objectives and areas for improvement. We performed non-parametric statistical analyses to evaluate trends in survey responses. Results: Over three academic years, 92 students participated in CCC. Students from the US had statistically significant increases in their self-reported understanding of the Peruvian healthcare and medical education systems (p = 0.013). US students also saw an increase in cultural sensitivity scores, with statistically significant increases in the knowledge (p = 0.035) and motivation components (p = 0.031). The most frequently reported challenges encountered throughout the course included: competing coursework assignments, scheduling conflicts, and language barriers. Discussion: Cross-cultural virtual electives demonstrate effectiveness in teaching trainees about international healthcare systems and can improve cultural sensitivity. Strategies to improve the elective include reducing workload, improving engagement for partner countries, and teaching bilingually. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01941-6.

Assessment of Household Food Insecurity During a Medical Mission to Chincha, Peru.

Introduction Food insecurity directly influences health outcomes and is an important consideration for medical missions seeking to address chronic disease, particularly those serving disaster-prone communities. The region of Peru in which we held an inaugural mission is vulnerable to developing food insecurity following natural disasters. We, therefore, sought to evaluate food insecurity to understand the community's needs and inform future public health efforts. Methods In this cross-sectional pilot study, a convenience sample representing the households of patients attending a student-run health fair at the community medical center in Chincha, Peru was assessed for food insecurity. An adult female (n = 30) of each randomly selected family attending the fair was asked to complete the Household Food Security Survey (HFSS) developed by the US Department of Agriculture. The survey items were aggregated into a single, continuous food security scale reflecting the severity of hunger within a household. Results Two-thirds of respondents (n = 20) acknowledged anxiety about having enough food at home over the past 12 months, making it the most common concern. Nearly three in five respondents were concerned about their ability to provide a balanced diet. We found that 16.7% of all households were food insecure with severe hunger, 26.7% were food insecure with moderate hunger, 30% were food insecure without hunger, and 26.7% were food secure. Conclusion Nearly three-quarters of families attending our clinic experience some degree of food insecurity. Families with children were disproportionately affected. The high levels of food insecurity many years after a natural disaster support the development of future social programs such as food pantries. We intend to continue our partnership in Chincha and perform the HFSS survey on a periodic basis to monitor hunger.

An assessment of drinking water contamination with Helicobacter pylori in Lima, Peru.

BACKGROUND: Helicobacter pylori is a gut bacterium that is the primary cause of gastric cancer. H. pylori infection has been consistently associated with lack of access to sanitation and clean drinking water. In this study, we conducted time-series sampling of drinking water in Lima, Peru, to examine trends of H. pylori contamination and other water characteristics. MATERIALS AND METHODS: Drinking water samples were collected from a single faucet in Lima's Lince district 5 days per week from June 2015 to May 2016, and pH, temperature, free available chlorine, and conductivity were measured. Quantities of H. pylori in all water samples were measured using quantitative polymerase chain reaction. Relationships between the presence/absence and quantity of H. pylori and water characteristics in the 2015-2016 period were examined using regression methods accounting for the time-series design. RESULTS: Forty-nine of 241 (20.3%) of drinking water samples were contaminated with H. pylori. Statistical analyses identified no associations between sampling date and the likelihood of contamination with H. pylori. Statistically significant relationships were found between lower temperatures and a lower likelihood of the presence of H. pylori (P < .05), as well as between higher pH and higher quantities of H. pylori (P < .05). CONCLUSIONS: This study has provided evidence of the presence of H. pylori DNA in the drinking water of a single drinking water faucet in the Lince district of Lima. However, no seasonal trends were observed. Further studies are needed to determine the presence of H. pylori in other drinking water sources in other districts in Lima, as well as to determine the viability of H. pylori in these water sources. Such studies would potentially allow for better understanding and estimates of the risk of infection due to exposure to H. pylori in drinking water.

Cytotoxic and Immunomodulatory Potential Activity of Physalis peruviana Fruit Extracts on Cervical Cancer (HeLa) and Fibroblast (L929) Cells.

