Toxicokinetics of plasmatic VX in a swine model: comparison of a simple enzymatic titration method with a mass spectrometry method.

Recent events have shown that organophosphorus nerve agents (OPNAs) are a serious threat. Cholinesterase inhibition by OPNAs results in acetylcholine accumulation, a cholinergic crisis leading to death if untreated. Efficacy assessment of new medical countermeasures against OPNAs relies on translational animal models. We developed a swine model of percutaneous VX intoxication and a simple plate reader-based enzymatic method to quantify plasmatic VX over time. Juvenile pigs anesthetized with sevoflurane were poisoned with a single supralethal (n = 5; 1200 µg/kg) or sublethal (n = 6; 320 µg/kg) percutaneous dose of VX. These intoxicated animals were compared to 7 control animals. Repeated blood sampling was performed up to 6 h post-intoxication. Blood cholinesterase activities were measured using the Ellman assay. Nanomolar plasma concentrations of VX were measured by exogenous butyrylcholinesterase added to an aliquot of plasma. As expected, we observed a steady increase in plasma concentration of VX over time concomitant to a decrease in blood cholinesterase activities for all intoxicated pigs. Despite the simplicity of the enzymatic method, the results obtained are in good agreement with those of the liquid chromatography-mass spectrometry method. This method is also applicable to other OPNAs such as novichoks with minor adaptations.

Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer.

PURPOSE: Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. METHODS: Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. RESULTS: At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. CONCLUSIONS: In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

Expected and paradoxical effects of obesity on cancer treatment response.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

Thyroid nodule recurrence following lobo-isthmectomy: incidence, patient's characteristics, and risk factors.

PURPOSE: This study was aimed at assessing the incidence and timing of thyroid nodules recurrence, defined as appearance of new benign or malignant nodules in contralateral lobe in patients with benign thyroid nodules or thyroid microcarcinoma treated with lobo-isthmectomy. Patient's characteristics and risk factors associated with this phenomenon were also investigated. METHODS: A retrospective study was performed by evaluating 413 patients undergoing lobo-isthmectomy with a minimum follow-up of 1 year. Clinical characteristics, surgical interventions and complications, histological diagnosis, and thyroid function at last follow-up were collected. RESULTS: Single or multiple thyroid nodule recurrence equally occurred in 80 patients (23%) with a median time to relapse of ~ 5 years (range 0.3-34.5 years) after lobo-isthmectomy. Recurrence was significantly associated with younger age (< 46 years) and number of pregnancies in women. Development of hypothyroidism was not rare either (~ 10%) and appeared in 3-19 months; a preoperative TSH level > 2.43 mIU/L was associated with the need of l-thyroxin replacement therapy after surgery. The most frequent surgical complication was transient hypoparathyroidism (4.6%), while the rate of permanent hypoparathyroidism significantly increased in patients submitted to completion thyroidectomy (5.3%). CONCLUSIONS: Thyroid nodules recurrence following lobo-isthmectomy is not a rare event and occurs within 5 years after surgery, more frequently in younger patients with family history of nodular goiter and in women with multiple pregnancies. Pre-surgical TSH levels may predict the development of post-surgical hypothyroidism, possibly improving the management of patients addressed to surgery.

Gonadal status in long-term male survivors of childhood cancer.

PURPOSE: To evaluate the prevalence of gonadal dysfunction and the associated risk factors in a cohort of male childhood cancer survivors (CCS). METHODS: Gonadal function was evaluated measuring FSH, LH, inhibin B and total testosterone levels. Patients with total testosterone <3 ng/dl were considered to have hypogonadism. Patients with FSH >10 UI/l and inhibin B <100 pg/ml were considered to have spermatogenesis damage (SD). To assess the impact of risk factors, we estimated crude and adjusted OR performing logistic regression models. RESULTS: One hundred and ninety-nine male CCS were enrolled; the median follow-up time was 14.01 years. SD was diagnosed in 68 patients, 16 CCS had primary hypogonadism, and 13 had central hypogonadism. The prevalence of gonadal dysfunction (SD or primary hypogonadism) was 45 %, similar in the three considered periods of pediatric cancer diagnosis (1985-1989, 1990-1999, >2000). The adjusted risk of gonadal dysfunction was higher in patients treated with radiotherapy (OR = 8.72; 95 % CI 3.94-19.30) and in those exposed to both alkylating and platinum-derived agents (OR = 9.22; 95 % CI 2.17-39.23). Sarcomas were the cancer diagnosis associated with the higher risk of gonadal dysfunction (OR = 3.69; 95 % CI 1.11-12.22). An extremely high rate of gonadal dysfunction was detected in patients who underwent hematopoietic stem cell transplantation and/or total body irradiation. CONCLUSIONS: Gonadal dysfunction still remains a significant late effect of anticancer therapies; thus, it is mandatory to inform patients (and parents) about this risk, and semen cryopreservation should be offered to all boys who are able to produce semen.

