Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

PURPOSE: Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24 mg poziotinib on an intermittent dosing schedule (cohort 1) or 16 mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. RESULTS: A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. CONCLUSION: Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

Eflapegrastim, a Long-Acting Granulocyte-Colony Stimulating Factor for the Management of Chemotherapy-Induced Neutropenia: Results of a Phase III Trial.

BACKGROUND: Eflapegrastim, a novel, long-acting recombinant human granulocyte-colony stimulating factor (rhG-CSF), consists of a rhG-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Preclinical and phase I and II pharmacodynamic and pharmacokinetic data showed increased potency for neutrophil counts for eflapegrastim versus pegfilgrastim. This open-label phase III trial compared the efficacy and safety of eflapegrastim with pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. MATERIALS AND METHODS: Patients with early-stage breast cancer were randomized 1:1 to fixed-dose eflapegrastim 13.2 mg (3.6 mg G-CSF) or standard pegfilgrastim (6 mg G-CSF) following standard docetaxel plus cyclophosphamide chemotherapy for 4 cycles. The primary objective was to demonstrate the noninferiority of eflapegrastim compared with pegfilgrastim in mean duration of severe neutropenia (DSN; grade 4) in cycle 1. RESULTS: Eligible patients were randomized 1:1 to study arms (eflapegrastim, n = 196; pegfilgrastim, n = 210). The incidence of cycle 1 severe neutropenia was 16% (n = 31) for eflapegrastim versus 24% (n = 51) for pegfilgrastim, reducing the relative risk by 35% (p = .034). The difference in mean cycle 1 DSN (-0.148 day) met the primary endpoint of noninferiority (p < .0001) and also showed statistical superiority for eflapegrastim (p = .013). Noninferiority was maintained for the duration of treatment (all cycles, p < .0001), and secondary efficacy endpoints and safety results were also comparable for study arms. CONCLUSION: These results demonstrate noninferiority and comparable safety for eflapegrastim at a lower G-CSF dose versus pegfilgrastim. The potential for increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study in patients at higher risk for CIN. IMPLICATIONS FOR PRACTICE: Chemotherapy-induced neutropenia (CIN) remains a significant clinical dilemma for oncology patients who are striving to complete their prescribed chemotherapy regimen. In a randomized, phase III trial comparing eflapegrastim to pegfilgrastim in the prevention of CIN, the efficacy of eflapegrastim was noninferior to pegfilgrastim and had comparable safety. Nevertheless, the risk of CIN remains a great concern for patients undergoing chemotherapy, as the condition frequently results in chemotherapy delays, dose reductions, and treatment discontinuations.

Pilot study evaluating the safety of a combined central venous catheter and inferior vena cava filter in critically ill patients at high risk of pulmonary embolism.

The objectives of this pilot trial were to assess the safety of a new device for pulmonary embolism (PE) prophylaxis. The device, the Angel Catheter, was placed in eight patients who were in the intensive care unit and were at high risk of PE. The device was inserted at the bedside without fluoroscopic guidance via a femoral venous approach. All eight devices were inserted and subsequently retrieved without complications (follow-up, 33-36 d). One filter trapped a large clot.

Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial.

INTRODUCTION: Critically ill patients can develop hyperglycaemia even if they do not have diabetes. Intensive insulin therapy decreases morbidity and mortality rates in patients in a surgical intensive care unit (ICU) and decreases morbidity in patients in a medical ICU. The effect of this therapy on patients in a mixed medical/surgical ICU is unknown. Our goal was to assess whether the effect of intensive insulin therapy, compared with standard therapy, decreases morbidity and mortality in patients hospitalised in a mixed ICU. METHODS: This is a prospective, randomised, non-blinded, single-centre clinical trial in a medical/surgical ICU. Patients were randomly assigned to receive either intensive insulin therapy to maintain glucose levels between 80 and 110 mg/dl (4.4 to 6.1 mmol/l) or standard insulin therapy to maintain glucose levels between 180 and 200 mg/dl (10 and 11.1 mmol/l). The primary end point was mortality at 28 days. RESULTS: Over a period of 30 months, 504 patients were enrolled. The 28-day mortality rate was 32.4% (81 of 250) in the standard insulin therapy group and 36.6% (93 of 254) in the intensive insulin therapy group (Relative Risk [RR]: 1.1; 95% confidence interval [CI]: 0.85 to 1.42). The ICU mortality in the standard insulin therapy group was 31.2% (78 of 250) and 33.1% (84 of 254) in the intensive insulin therapy group (RR: 1.06; 95%CI: 0.82 to 1.36). There was no statistically significant reduction in the rate of ICU-acquired infections: 33.2% in the standard insulin therapy group compared with 27.17% in the intensive insulin therapy group (RR: 0.82; 95%CI: 0.63 to 1.07). The rate of hypoglycaemia (< or = 40 mg/dl) was 1.7% in the standard insulin therapy group and 8.5% in the intensive insulin therapy group (RR: 5.04; 95% CI: 1.20 to 21.12). CONCLUSIONS: IIT used to maintain glucose levels within normal limits did not reduce morbidity or mortality of patients admitted to a mixed medical/surgical ICU. Furthermore, this therapy increased the risk of hypoglycaemia. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: 4374-04-13031; 094-2 in 000966421.