It was purposed to evaluate the biological potential of ethanol and isopropanol crude extracts of ripe Physalis peruviana fruits. Cytotoxic and immunomodulatory effects of the expression of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 (MCP-1) were evaluated on human cervical cancer (HeLa) and murine fibroblast (L929) cells. The composition was evaluated by high-performance liquid chromatography diode-array detection and high-performance liquid chromatography ultraviolet/visible detection. The presence of ursolic acid and rosmarinic acid was found in both solvents. However, gallic acid, quercetin, and epicatechin were higher in isopropanol extracts ( P < .05). The results indicated a relationship among the total polyphenol content, antioxidant activity, and cytotoxic activity that was dependent on the solvent used. Isopropanol extracts presented a half-maximal inhibition concentration value (IC50) of 60.48 ± 3.8 µg/mL for HeLa cells and 66.62 ± 2.67 µg/mL for L929 fibroblasts. The extracts reduced the release of interleukin-6, interleukin-8, and MCP-1 in a dose-dependent manner. Extracts showed anticancer and immunomodulatory potential for new complementary pharmaceutical products development.

Reduced infectivity of waterborne viable but nonculturable Helicobacter pylori strain SS1 in mice.

BACKGROUND: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable (VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNCH. pylori could cause gastric infection. MATERIALS AND METHODS: We performed five mouse experiments to assess the infectivity of VBNCH. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNCH. pylori in water were chosen to test the "worst-case" scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology. RESULTS: VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNCH. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNCH. pylori. The positive controls exposed to viable, culturable H. pylori did become infected. CONCLUSIONS: While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water.

Antibiotic resistance among Helicobacter pylori clinical isolates in Lima, Peru.

OBJECTIVES: Gastric carcinoma is the most common cancer and cause of cancer mortality in Peru. Helicobacter pylori, a bacterium that colonizes the human stomach, is a Group 1 carcinogen due to its causal relationship to gastric carcinoma. While eradication of H. pylori can help prevent gastric cancer, characterizing regional antibiotic resistance patterns is necessary to determine targeted treatment for each region. Thus, we examined primary antibiotic resistance in clinical isolates of H. pylori in Lima, Peru. MATERIALS AND METHODS: H. pylori strains were isolated from gastric biopsies of patients with histologically proven H. pylori infection. Primary antibiotic resistance among isolates was examined using E-test strips. Isolates were examined for the presence of the cagA pathogenicity island and the vacA m1/m2 alleles via polymerase chain reaction. RESULTS: Seventy-six isolates were recovered from gastric biopsies. Clinical isolates showed evidence of antibiotic resistance to 1 (27.6%, n=21/76), 2 (28.9%, n=22/76), or ≥3 antibiotics (40.8%). Of 76 isolates, eight (10.5%) were resistant to amoxicillin and clarithromycin, which are part of the standard triple therapy for H. pylori infection. No trends were seen between the presence of cagA, vacA m1, or vacA m2 and antibiotic resistance. CONCLUSION: The rate of antibiotic resistance among H. pylori isolates in Lima, Peru, is higher than expected and presents cause for concern. To develop more targeted eradication therapies for H. pylori in Peru, more research is needed to better characterize antibiotic resistance among a larger number of clinical isolates prospectively.

Phase II Trial of Dose-dense Pemetrexed, Gemcitabine, and Bevacizumab in Patients With Advanced, Non-Small-cell Lung Cancer.

INTRODUCTION: Platinum-based chemotherapy is standard for untreated, advanced non-small-cell lung cancer (NSCLC). We investigated the activity and tolerability of the novel combination of dose-dense pemetrexed, gemcitabine, and bevacizumab in patients with advanced NSCLC. METHODS: This multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (400 mg/m2), gemcitabine (1200 mg/m2), and bevacizumab (10 mg/kg), given every 14 days in patients with untreated, advanced NSCLC. The primary endpoint was progression-free survival with secondary endpoints of response rate and overall survival. RESULTS: Thirty-nine patients were enrolled. Treatment was well tolerated; the most common grade 3-4 toxicities were neutropenia and fatigue. Of the 38 patients evaluable for tumor response, 1 (3%) had complete response, 15 (39%) had partial response, 12 (31%) had stable disease, and 10 (26%) had progressive disease. Median progression-free survival was 6.1 months (95% confidence interval [CI], 4.2-7.9) and median overall survival was 18.4 months (95% CI, 13.1-29.5). The 1-year overall survival rate was 64% (95% CI, 51%-81%) and the 2-year overall survival rate was 41% (95% CI, 28%-60%). CONCLUSIONS: Treatment with dose-dense pemetrexed, gemcitabine, and bevacizumab met the primary endpoint with promising efficacy and a manageable safety profile in patients with untreated advanced NSCLC. This regimen represents a reasonable therapeutic option.

