De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.

BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Human Mycobacterium bovis infection in Buenos Aires: epidemiology, microbiology and clinical presentation.

We performed a retrospective study of clinical, epidemiological and microbiological characteristics of patients with confirmed Mycobacterium bovis infection treated at Francisco Muñiz Hospital, Buenos Aires, Argentina, between 1996 and 2008. A total of 39 patients were included, accounting for 0.4% of tuberculosis cases in our hospital. Of these, 93% had at least one risk factor for M. bovis; the most frequent was occupational exposure (65%), followed by history of living in a rural area (31%) and consumption of unpasteurised milk (4%). Pulmonary disease was the most frequent clinical presentation. Rifampicin resistance and multidrug resistance were seen in two patients, both of whom had human immunodeficiency virus infection.

[Tuberculous peritonitis in HIV-infected patients]. / Peritonitis tuberculosa en pacientes infectados por el virus de la inmunodeficiencia humana.

UNLABELLED: In order to describe the clinical and laboratory findings of Mycobacterium tuberculosis peritonitis M. tuberculosis in HIV+ patients, we conducted a retrospective analysis of the medical records of HIV+ patients with isolation of M. tuberculosis from ascitic fluid (AF), assisted at Hospital Muñiz, Buenos Aires, Argentina (1996-2005). RESULTS: 21 patients were included. Median age: 33, male sex: 52%; peripheral blood CD4-T lymphocyte count (median): 85/mm3; prior history of tuberculosis: 40%; cirrhosis: 65%; enolism: 45%; HCV coinfection: 85%. The most frequent symptoms were abdominal distension (71%), fever (62%) and abdominal pain (19%). The chemical characteristics of the AF were (median): leukocyte count: 751/mm3 (mononuclear predominance: 79%), protein: 3.1 g/dl, LDH: 351 IU/l. AF samples positive for acid fast bacilli at direct microscopic examination: 14%. Infection with multidrug resistant M. tuberculosis (TB-MR): 20%. M. tuberculosis was isolated from other clinical samples in 79%. Fifteen patients received treatment for tuberculosis; in 30% of cases, it was not appropriate due to the susceptibility of the isolated strain. Overall mortality was 66.4%. CONCLUSION: high mortality was observed, which may be attributable to the high frequency of TB-MR, the level of immunosuppression and the prevalence of cirrhosis secondary to enolism and/or HCV coinfection.

Tuberculous meningitis in HIV-infected and non-infected patients: comparison of cerebrospinal fluid findings.

We performed a retrospective comparison of cerebrospinal fluid (CSF) characteristics and drug susceptibility profile in human immunodeficiency virus (HIV) infected and non-infected patients with a diagnosis of tuberculous meningitis. HIV-infected patients had a higher frequency of non-inflammatory CSF (absence of pleocytosis) and of infection by multidrug-resistant strains of Mycobacterium tuberculosis. Protein CSF levels were lower in HIV-infected patients, while and glucose concentration was similar in both groups. Hospital mortality was significantly higher in HIV-infected patients (63.3% [64/101] vs. 17.5% [7/40]).

Multidrug-resistant tuberculosis outbreak among transvestite sex workers, Buenos Aires, Argentina.

We describe the first outbreak of multidrug-resistant tuberculosis (MDR-TB) that occurred in Argentina among transvestite sex workers, and actions undertaken for its control. In Buenos Aires city, transmission was documented between 2001 and 2004 by conventional and molecular methods in a hotel where transvestites used to reside and work. The source case was traced back to 1998. Six secondary cases were diagnosed and treated. Thirty-two contacts were investigated. The outbreak strain had formerly caused nosocomial transmission in Rosario, a city 300 km from Buenos Aires. Our findings highlight the difficulties controlling MDR-TB in Argentina.

[Mycobacterium bovis tuberculosis in a female patient with AIDS]. / Tuberculosis por Mycobacterium bovis en una mujer con SIDA.

M. bovis, the agent of bovine tuberculosis, was in other times, the main ethiological agent of tuberculosis (TBC) in industrialized countries. At the moment, the human cases have become not very frequent, except in those countries where the illness is even endemic. In patients with immunodeficiency syndrome, it usually presents as a systemic illness. We present the case of a woman with AIDS and disseminated TBC caused by M. bovis. The isolated micobacteria turned out to be resistant to rifampin and pyrazinamide. She was treated with isoniazid, ethambutol and ofloxacin with good clinical evolution. This case turned out to be the first isolation of M. bovis in a patient with AIDS, in Muñiz hospital.