Kaposi sarcoma incidence in females is nearly four-fold higher in the Lower Rio Grande Valley compared to the Texas average.

The Lower Rio Grande Valley (LRGV) is located on U.S.-Mexican border with a population that is 90% Hispanic [1]. Comprised of Hidalgo, Cameron, Starr and Willacy counties, this region has the highest poverty rate and one of the highest incidences of Type 2 diabetes in the United States [2-4]. Previous studies demonstrated a high prevalence of Human Herpes Virus 8 (HHV8) in the LRGV [5-7]. HHV8 infection has been causally linked to Kaposi Sarcoma (KS) [8]. Here, we retrospectively examine the incidence of KS in the LRGV in a set of HIV-negative Hispanic patients. Strikingly, the incidence of KS was higher in LRGV women compared to the Texas state average (nearly four-fold higher in McAllen-Edinburg-Pharr Metro Statistical Area). This unique profile aligns with the increased HHV8 prevalence in the LRGV, suggesting that HHV8 contributes to a high incidence of HIV-negative KS on the U.S.-Mexican border in Texas.

FGFR3-TACC3: A novel gene fusion in cervical cancer.

Cervical cancer epitomizes the success of cancer prevention through the human papillomavirus (HPV) vaccine, but significant challenges remain in the treatment of advanced disease. We report the first three cases of cervical carcinoma harboring an FGFR3-TACC3 fusion, which serves as a novel therapeutic target. The fusion, identified by comprehensive genomic profiling, activates the FGFR pathway that has been implicated in HPV-driven carcinogenesis. One of the patients whose tumor contained the FGFR3-TACC3 fusion was treated with an investigational FGFR tyrosine kinase inhibitor. Concomitant molecular alterations involving the PI3K/AKT/mTOR and RAF/MEK pathways were also identified and suggest other treatment strategies that deserve investigation. This case series highlights the role of comprehensive genomic profiling in the identification of new therapeutic targets and in targeted therapy selection for patients with cervical cancer.

The potential impact of admission insulin levels on patient outcome in the intensive care unit.

BACKGROUND: Blood levels of insulin in patients with critical illness at admission to the intensive care unit (ICU) and its association with in-hospital mortality are not fully defined. Our objective was to determine this association in a cohort of patients with critical illness who attended in a mixed ICU. METHODS: Prospective cohort was nested in a randomized clinical trial conducted in a 12-bed mixed ICU in a tertiary hospital in Medellin (Colombia). One hundred sixty consecutively admitted patients, 15 years or older, were analyzed. Blood insulin and blood glucose levels were measured at admission to the ICU, as well as Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. A logistic regression model was created with in-hospital mortality as the outcome. RESULTS: In-hospital mortality was 57 (35.6%) of 160. Survivors had lower Acute Physiology and Chronic Health Evaluation II (median, 13 vs. 17) and lower insulin levels (median, 6.5 vs. 9 µU/mL) than did nonsurvivors. More women than men died (27 [48.2%] of 56 vs. 30 [28.8%] of 104), and 39% of the deaths (n = 22) occurred in patients with sepsis. Patients with insulin levels greater than 15 µU/mL had a higher mortality rate compared with patients with values of 5 µU/mL to 15 µU/mL (odds ratio, 3.57; 95% confidence interval, 1.18-10.8). CONCLUSION: At admission to the ICU, patients with critical illness showed hyperglycemia and relatively decreased insulin levels. High levels of insulin were independently associated with in-hospital mortality in this study population. LEVEL OF EVIDENCE: Prognostic study, level II.

