A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study.

BACKGROUND: Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies. RESULTS: Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling. CONCLUSIONS: The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors.

Merkel cell polyomavirus and human papilloma virus in proliferative skin lesions arising in patients treated with BRAF inhibitors.

The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.

Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BACKGROUND: This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. METHODS: Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. RESULTS: Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). CONCLUSION: Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.

BRAF inhibitors: experience in thyroid cancer and general review of toxicity.

The US Food and Drug Administration-approved BRAF inhibitors, vemurafenib and dabrafenib, have demonstrated superior efficacy in patients with BRAF-mutant melanomas but have limited efficacy in BRAF-mutant colorectal cancer. Little is known at this time regarding BRAF inhibitors in thyroid cancer. Initial reports in patients with progressive, radioactive iodine-refractory BRAF-mutant papillary thyroid cancer suggest response rates of approximately 30-40%. In this review, we discuss BRAF inhibitors in the context of thyroid cancer, the toxicities associated with BRAF inhibitors, and the suggested management of those toxicities. The management of vemurafenib and dabrafenib toxicities is applicable across all tumor types and may serve as a practical guide to their use.

First-in-human study of pbi-05204, an oleander-derived inhibitor of akt, fgf-2, nf-κΒ and p70s6k, in patients with advanced solid tumors.

BACKGROUND: PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100% using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5%), nausea (19 patients, 41.3%) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade ≥ 3 was observed in seven patients treated. Seven patients (15%) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 µg/L*hr and a half-life range of 5-13 h. There was an average 10% and 35% reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.

The prognostic significance of left ventricular ejection fraction in patients with advanced cancer treated in phase I clinical trials.

BACKGROUND: New targeted agents may cause acute cardiac events. The purpose of our study was to investigate the incidence and the prognostic significance of left ventricular ejection fraction (LVEF) in phase I trials. PATIENTS AND METHODS: Between October 2008 and September 2011, the records of 1166 consecutive patients with advanced cancer treated in the Phase I Clinic who underwent echocardiography were retrospectively reviewed. RESULTS: Most of the patients were White (78%), and the most common tumor types were colorectal cancer and melanoma. Of 1166 patients, 177 (15.2%) patients had an LVEF of <50%. No difference in overall survival (OS) between patients with LVEF ≥ 50% and patients with LVEF < 50% was seen (median OS 7.4 versus 7.0 months, P = 0.84). Patients with LVEF ≤ 35% had shorter survival compared with those with LVEF between 35% and 50% (median 4.2 versus 8.0 months; P = 0.005). In multivariate analysis of patients with LVEF < 50%, independent factors predicting longer survival were LVEF > 35%, ≤2 prior systemic therapies, ≤2 metastatic sites, and normal lactate dehydrogenase and albumin levels. CONCLUSION: Echocardiography would improve patient selection for enrollment in phase I clinical trials. These data suggest that it is safe to treat patients with LVEF between 35% and 50%.

A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors.

The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer.

BACKGROUND: Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses. PATIENTS AND METHODS: We conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response. RESULTS: Twenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) ≥6 months and partial or complete remission (PR/CR) was 50% (five patients with SD ≥6 months; seven PRs (including one unconfirmed); one CR). The rate of SD ≥6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels. CONCLUSIONS: The combination of trastuzumab, lapatinib and bevacizumab was well-tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation. CLINTRIALSGOV ID: NCT00543504.

Melanoma patients in a phase I clinic: molecular aberrations, targeted therapy and outcomes.

