Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation

AbstractEndothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients.Biol Blood Marrow Transplant 2000;6(3A):301-8

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P \u3c .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN

Rapid implementation mapping to identify implementation determinants and strategies for cervical cancer control in Nigeria

BackgroundCervical cancer constitutes a huge burden among women in Nigeria, particularly HIV-infected women. However, the provision and uptake of cervical cancer screening and treatment is limited in Nigeria. Understanding implementation determinants is essential for the effective translation of such evidence-based interventions into practice, particularly in low-resource settings. COVID-19 pandemic necessitated online collaboration making implementation mapping challenging in some ways, while providing streamlining opportunities. In this study, we describe the use of a virtual online approach for implementation mapping (steps 1–3) to identify implementation determinants, mechanisms, and strategies to implement evidence-based cervical cancer screening and treatment in existing HIV infrastructure in Nigeria.MethodsThis study used a mixed methods study design with a virtual modified nominal group technique (NGT) process aligning with Implementation Mapping steps 1–3. Eleven stakeholders (six program staff and five healthcare providers and administrators) participated in a virtual NGT process which occurred in two phases. The first phase utilized online surveys, and the second phase utilized an NGT and implementation mapping process. The Exploration, Preparation, Implementation and Sustainment (EPIS) framework was used to elicit discussion around determinants and strategies from the outer context (i.e., country and regions), inner organizational context of existing HIV infrastructure, bridging factors that relate to bi-directional influences, and the health innovation to be implemented (in this case cervical cancer screening and treatment). During the NGT, the group ranked implementation barriers and voted on implementation strategies using Mentimeter.ResultsEighteen determinants to integrating cervical cancer screening and treatment into existing comprehensive HIV programs were related to human resources capacity, access to cervical cancer services, logistics management, clinic, and client-related factors. The top 3 determinants included gaps in human resources capacity, poor access to cervical cancer services, and lack of demand for services resulting from lack of awareness about the disease and servicesA set of six core implementation strategies and two enhanced implementation strategies were identified.ConclusionsRapid Implementation Mapping is a feasible and acceptable approach for identifying and articulating implementation determinants, mechanisms, and strategies for complex healthcare interventions in LMICs

E. coli growth inhibition by a high copy number derivative of plasmid pBR322

We have observed that plasmid pKH47, a pBR322-derivative containing a 100bp poly(dA)-poly(dT) insertion, causes growth inhibition of host E. coli cells harboring it. In this paper we show that this inhibitory effect is due to an increased copy number property of this plasmid, which is turn leads to an over expression of the plasmid-encoded tet gene. Our work also indicates that contrary to other pleiotropic effects caused by the tet gene product, which solely depend on the expression of the 5' end of the gene, growth inhibition requires an intact tet gene. In addition we present the isolation of an E. coli mutant that is refractive to the inhibitory effect of pKH47 and shares some properties with the parental bacteria containing plasmid pKH4

Single Agent Irinotecan for the Treatment of Metastatic or Recurrent Squamous Carcinoma of the Head and Neck (SCCHN)

Background Patients with recurrent or metastatic head and neck cancer (HNC) have a poor response and survival with currently available chemotherapy agents. Thus new agents are needed. We report the results of a phase II trial of irinotecan in patients with metastatic or recurrent HNC. Patients and Methods Chemonaive patients were treated with irinotecan 125 mg/m 2 on a weekly schedule for four weeks, followed by a two week rest. However, due to excessive toxicity, the dose and schedule of irinotecan was changed to 75 mg/m 2 on days 1 and 8 of a 21 day cycle. All previously treated patients received 75 mg/m 2 on days 1 and 8 of a 21 day cycle. Results Forty-nine patients were enrolled on study. The response rate was 20% in the chemonaive patients treated at the 125 mg/m 2 dose. The response rate decreased to 12.5% at the 75 mg/m 2 dose. In the previously treated cohort, the response rate was 20%. Median survival for the chemonaive and previously treated cohorts were 6.7 months and 5.0 months, respectively. Conclusions Irinotecan has modest activity in chemonaive and previously treated HNC, thus it merits further study in this advanced disease population