Diagnóstico y tratamiento de pacientes con linfomas primarios del sistema nerviosos central (LPSN) y sindrome de inmunodeficiencia adquirida (SIDA) / Diagnostic and treatment of patients with primary lymphomas of the central nervous system and required inmunodeficiency syndrome

La incidencia del linfoma primario del sistema nervioso central (LPSNC) ha crecido rápidamente. El LPSNC es una complicación letal en pacientes con SIDA. Objetivo: Nuestro objetivo fue estudiar la historia natural, métodos diagnósticos, al tratamiento y los factores pronósticos para la sobrevida de 75 pacientes con LPSNC y SIDA seguidos en el Jackson Memorial Hospital/Universidad de Miami. Resultados: La edad media fue de 37 años. El 84 por ciento de los pacientes eran hombres y el 55 por ciento hispanos. Factores de riesgo más comunes para SIDA fueron homosexualidad y múltiples compañeros sexuales. La cuenta promedio de CD4 fue de 15/ul y al promedio de LDH fue 1.5 veces al normal. La tomografía computarizada del cerebro mostraba lesiones múltiples en el 44 por ciento de los pacientes. Gammagrafia computarizada de emisión de fotones con talio-201 (Spect) del cerebro se realizó en 2/3 de los pacientes. Las histologías más comunes en las biopsias fueron: linfoma inmunoblástico y linfoma de células grandes. La radiación craneana fue ineficiente en el 50 por ciento de los pacientes tratados. La sobrevida promedio del grupo fue de 2.2 meses. Análisis univariado y multivariado mostraron que la mayor sobrevida se asociaba con una buena capacidad funcional (ECOG igual 1-2 vs 3-4). La presencia previa de infecciones oportunistas, la presencia de factores de riesgo de SIDA, las cuentas de CD4, niveles de LDH y raza no mostraron influencia en la sobrevida. Conclusiones: LPSNC es una neoplasia con pronóstico muy pobre y corta sobrevida aun con radioterapia del SNC. La capacidad funcional parece ser al factor de sobrevida más importante. No se encontraron diferencias en la presentación clínica ni el resultado entre pacientes hispanos y no hispanos.

Endocarditis infecciosa. Descripción clínico-epidemiológica

Se estudiaron en forma retrospectiva en tres hospitales de referencia los datos clínicos de 92 pacientes con diagnóstico de endocarditis infecciosa que cumplieron los criterios de von Reyn et al modificados, durante el período comprendido entre junio de 1982 y junio de 1993. Se clasificaron como endocarditis definida 5.4 por ciento, probable 78.2 por ciento y posible 16.3 por ciento. Se encontró una incidencia de 8.3 por ciento pacientes/año y un promedio de edad de presentación para hombres de 39.7 años y para mujeres de 30.8 años (p<0.02). La enfermedad cardiaca reumática fue la lesión preexistente más frecuente (25 por ciento), seguidas por las cardiopatías congénitas (9.7 por ciento). La ecocardiografía bidimensional detectó vegetación en 60.8 por ciento de los casos, siendo mayor el compromiso mitral (41.3 por ciento) y aórtico (39.1 por ciento). Los hemocultivos fueron negativos en 35.8 por ciento. El germen aislado en mayor número fue el estafilococo dorado. En este grupo se observó una mayor frecuencia de complicaciones, mayor compromiso articular y un mayor número de infecciones en válvula nativa (P<0.05). La mortalidad global fue 16.3 por ciento.

Cuantificación de la demamda insatisfecha en el tratamiento de la insuficiencia renal crónica

Actualmente una indefinida proporción de comunidad conoce sobre la existencia de la terapia de reemplazo renal. No obstante, a pesar de que la mayoría de los pacientes institucionales tiene acceso a ella, un gran número de los llamados "clasificados económicos" no pueden ser admitido en estos programas, con la consecuente mortalidad implicada. Emprendimos el presente estudio con el objeto de cuantificar con mayor exactitud las dimensiones de este fenómeno. Entre febrero y mayo de 1992, evaluamos prospectivamente todos los pacientes con insuficiencia renal crónica que consultaron HUSVP a quienes fue imposible ofrecerles este tratamiento. Encontramos 35 casos, 23 hombres (66 por ciento), con una edad promedio de 31+-2 años (rango 13 a 63), 17 (49 por ciento) procedían de Medellín y su área metropolitana, 23 (66 por ciento) eran casados, 24 (69 por ciento) provenían del área urbana, y 19 (54 por ciento) carecían de empleo. La etiología de la falla renal fue desconocida en 23 casos (66 por ciento). Las pruebas de función renal al momento de la evaluación fueron : nitrógeno ureico 137.4+-2.2 mg/dL (rango 60-200) y creatinina 16.3+-0.3 mg/dL (5.2-27.8). En todos los casos, la razón fundamental para no ser admitidos a diálisis o traspalnte renal fue su precaria situación socioeconómica; durante el período del estudio fueron recibidos dos enfermos en el programa de reemplazo renal, representando una satisfacción de la demanda de uno por cada 18.5 casos. En conclusión, aunque en nuestra Unidad realizamos 70 a 90 trasplantes y 6.000 a 7.000 diálisis por año, este trabajo demuestra la pobre satisfacción de la demanda de terapia de reemplazo renal en los enfermos sin seguridad social y la magnitud del problema que no logramos resolver.