BACKGROUND: The purpose of the study was to assess the outcome of patients with advanced melanoma treated with matched molecularly targeted therapy. PATIENTS AND METHODS: We reviewed 160 consecutive patients with metastatic melanoma treated in the phase I program (N = 35 protocols). Treatment was considered to be 'matched' (N = 84) if at least one drug in the regimen was known to inhibit the functional activity of at least one of the patient's mutations. RESULTS: Of 160 patients, 134 (83.7%) had adequate tissue for molecular analysis; 69% (110 of 160) had ≥1 mutation: 61.2% (82 of 134), BRAF; 20.7% (23 of 111), NRAS; 2.6% (2 of 77), KIT; 2.3% (1 of 44), KRAS; 20% (1 of 5), GNAQ; 11.1% (1 of 9), P53 and 2.6% (1 of 39), coexisting mutations in BRAF and PIK3CA. Eighty-four patients (52.4%) were treated with matched-targeted agents, most of whom had BRAF mutations (N = 74). Twenty-six percent of patients (41 of 160) achieved a complete or partial remission (CR/PR) [40% (34 of 84)) on a matched phase I protocol versus 9.2% (7 of 76) for those on a non-matched study (P ≤ 0.0001)]. The median progression-free survival (PFS) (95% CI) was longer for patients treated on a matched phase I trial than on their prior first standard treatment [5.27 (4.10, 6.44) versus 3.10 (1.92, 4.28) months, P = 0.023], but not on non-matched phase I treatment. Multivariable analysis showed that matched therapy was an independent predictor of higher CR/PR rates, prolonged PFS and survival. CONCLUSIONS: For melanoma patients, especially those with BRAF mutations, administering molecularly matched agents can be associated with better outcomes, including longer PFS compared with their first-line systemic therapy.

BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance.

Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers. PATIENTS AND METHODS: Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy. RESULTS: EGFR aberrations were detected in 34 of 958 patients (3.5%). Though EGFR mutations were most frequent in NSCLC (21 of 131, 16%), they were also present in a variety of other solid tumors (13 of 827 patients, 1.6%) including adrenocortical (1/10 patients), skin (1/24), breast (1/55), carcinoid (1/8), cholangiocarcinoma (1/20), head and neck (1/61), ovarian (1/84), parathyroid (1/1), salivary gland (1/20), renal (1/17), sarcoma (2/38), and thymic carcinomas (1/7). Of the 13 EGFR aberration-positive non-NSCLC patients (median number of prior systemic therapies = 3), 6 had treatment with an EGFR inhibitor. Two patients (diagnosis = parathyroid tumor and basal cell carcinoma) achieved stable disease (SD), lasting 6 and 7 months, respectively. CONCLUSION: We found EGFR aberrations in 1.6% of a large group of patients with diverse tumors other than NSCLC, and treatment with an EGFR inhibitor could be associated with prolonged SD.

Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs.

BACKGROUND: Cardiac sequelae from oncologic drugs are important in early cancer drug development. Prolongation of the corrected QT interval (QTc) by noncardiac drugs is the most common cause of drug development delays, nonapprovals and postmarketing withdrawals by the US Food and Drug Administration. PATIENTS AND METHODS: We analyzed 8518 electrocardiograms (ECGs) in 525 consecutive cancer patients enrolled in 22 industry-sponsored phase I clinical trials, starting 1 January 2006. RESULTS: Seventy-four patients [14%, 95% confidence interval (CI) 11% to 17%] with normal QTc at baseline had QTc intervals above upper limit of normal after treatment initiation; 33 (6%, 95% CI 4% to 9%) had prolonged QTc intervals at baseline, and only one (3%, 95% CI 0% to 16%) worsened after dosing. Seven of 33 patients (21%, 95% CI 9% to 39%) with prolonged baseline QTc had normalization of QTc intervals after dosing. All QTc prolongations were clinically insignificant; study drugs were continued uneventfully. Two of 525 patients (0.4%, 95% CI 0% to 1%) experienced cardiac serious adverse events (myocardial infarction possibly related to drug and unstable atrial flutter related to metastatic disease). Both cardiac events were detected by clinical assessment, not surveillance ECGs. CONCLUSION: Frequent ECG monitoring provided no clinically significant information in 525 patients in early phase trials.

Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience.

BACKGROUND: This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents. PATIENTS AND METHODS: An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out. RESULTS: All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a cytotoxic agent were selected as independent factors associated with serious toxicity. CONCLUSION: Phase I trials of primarily targeted agents showed low rates of toxicity, with 10.3% of patients experiencing grade 3 or 4 toxicity and a 0.4% rate of death, at least possibly drug related.

Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies.