The Globalization of Cooperative Groups.

The National Cancer Institute (NCI)-supported adult cooperative oncology research groups (now officially Network groups) have a longstanding history of participating in international collaborations throughout the world. Most frequently, the US-based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the United States, and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the United States or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the United States and Canada, such as those frequently associated with infections in Latin America, Asia, and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to US policies that restrict drug distribution outside the United States. This article serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future.

Correlación entre síntomas gastrointestinales funcionales y la histopatología de la mucosa gástrica, incluyendo la infección por Helicobacter pylori, en Lima, Perú.

OBJECTIVE: This study aims to investigate the relationship between functional gastrointestinal disorders and histopathology characteristics, including H. pylori infection, of gastric mucosa, at Cayetano Heredia National Hospital, Lima-Peru, in 2013. MATERIALS AND METHODS: 112 patients were interviewed prospectively between June and July 2013 in the gastroenterology service. Dyspepsia, irritable bowel syndrome, and postprandial distress syndrome were characterized using the Rome III Survey. RESULTS: Pathology results were determined by gastric biopsies obtained by endoscopy. Of the patients interviewed, biopsy results were obtained for 101. 22.8% had atrophy, 24.8% had intestinal metaplasia, 57.4% presented with H pylori. CONCLUSIONS: Using chi-square analysis, no statistically significant relationship could be identified between clinical presentation and biopsy results.

Correlación entre síntomas gastrointestinales funcionales y la histopatología de la mucosa gástrica, incluyendo la infección por Helicobacter pylori, en Lima, Perú / Correlation between functional gastrointestinal disorders and gastric mucosa histopathology findings, including Helicobacter pylori infection, in Lima, Peru

This study aims to investigate the relationship between functional gastrointestinal disorders and histopathology characteristics, including H. pylori infection, of gastric mucosa, at Cayetano Heredia National Hospital, Lima-Peru, in 2013. Materials and methods: 112 patients were interviewed prospectively between June and July 2013 in the gastroenterology service. Dyspepsia, irritable bowel syndrome, and postprandial distress syndrome were characterized using the Rome III Survey. Results: Pathology results were determined by gastric biopsies obtained by endoscopy. Of the patients interviewed, biopsy results were obtained for 101. 22.8% had atrophy, 24.8% had intestinal metaplasia, 57.4% presented with H pylori. Conclusions: Using chisquare analysis, no statistically significant relationship could be identified between clinical presentation and biopsy results...

El objetivo de este estudio fue investigar la correlación que existe entre la presencia de síntomas gastrointestinales y los hallazgos histopatológicos de la biopsia gástrica incluyendo la presencia de la infección por Helicobacter pylori. Materiales y métodos: Este estudio prospectivo comprendió a 112 pacientes que se incluyeron entre junio y julio de 2013 en el Servicio de Gastroenterología del Hospital Nacional Cayetano Heredia, Lima-Perú a los que se les hizo endoscopía y biopsia gástrica. Los síntomas de dispepsia, síndrome de intestino irritable y síndrome de distrés post prandial fueron obtenidos usando las encuestas de Roma III. Resultados: De los pacientes a los que se les hizo la encuesta sólo en 101 se les evaluó la biopsia. 22,8% tuvo atrofia, 24,8% presentó metaplasia intestinal, y en 57,4% se reportó la infección por Helicobacter pylori. Conclusiones: Usando el análisis con chi-cuadrado no se pudo establecer ninguna correlación estadísticamente significativa entre la presentación clínica y los resultados de las biopsias...

Animal Model Reveals Potential Waterborne Transmission of Helicobacter pylori Infection.