Concurrent chemoradiotherapy using carboplatin/cetuximab regimen in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) not eligible for high-dose cisplatin (HD-DDP)

e16001 Background: Cetuximab (Cx) + radiation therapy (RT) is well tolerated and has improved survival in patients (pts) with LA-HNSCC. However, its efficacy when compared to HD-DDP + RT has been questioned. At our institution, low-dose weekly carboplatin (Carbo) is added to Cx + RT for pts unsuitable for HD-DDP. Methods: We reviewed records of 16 pts with LA-HNSCC treated with definitive Cx + Carbo + RT at the University of Miami from 2007-2011. Median follow-up was 9.4 months (range: 1-50 months). Results: Median age: 71.5 years (range: 57-90 years); 15 male, 1 female.ECOG PS 0=15, 1=1. TNM staging was: T1= 1, T2= 5, T3=8, T4=2; N stage: N0=8, N1=5, N2a=2, N2b=1. All pts received weekly Carbo (AUC 1.5-2), Cx given conventionally and daily conventionally-fractionated RT. Median total weeks of concurrent systemic therapy= 7 (range: 3-8 weeks). RT was delivered to a median total dose of 70 Gy (range 30-74 Gy). Of the 15 evaluable pts, there were: 12 CR, 2 PR, and 1 PD. There were 2 local in-field failures, 1 regional failure, and 3 distant failures. At last follow-up, 11/16 pts remained with NED. 3-year locoregional recurrence was 29.5% (95% CI: 5.3%-45.9%). Toxicity (NCI-CTCAE v4.0): Mean percentage of weight loss was 14% (range: 6-26%). Two pts required systemic therapy dose-reduction. Three pts experienced a treatment delay and 3 did not finish RT as planned including one pt who received only 30Gy due to death secondary to MI during treatment. Conclusions: In this small retrospective series, Carbo/Cx/RT was well-tolerated and efficacious in pts unsuitable for HD-DDP having LA-HNSCC. Acute toxicities were similar to Cx + RT, likely due to the non-overlapping toxicity profiles of the two systemic agents. We hypothesize that the addition of a well-tolerated cytotoxic chemotherapy agent may improve the therapeutic ratio of Cx + RT in pts who are poor candidates for more aggressive therapies and warrants evaluation in a prospective manner. [Table: see text

Efficacy and Safety of Glembatumumab Vedotin in Patients With Advanced or Metastatic Squamous Cell Carcinoma of the Lung (PrECOG 0504)

Glycoprotein NMB is a transmembrane protein linked with poor prognosis and is expressed in most squamous lung cancer. Glembatumumab vedotin is an antibody-drug conjugate targeting glycoprotein NMB, administered intravenously every 3 weeks in this phase 1 study to determine the safety, tolerability, and maximum tolerated dose in patients who had progressed on any number of previous therapies. A total of 13 patients were enrolled; adverse events (of any grade) including dyspnea, neutropenia, respiratory failure, anemia, increased aspartate transaminase/alanine transaminase, diarrhea, and hypophosphatemia were seen in 15% of patients. Grade 5 events included two cases of respiratory failure, either completely or partially attributed to cancer progression. The only other grade 5 event was “disease progression.” The most common adverse events (23%) were decreased appetite, fatigue, rash, and weight loss. The median overall and progression-free survivals were 5.7 months (90% confidence interval: 2.5–16.8) and 2.5 months (90% confidence interval: 1.6–5.8) respectively. Glembatumumab vedotin exhibited no serious or unexpected toxicity in this heavily pretreated population, except those caused by disease progression. Modest anticancer activity was observed with a recommendation for a phase 2 dose of 1.9 mg/kg. This portion of the study was not undertaken owing to the company’s decision to discontinue drug development