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.

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.

Geographic name resolution service: A tool for the standardization and indexing of world political division names, with applications to species distribution modeling.

Massive biological databases of species occurrences, or georeferenced locations where a species has been observed, are essential inputs for modeling present and future species distributions. Location accuracy is often assessed by determining whether the observation geocoordinates fall within the boundaries of the declared political divisions. This otherwise simple validation is complicated by the difficulty of matching political division names to the correct geospatial object. Spelling errors, abbreviations, alternative codes, and synonyms in multiple languages present daunting name disambiguation challenges. The inability to resolve political division names reduces usable data, and analysis of erroneous observations can lead to flawed results. Here, we present the Geographic Name Resolution Service (GNRS), an application for correcting, standardizing, and indexing world political division names. The GNRS resolves political division names against a reference database that combines names and codes from GeoNames with geospatial object identifiers from the Global Administrative Areas Database (GADM). In a trial resolution of political division names extracted from >270 million species occurrences, only 1.9%, representing just 6% of occurrences, matched exactly to GADM political divisions in their original form. The GNRS was able to resolve, completely or in part, 92% of the remaining 378,568 political division names, or 86% of the full biodiversity occurrence dataset. In assessing geocoordinate accuracy for >239 million species occurrences, resolution of political divisions by the GNRS enabled the detection of an order of magnitude more errors and an order of magnitude more error-free occurrences. By providing a novel solution to a significant data quality impediment, the GNRS liberates a tremendous amount of biodiversity data for quantitative biodiversity research. The GNRS runs as a web service and is accessible via an API, an R package, and a web-based graphical user interface. Its modular architecture is easily integrated into existing data validation workflows.

A phase 1 study of intermittently administered pazopanib in combination with continuous daily dosing of lapatinib in patients with solid tumors.

PURPOSE: Preclinically, pazopanib/lapatinib combination acted synergistically to suppress the activity of multiple tyrosine kinases, including VEGFR-1, 2, 3, PDGFR and c-kit (pazopanib), HER1/EGFR and HER2 (lapatinib), and several other tyrosine kinases including c-Met through, plausibly, network inhibition effects. Clinically, continuous dosing of pazopanib/lapatinib combination was associated with a higher response rate than with lapatinib monotherapy, with poor tolerance. We explored multiple intermittent dose levels of pazopanib combined with continuous daily dosing of lapatinib in patients with solid tumors. METHODS: The present study used a phase 1, modified 3 + 3, dose-escalation design to evaluate the safety and tolerability of the combination of orally received pazopanib once every other day with continuous daily dosing of lapatinib for 28 days. In the expansion phase, tumor response was evaluated in patients with specific genetic alterations (HER2 amplification, HER2 mutation, c-Met amplification, c-Met mutation, and EGFR mutation). RESULTS: Twenty-four patients were treated. The most common drug-related adverse events were fatigue 7/24 (29%), skin rash 5/21 (21%), and diarrhea 3/24 (17%), with 4/24 (16%) patients experiencing grade ≥3 drug-related adverse events. Escalation to the FDA-approved dose (800 mg daily for pazopanib and 1500 mg every day for lapatinib) was not feasible due to toxicities. Pazopanib 200 mg every other day + lapatinib 500 mg daily was considered the maximum tolerated dose (MTD). No tumor response was observed, including in patients with the specific molecular genetic alterations tested. CONCLUSION: Every other day dosing of pazopanib combined with daily lapatinib was tolerated at the established MTD, but no complete or partial tumor responses were observed at these dose levels.

Body weight and the pituitary response to hypothalamic releasing hormones in patients with anorexia nervosa.

Fifteen women with anorexia nervosa were studied before and after weight gain. Basal plasma thyroid stimulating hormone (TSH) and prolactin (PRL), and the responses of both these hormones to thyrotropin releasing hormone (TRH), were normal. Basal plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) were low in patients who were emaciated, and their responses to gonadotropin releasing hormone (GnRH) were impaired. Both basal and stimulated levels of LH and FSH rose with weight gain, with a linear correlation between gonadotropin levels and body weight expressed as a percentage of standard. The FSH response became greater than normal in patients who had regained weight to more than 70% of standard, while the LH response to GnRH was exaggerated in those who had regained weight to more than 80%. Basal plasma estradiol (E2) levels were low at first, but returned to within the normal range in patients over 80% of standard. Menstruation resumed in some patients after they had regained weight. The relationship between body weight and gonadotropin levels appears to be an important feature of the menstrual disturbance in anorexia nervosa. The restoration of a normal body weight is a prerequisite for the resumption of menstruation in this condition, but other as yet unidentified factors may also be involved.

A case of tranylcypromine ('Parnate') addiction.

A case of addiction to tranylcypromine is described where tolerance occurred and a severe withdrawal illness followed discontinuation of the drug. Previous reports in the literature of similar cases are reviewed and comparisons made, and the implications for management are discussed.

Compulsory treatment of 50 alcoholic drunken drivers. A follow-up study.

Fifty alcoholic drunken drivers receiving treatment as part of a suspended sentence were studied to assess the efficacy of compulsory treatment. Twenty-six showed improvement in drinking behaviour, 12 did not co-operate and were referred back to court, 7 were re-arrested on further charges of drunken driving and 4 were committed to long-term rehabilitation centres (1 patient died too early to allow for adequate follow-up). The results compare favourably with improvement in alcoholics treated voluntarily. When regarded as their own controls, patients who had previously been arrested for drunken driving but had not been referred for treatment showed considerable improvement in their behaviour, as did patients who had had previous unsuccessful voluntary treatment. This programme appears to be worth while, at least for the duration of the suspended sentence. It also encourages early identification of alcoholics and their referral for treatment.

"Dieters" and "vomiters and purgers" in anorexia nervosa.

Thirty-one females with primary anorexia nervosa were studied by means of a retrospective analysis of hospital notes. The patients were divided into 2 groups. The first group consisted of subjects who had become emaciated solely because of dieting, food refusal and excessive exercising ("dieters"); the second of those who had used additional means to bring about weight loss such, as habitual vomiting and the abuse of purgatives ("vomiters and purgers"). Most "dieters" were intense, introverted, socially withdrawan individuals whose anorexia behaviour had started in response to psychological stress. They had become completely preoccupied with thoughts of food, eating and losing weight. Several did well in treatment, and recovered fully from their anorexic symptoms. "Vomiters and purgers", on the other hand, were more outgoing in respect to personality. Most had previously been obese and, as they had been unable to keep themselves thin by simply abstaining from food, they had learnt to use other means to control their weight. These latter patients did less well in treatment. They continued to experience difficulty in controlling their weight, and the majority persisted with their abnormal behaviour.

Some personality characteristics of patients with anorexia nervosa.

Twenty-two female patients with anorexia nervosa were assessed by means of objective personality testing. The EPI, Leyton Obsessional Inventory, Cattell's 16 PF and Raven's Matrices were used for this purpose. The personality profile that emerged was of a highly neurotic and introverted person with moderately severe obsessional features and average intelligence.