BACKGROUND: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne H. pylori could cause gastric infection. MATERIALS AND METHODS: Groups of immunocompetent C57/BL6 Helicobacter-free mice were exposed to static concentrations (1.29 × 10(5), 10(6), 10(7), 10(8), and 10(9) CFU/L) of H. pylori in their drinking water for 4 weeks. One group of Helicobacter-free mice was exposed to uncontaminated water as a negative control. H. pylori morphology changes in water were examined using microscopy Live/Dead staining. Following exposure, H. pylori infection and inflammation status in the stomach were evaluated using quantitative culture, PCR, the rapid urease test, and histology. RESULTS: None of the mice in the negative control or 10(5) groups were infected. One of 20 cages (one of 40 mice) of the 10(6) group, three of 19 cages (four of 38 mice) of the 10(7) CFU/L group, 19 of 20 cages (33 of 40 mice) of the 10(8) group, and 20 of 20 cages (39 of 40 mice) of the 10(9) CFU/L group were infected. Infected mice had significantly higher gastric inflammation than uninfected mice (27.86% higher inflammation, p < .0001). CONCLUSIONS: We offer proof that H. pylori in water is infectious in mice, suggesting that humans drinking contaminated water may be at risk of contracting H. pylori infection. Much work needs to be performed to better understand the risk of infection from drinking H. pylori-contaminated water.

Risk of recurrent Helicobacter pylori infection 1 year after initial eradication therapy in 7 Latin American communities.

IMPORTANCE: The long-term effectiveness of Helicobacter pylori eradication programs for preventing gastric cancer will depend on recurrence risk and individual and community factors. OBJECTIVE: To estimate risk of H. pylori recurrence and assess factors associated with successful eradication 1 year after treatment. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of 1463 randomized trial participants aged 21 to 65 years from 7 Latin American communities, who were treated for H. pylori and observed between September 2009 and July 2011. INTERVENTIONS: Randomization to 1 of 3 treatment groups: 14-day lansoprazole, amoxicillin, and clarithromycin (triple therapy); 5-day lansoprazole and amoxicillin followed by 5-day lansoprazole, clarithromycin, and metronidazole (sequential); or 5-day lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant). Participants with a positive (13)C-urea breath test (UBT) 6 to 8 weeks posttreatment were offered voluntary re-treatment with 14-day bismuth-based quadruple therapy. MEASUREMENTS: Recurrent infection after a negative posttreatment UBT and factors associated with successful eradication at 1-year follow-up. RESULTS: Among participants with UBT-negative results who had a 1-year follow-up UBT (n=1091), 125 tested UBT positive, a recurrence risk of 11.5% (95% CI, 9.6%-13.5%). Recurrence was significantly associated with study site (P = .03), nonadherence to initial therapy (adjusted odds ratio [AOR], 2.94; 95% CI, 1.31-6.13; P = .01), and children in the household (AOR, 1.17; 95% CI, 1.01-1.35 per child; P = .03). Of the 281 with positive posttreatment UBT results, 138 completed re-treatment, of whom 93 tested UBT negative at 1 year. Among the 1340 who had a 1-year UBT, 80.4% (95% CI, 76.4%-83.9%), 79.8% (95% CI, 75.8%-83.5%), and 77.8% (95% CI, 73.6%-81.6%) had UBT-negative results in the triple, sequential, and concomitant groups, respectively (P = .61), with 79.3% overall effectiveness (95% CI, 77.1%-81.5%). In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4% (95% CI, 69.9%-74.8%) and was significantly associated with study site (P < .001), adherence to initial therapy (AOR, 0.26; 95% CI, 0.15-0.42; P < .001), male sex (AOR, 1.63; 95% CI, 1.25-2.13; P < .001), and age (AOR, 1.14; 95% CI, 1.02-1.27 per decade; P = .02). One-year effectiveness among all 1463 enrolled participants, considering all missing UBT results as positive, was 72.7% (95% CI, 70.3%-74.9%). CONCLUSIONS AND RELEVANCE: One year after treatment for H. pylori infection, recurrence occurred in 11.5% of participants who had negative posttreatment UBT results. Recurrence determinants (ie, nonadherence and demographics) may be as important as specific antibiotic regimen in determining the long-term success of H. pylori eradication interventions. Study findings are relevant to the feasibility of programs for the primary prevention of gastric cancer in high-incidence regions of Latin America. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01061437.

Cancer survivors in the United States: a review of the literature and a call to action.