Non-scheduled consultation in oncologic patients. How many of them are true emergencies? An observational prospective study.

Oncologic emergencies have been extensively described and clearly defined. In oncology daily practice, cancer patients seek non-scheduled medical care in situations they perceive as a medical emergency, but which may not be a true emergency. The aim of the study was to identify the main symptoms leading to a non-scheduled consultation (NSC) and their relationship to the type of cancer, and to evaluate whether the diagnosis at discharge of patients admitted as result of a NSC correlates with a true oncologic emergency. This was a prospective observational study. Between July 2002 and April 2003, 365 NSCs were recorded. The most frequent baseline diseases were breast cancer (70), lung cancer (67), gastrointestinal cancer (52), lymphoma (42) and ovarian cancer (22). The most common symptoms for consultation were: fever (84), pain (81), cutaneous manifestations (26), dyspnea (23), bleeding (16) and abdominal distention (16). Overall, 114 of 365 NSCs (31%) resulted in admission. The most frequent symptoms resulting in admission were fever (42), pain (16), dyspnea (11), vomiting (9), neurologic manifestations (7), abdominal distention (6) and anuria (6). At discharge, only 30 patients (26%) admitted after a NSC were diagnosed with a defined oncologic emergency: febrile neutropenia (13), intestinal occlusion (12), obstructive uropathy (4) and abdominal perforation (1). True emergencies were not the most frequent causes of NSC at our institution.

Reacciones agudas de hipersensibilidad secundarias a la infusión de quimioterapia ambulatoria: experiencia del Instituto Alexander Fleming / Secondary hypersensitivity reactions to antineoplastic agents: report of Instituto Alexander Fleming (Argentina)

Objetivo: Evaluar retrospectivamente las características de nuestra población, sus patologías prevalentes y las drogas recibidas; evaluar la naturaleza de las reacciones agudas de hipersensibilidad (RAH) producidas por la infusión de agentes antineoplásicos; evaluar las maniobras médicas instauradas y la necesidad de que estos tratamientos sean realizados en el ámbito hospitalario. Material y métodos: Se consideraron los pacientes (ptes.) que concurrieron a hospital de día para recibir tratamiento ambulatorio; se categorizaron las reacciones agudas en severas (requieren maniobras médicas activas para reestablecer la estabilidad clínica y se debe suspender la infusión) y moderadas (requieren maniobras médicas activas pero se puede reiniciar la infusión) sin considerarse las reacciones leves (por ej.: acatisia, eritema facial) ni las extravasaciones, se categorizaron las maniobras médicas en complejas (inotrópicos, internación) y no complejas (corticoides, antihistamínicos, alta institucional)...

Tratamiento en cáncer de próstata avanzado con flutamida y finasteride con preservación de la potencia sexual: seguimiento a largo plazo / Flutamide and finasteride in men with advanced prostatic cancer, with preservation of sexual potency: long term follow-up