BACKGROUND: Preclinical data suggest synergistic activity of bortezomib, gemcitabine, and liposomal doxorubicin. Because tolerance to therapy may be attenuated in elderly patients, we performed an age-stratified phase I trial of this combination. PATIENTS AND METHODS: Two parallel age-stratified arms (< 65 and ≥ 65 years old) were accrued (3 + 3 design). Starting doses included bortezomib 0.7 mg/m(2) (days 1 and 8), gemcitabine 500 mg/m(2) (days 1 and 8), and liposomal doxorubicin 20 mg/m(2) (day 1). RESULTS: In the < 65-year-old group, 65 patients were treated; the maximum-tolerated dose was bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 35 mg/m(2). In the ≥ 65-year-old group, 28 patients were treated; the recommended phase II dose was bortezomib 1.0 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 20 mg/m(2). Dose-limiting toxicities included thrombocytopenia and neutropenia. The most common toxicities were mild cytopenias, fatigue, and neuropathy. Ten patients achieved partial responses (6 of 7 patients with cutaneous T-cell lymphoma; 4 of 16 patients with small cell carcinomas, including lung, prostate, ovarian, and nasopharyngeal). CONCLUSION: Combination of bortezomib, gemcitabine, and liposomal doxorubicin is well tolerated, but with a lower recommended phase II dose in elderly patients, and demonstrated antitumor activity, especially in T-cell and small cell histology malignancies.

Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma; treatment with standard anthracycline-containing chemotherapy regimens has been disappointing, and an optimal treatment strategy for this patient population has not yet been determined. METHODS: We identified 15 cases of pathologically confirmed HSTCL in the institution's database. Clinical characteristics and treatment results were reviewed. RESULTS: Complete responses (CRs) were achieved in 7 of 14 patients who received chemotherapy. Achievement of CR was followed by hematopoietic stem-cell transplantation in three patients. Median duration of CR was 8 months (range 2 to 32+ months) with four patients currently alive and in CR at 5, 8, 12, and 32 months, respectively. Median overall survival (OS) was 11 months (range 2 to 36+ months). Patients who achieved a CR had a median OS of 13 months, compared with 7.5 months in patients who did not achieve a CR. Risk factors associated with worse outcome included male gender, failure to achieve a CR, history of immunocompromise, and absence of a T-cell receptor gene rearrangement in the gamma chain. CONCLUSION: A better understanding of the pathophysiology of HSTCL and new therapeutic strategies are needed.

Tuberculosis screening, referral, and treatment in an inner city homeless shelter in Orleans parish.

Tuberculosis screening and preventive therapy among the homeless has been a challenge because of the lack of coordinated follow-up. Homeless persons at a homeless shelter in inner city New Orleans were screened for tuberculosis infection and referred for follow-up evaluation and preventive therapy. Fifty-two percent of the 104 persons screened completed the initial evaluation. Twenty-two percent of these patients had latent tuberculosis infection. Forty-two percent of infected patients completed the referral and follow-up process. Patients during the second 3 months of the program were twice as likely to complete the initial evaluation, the referral, and the follow-up process as were patients during the first 3 months due to enhanced awareness and increased educational intervention. A competent referral system for homeless persons may be achieved by implementing a single-clinic, on-site tuberculosis screening and follow-up system with the active participation and coordination of state agencies, the medical community, and organizations which operate homeless facilities.

Sensitivity of neurons in somatosensory cortex (S1) to cutaneous stimulation of the hindlimb immediately following a sciatic nerve crush.

While a large number of studies have examined receptive field alterations in the cerebral cortex after peripheral nerve injury, descriptions of neuronal sensitivity have been largely qualitative. In the present study, quantitative changes in minimal force thresholds evoking cortical responses were examined in somatosensory cortex (S1) of the rat after peripheral nerve injury. Cutaneous receptive fields were defined by conventional multi-unit recording techniques. Thresholds for evoking cortical responses were defined using Semmes-Weinstein monofilaments to stimulate the skin over the distal and proximal hindlimb, and over the adjacent tail, lower back and abdomen. Then minimal force thresholds and representational areas were compared. Receptive fields were recorded before and within 3 h after a sciatic nerve crush injury. Group comparisons were also made with intact (control) rats in which more detailed maps were derived. The results show that the minimal force thresholds for activation of newly emerged responses were not statistically different from thresholds for evoking pre-crush responses. These quantitative data provide strong support for the notion that functional boundaries in S1 between saphenous and sciatic representations and between distal and proximal hindlimb representations are actively maintained by selective inhibition of subsets of overlapping inputs. Formerly inhibited responses can be activated by low-threshold cutaneous stimulation immediately following peripheral nerve injury.