BACKGROUND: The number of cancer survivors in the U.S. has increased from 3 million in 1971, when the National Cancer Act was enacted, to over 12 million today. Over 70% of children affected by cancer survive more than 10 years, and most are cured. Most cancer survivors are adults, with two-thirds of them 65 years of age or older and two-thirds alive at five years. The most common cancer diagnoses among survivors include breast, prostate and colorectal cancers. This review was conducted to better appreciate the challenges associated with cancer survivors and the opportunities healthcare providers have in making a difference for these patients. METHODS: Comprehensive review of literature based on PubMed searches on topics related to cancer survivorship, and associated physical, cognitive, socio-economic, sexual/behavioral and legal issues. RESULTS: At least 50% of cancer survivors suffer from late treatment-related side effects, often including physical, psychosocial, cognitive and sexual abnormalities, as well as concerns regarding recurrence and/or the development of new malignancies. Many are chronic in nature and some are severe and even life-threatening. Survivors also face issues involving lack of appropriate health maintenance counseling, increased unemployment rate and workplace discrimination. CONCLUSIONS: Advances in the diagnosis and treatment of cancer will lead to more survivors and better quality of life. However, tools to recognize potentially serious long-lasting side effects of cancer therapy earlier in order to treat and/or prevent them must be developed. It is incumbent upon our health care delivery systems to make meeting these patients' needs a priority.

14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial.

BACKGROUND: Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori-associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy. METHODS: Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21-65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6-8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, registration number NCT01061437. FINDINGS: 1463 participants aged 21-65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82·2% (401 of 488), which was 8·6% higher (95% adjusted CI 2·6-14·5) than with concomitant therapy (73·6% [360 of 489]) and 5·6% higher (-0·04% to 11·6) than with sequential therapy (76·5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites. INTERPRETATION: Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations. FUNDING: Bill & Melinda Gates Foundation, US National Institutes of Health.

Phase II study of pemetrexed and cisplatin, with chest radiotherapy followed by docetaxel in patients with stage III non-small cell lung cancer.

BACKGROUND: Pemetrexed has emerged as one of the most active agents for the treatment of patients with advanced non-small cell lung cancer (NSCLC). We conducted a phase II study to assess the efficacy and feasibility of integrating pemetrexed in a concurrent therapy plan for patients with stage III NSCLC. METHODS: Patients with stage III NSCLC with performance status 0 to 1, adequate organ function including pulmonary function, and V20 less than 40% were eligible. Patients were treated with cisplatin 75 mg/m² (first five patients 60 mg/m²) and pemetrexed 500 mg/m² every 21 days for three cycles with chest radiotherapy to 66 Gy. Patients then received three cycles of docetaxel 75 mg/m² every 21 days. Tumors were analyzed for Excision Repair Cross Complementation Group 1 and thymidylate synthase. RESULTS: Patient characteristics (N = 28) were median age, 60; males, 68%; stage IIIB, 64%; and squamous cell, 43%. Twenty-four patients (86%) completed all three cycles of cisplatin/pemetrexed. Of the 24 patients eligible for docetaxel, 21 (87%) received it. Grade 3/4 toxicities were neutropenia (39%), febrile neutropenia (14%), esophagitis (14%), and pneumonitis (4%). Median survival was 34 months, and 1-year survival was 66%. Survival was not significantly different in squamous and other histology patients. Tumor analysis in 16 patients showed that moderate/strong expression of thymidylate synthase was significantly associated with progression-free survival and overall survival. CONCLUSION: Integrating pemetrexed in a concurrent therapy regimen for patients with stage III NSCLC is feasible and was associated with a median survival of 34 months.

A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies.

PURPOSE: BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s). METHODS: This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m(2)/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days. RESULTS: Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m(2)/day to 18 mg/m(2)/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m(2)/day and 18 mg/m(2)/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m(2). Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis. CONCLUSIONS: BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.

A first-in-human study of conatumumab in adult patients with advanced solid tumors.

PURPOSE: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks. RESULTS: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response. CONCLUSIONS: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks.

Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors.

PURPOSE: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors. EXPERIMENTAL DESIGN: Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed. RESULTS: Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1). CONCLUSIONS: Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.

A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871.

PURPOSE: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients. EXPERIMENTAL DESIGN: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done. RESULTS: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied. CONCLUSIONS: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.