Introducción: los efectos adversos del tratamiento andrógeno ablativo en pacientes con cáncer de próstata avanzado han estimulado la búsqueda de nuevas combinaciones de tratamiento con actividad similar pero con menor toxicidad. La combinación de un antiandrogógeno periférico como flutamida o bicalutamida con el inhibidor de la 5-alfa reductasa, finasteride, constituye un desarrollo racional para el tratamiento del cáncer de próstata avanzado. Pacientes y métodos: flutamida 750 mg/día o bicalutamida 50 mg/día más finasteride 5 mg fue administrado a pacientes con cáncer de próstata avanzado que rechazaron bloqueo con análogos o, una vez iniciado el mismo, se negaron a continuar con dicho tratamiento. Entre 2/96 y 4/02 realizaron tratamiento 32 ptes., edad mediana de 67 (r 48-80) grupo A y 69,5 (r 49-88) grupo B; mediana de score de Gleason 6. Seis pacientes realizaron previamente tratamiento andrógeno ablativo por una mediana de 5 meses...

Reacciones agudas de hipersensibilidad secundarias a la infusión de quimioterapia ambulatoria: experiencia del Instituto Alexander Fleming / Secondary hypersensitivity reactions to antineoplastic agents: report of Instituto Alexander Fleming (Argentina)

Objetivo: Evaluar retrospectivamente las características de nuestra población, sus patologías prevalentes y las drogas recibidas; evaluar la naturaleza de las reacciones agudas de hipersensibilidad (RAH) producidas por la infusión de agentes antineoplásicos; evaluar las maniobras médicas instauradas y la necesidad de que estos tratamientos sean realizados en el ámbito hospitalario. Material y métodos: Se consideraron los pacientes (ptes.) que concurrieron a hospital de día para recibir tratamiento ambulatorio; se categorizaron las reacciones agudas en severas (requieren maniobras médicas activas para reestablecer la estabilidad clínica y se debe suspender la infusión) y moderadas (requieren maniobras médicas activas pero se puede reiniciar la infusión) sin considerarse las reacciones leves (por ej.: acatisia, eritema facial) ni las extravasaciones, se categorizaron las maniobras médicas en complejas (inotrópicos, internación) y no complejas (corticoides, antihistamínicos, alta institucional)...(AU)

Tratamiento en cáncer de próstata avanzado con flutamida y finasteride con preservación de la potencia sexual: seguimiento a largo plazo / Flutamide and finasteride in men with advanced prostatic cancer, with preservation of sexual potency: long term follow-up

Introducción: los efectos adversos del tratamiento andrógeno ablativo en pacientes con cáncer de próstata avanzado han estimulado la búsqueda de nuevas combinaciones de tratamiento con actividad similar pero con menor toxicidad. La combinación de un antiandrogógeno periférico como flutamida o bicalutamida con el inhibidor de la 5-alfa reductasa, finasteride, constituye un desarrollo racional para el tratamiento del cáncer de próstata avanzado. Pacientes y métodos: flutamida 750 mg/día o bicalutamida 50 mg/día más finasteride 5 mg fue administrado a pacientes con cáncer de próstata avanzado que rechazaron bloqueo con análogos o, una vez iniciado el mismo, se negaron a continuar con dicho tratamiento. Entre 2/96 y 4/02 realizaron tratamiento 32 ptes., edad mediana de 67 (r 48-80) grupo A y 69,5 (r 49-88) grupo B; mediana de score de Gleason 6. Seis pacientes realizaron previamente tratamiento andrógeno ablativo por una mediana de 5 meses...(AU)

[Phaeohyphomicosis by Wangiella dermatitidis in Republic Argentine.]. / Feohifomicosis producida por Wangiella dermatitidis en la República Argentina.

We are presenting the case of a 54 year-old woman, who had a kidney transplant. She came to our laboratory to consult for two cutaneous lesions: a cystic one at the back of her right leg and one localized on dorsum of left forearm. Biopsies of both lesions were performed for a histopathologic study as well as microbiological (both bacteriologic and mycologic) cultures. The histopathologic study showed a lesion compatible with a B type cutaneous lymphoma in the lesion in her leg, while in the mycologic study of the cystic lesion elements compatible with phaeohyphomycosis were observed. Development of Wangiella dermatitidis was obtained in the cultures. The cystic lesion localized on forearm was completely removed by surgery, while the lesion in the leg received oncological treatment. The aim of this paper is to describe the first published case of phaeohyphomycosis, by W. dermatitidis, in the Argentine Republic.