Tuberculosis por Mycobacterium bovis en una mujer con SIDA / [Mycobacterium bovis tuberculosis in a female patient with AIDS]

M. bovis, the agent of bovine tuberculosis, was in other times, the main ethiological agent of tuberculosis (TBC) in industrialized countries. At the moment, the human cases have become not very frequent, except in those countries where the illness is even endemic. In patients with immunodeficiency syndrome, it usually presents as a systemic illness. We present the case of a woman with AIDS and disseminated TBC caused by M. bovis. The isolated micobacteria turned out to be resistant to rifampin and pyrazinamide. She was treated with isoniazid, ethambutol and ofloxacin with good clinical evolution. This case turned out to be the first isolation of M. bovis in a patient with AIDS, in Muñiz hospital.

Mastitis por Mycobacterium fortuitum en una paciente HIV negativa / Mastitis due to Mycobacterium fortuitum in an HIV negative patient

A case of a 39 year old HIV negative female patient with a Mycobacterium fortuitum mastitis without previous pathogenic history is reported. She was treated on the bases of drug-susceptibility testing and bibliographic empirical evidence with kanamycin, doxicicline, ciprofloxacin and trimetoprim-sulfametoxazol. A complete remission of her lesions was obtained after 15 months of treatment. Lesions due to this rapidly growing mycobacterium, diagnosis and treatment are commented.

Se presenta el caso de una paciente HIV negativa de 39 años con una mastitis por Mycobacterium fortuitum, sin antecedentes patogénicos previos. Fue tratada en base a las pruebas de susceptibilidad a antibióticos y quimioterápicos y a la evidencia empírica citada por la bibliografía, con kanamicina, doxiciclina, ciprofloxacina y trimetoprima-sulfametoxazol. Se obtuvo la remisión completa de sus lesiones luego de 15 meses de tratamiento. Se comenta la capacidad de producir lesiones de esta micobacteria de crecimiento rápido, su diagnóstico y tratamiento

Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina.

SETTING: An Argentinean reference hospital specialising in infectious diseases. OBJECTIVE: To assess the outcomes of all human immunodeficiency virus (HIV) negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or diagnosed at Hospital Muñiz. DESIGN: Clinical study for the period 1996-1999, with follow-up until June 2002. RESULTS: One hundred and forty-one adult patients (52.5% female) with resistance to two to seven drugs were studied. Fifty patients (35.5%) had not been treated previously. The most frequently used second-line drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based individually tailored three- to five-drug regimens. Hospital admission was associated with treatment success. Forty-five episodes of severe toxicity occurred. Treatment was successful in 51.8% of cases, but follow-up of 73 patients yielded 11.9% relapse. The mortality rate was 19.1% and default was 19.9%. Logistic regression analysis was statistically significant for treatment success in relation to patient admission, residence and resistance pattern. CONCLUSION: The burden of MDR-TB in this setting--prolonged infection, treatment cost and difficulties, low rates of cure and treatment adherence and high rates of fatality and relapse--can be improved by strengthening TB control programme activities and fighting against poverty and HIV/AIDS.

Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires.

A steep upsurge of human immunodeficiency virus (HIV)-associated multidrug-resistant tuberculosis (MDR-TB) was recently observed at a referral treatment center in Buenos Aires City. Between January 1994 and June 1995, TB isolates resistant to at least five drugs were recovered from 101 of 272 HIV-infected inpatients. Highly resistant isolates from 77 patients underwent restriction fragment length polymorphism study with IS6110. After cross-contamination was eliminated, a single TB strain was found to have caused disease in 68 patients with a history of on-site exposure. The frequency of smear-positive pulmonary disease was higher among these patients than among non-MDR-TB HIV-infected patients (50/68 vs. 60/148, P < .001), and the 1-year survival was dramatically reduced (5/68 vs. 92/148). The strain involved in the outbreak was traced back to patients hospitalized in 1992. Institutional infection control policies were and may still be inadequate to contain the spread of TB among immunodepressed subjects, as is the case in other large urban hospitals in Argentina.

Mycobacteria in HIV-infected patients in Buenos Aires.

SETTING: F. J. Muñiz Hospital and Department of Phthisiopneumonology, in Buenos Aires. OBJECTIVE: To analyze bacteriological findings concerning tuberculosis and other mycobacteriosis, in association with HIV infection and AIDS. DESIGN: From June 1985 to December 1991, 2521 samples from 1259 HIV-seropositive and AIDS patients were analyzed: 1133 samples were of bronchopulmonary origin and the remaining 1388 of extrapulmonary origin. Drug susceptibility tests were performed using the proportions method. RESULTS: Mycobacterial disease was confirmed by culture in 240 of the 1259 HIV/AIDS patients (19%). Mycobacterium tuberculosis was isolated in 223 of these cases (92.9%) and M. bovis in two, while M. avium-complex (MAC) strains were identified as the cause of disease in 14 patients (5.8%). In only one case was disease due to M. kansasii. Blood cultures were positive in 21.2% of these 240 cases. Resistance of M. tuberculosis to antituberculosis drugs was found in 9.4% of the 223 isolates. In only one case was multidrug resistance detected, in a patient who had received previous treatment. CONCLUSION: Smear examination, although less sensitive than in HIV-negative patients, was still a simple and reliable tool for the rapid diagnosis of mycobacterial disease. Blood culture aided in the successful diagnosis of about half of the cases of disseminated tuberculosis and of all cases of MAC disease. An alarming spread of tuberculosis was detected among a group of HIV-positive prisoners, and the possible emergence of multidrug resistance should be anticipated.

PIP: An increase in human immunodeficiency virus (HIV)-associated mycobacterial tuberculosis has led to a reversal of an earlier trend in Argentina toward a decline in the incidence of tuberculosis. A bacteriologic study conducted at the Muniz Hospital in Buenos Aires June 1985-December 1991 confirmed the reliability of smear examination for the rapid diagnosis of mycobacterial disease. 2521 samples were obtained from 1259 HIV-infected individuals during the study period and mycobacterial disease was confirmed by culture in 240 cases (19%). The smears were positive in 59.0% of the 122 pulmonary cases, 22.0% of the 72 extrapulmonary cases, and 56.5% of the 46 pulmonary-extrapulmonary cases. Blood cultures were positive in 21.2% of the 240 cases. In patients with pulmonary localization, acquired immunodeficiency syndrome (AIDS) was diagnosed between a few months to two years after the onset of tuberculosis; those with the two other localizations had already advanced to AIDS at the time of blood smear. Resistance to one or more antitubercular drugs was found in 9.4% of cases.

Enfermedad producida por micobacterias no tuberculosas en Buenos Aires, Argentina / Diseases caused by nontuberculous mycobacteria in Buenos Aires, Argentina

Se presentan los resultados de un estudio sobre la prevalencia de micobacterias no tuberculosas realizado en 4 894 pacientes de los cuales se extrajeron 8 006 cultivos estudiados durante cuatro anos (19771980)

Non tuberculous mycobacterioses in Buenos Aires.

Se estudiaron 5182 cultivos positivos para micobacterias obtenidos durante los anos 1977 y 1978 en el Laboratorio de la Catedra de Tisioneumonologia y del Hospital Muniz de Buenos Aires: 5120 de ellos eran M. tuberculosis y 62 micobacterias no tuberculosas. Los cultivos provenian de 3130 pacientes, de ellos 3120 tenian enfermedad producida por M. tuberculosis y 10 casos de otras micobacteriosis: 9 de localizacion pulmonar y uno de un granuloma cutaneo. En 5 de los casos pulmonares el agente causante pertenecia al complejo M. avium-intracellulare-scrofulaceum y en los otros 4 a la especie M. kansasii. Del granuloma cutaneo se aislo M. marinum. Esto representa un porcentaje de 0,32% de micobacteriosis no tuberculosas, sobre el total de los casos de tuberculosis diagnosticados. Los criterios seguidos para considerar una microbacteria "atipica" o no tuberculosa como agente causante de enfermedad fueron: obtencion de mas de un cultivo del paciente, salvo cuando la micobacteria fuera la unica cultivada de una biopsia de tejidos con lesiones granulomatosas; enfermedad comprobada; resistencia inicial a varias drogas antituberculosas, especialmente al PAS, coincidente con una evolucion lenta y dificil de la enfermedad

El problema del tuberculoso polirresistente: aspectos clinicos y terapeuticos. / The problem of the poliresistant tuberculous patient: clinical and therapeutic aspects

Se estudian 25 pacientes de ambos sexos con polirresistencia bacteriana al Mycobacterium tuberculosis a por lo menos 5 drogas y entre ellas siempre H, S, R, E. Correspondieron en su mayoria en mujeres jovenes y hombres mayores, con localizaciones exclusivamente pulmonares y con un 64% de asociaciones morbosas y un 80% de complicaciones. La evolucion demostro que el 48% de los pacientes fallecieron antes de los 5 anos de instalada la polirresistencia, el 24% permanecio eliminando bacilos (la mitad de ellos con progresion evolutiva) y el 28% alcanzo la curacion bacteriologica debiendo aplicar con frecuencia metodos complementarios quirurgicos