Neuroanatomical and functional characterization of CRF neurons of the amygdala using a novel transgenic mouse model.

The corticotropin-releasing factor (CRF)-producing neurons of the amygdala have been implicated in behavioral and physiological responses associated with fear, anxiety, stress, food intake and reward. To overcome the difficulties in identifying CRF neurons within the amygdala, a novel transgenic mouse line, in which the humanized recombinant Renilla reniformis green fluorescent protein (hrGFP) is under the control of the CRF promoter (CRF-hrGFP mice), was developed. First, the CRF-hrGFP mouse model was validated and the localization of CRF neurons within the amygdala was systematically mapped. Amygdalar hrGFP-expressing neurons were located primarily in the interstitial nucleus of the posterior limb of the anterior commissure, but also present in the central amygdala. Secondly, the marker of neuronal activation c-Fos was used to explore the response of amygdalar CRF neurons in CRF-hrGFP mice under different experimental paradigms. C-Fos induction was observed in CRF neurons of CRF-hrGFP mice exposed to an acute social defeat stress event, a fasting/refeeding paradigm or lipopolysaccharide (LPS) administration. In contrast, no c-Fos induction was detected in CRF neurons of CRF-hrGFP mice exposed to restraint stress, forced swimming test, 48-h fasting, acute high-fat diet (HFD) consumption, intermittent HFD consumption, ad libitum HFD consumption, HFD withdrawal, conditioned HFD aversion, ghrelin administration or melanocortin 4 receptor agonist administration. Thus, this study fully characterizes the distribution of amygdala CRF neurons in mice and suggests that they are involved in some, but not all, stress or food intake-related behaviors recruiting the amygdala.

Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility.

Ghrelin is an octanoylated peptide hormone that potently and rapidly increases food intake. The orexigenic action of ghrelin involves the hypothalamic arcuate nucleus (ARC), which is accessible to plasma ghrelin and expresses high levels of the ghrelin receptor. Local administration of ghrelin in a variety of other brain nuclei also increases food intake. It is currently unclear, however, whether these non-ARC ghrelin brain targets are impacted by physiological increases of plasma ghrelin. Thus, the present study aimed to clarify which ghrelin brain targets participate in the short-term orexigenic actions of ghrelin. First, c-Fos induction into mouse brains centrally or peripherally treated with ghrelin was analysed. It was confirmed that peripherally administered ghrelin dose-dependently increases food intake and mainly activates c-Fos in ARC neurones. By contrast, centrally administered ghrelin activates c-Fos in a larger number of brain nuclei. To determine which nuclei are directly accessible to ghrelin, mice were centrally or peripherally injected with a fluorescent ghrelin tracer. It was found that peripherally injected tracer mainly accesses the ARC, whereas centrally injected tracer reaches most brain areas known to express ghrelin receptors. Subsequently, the effects of ghrelin were tested in ARC-ablated mice and it was found that these mice failed to increase food intake in response to peripherally administered ghrelin but fully responded to centrally administered ghrelin. ARC-ablated mice showed patterns of ghrelin-induced c-Fos expression similar to those seen in control mice with the exception of the ARC, where no c-Fos was found. Thus, peripheral ghrelin mainly accesses the ARC, which is required for the orexigenic effects of the hormone. Central ghrelin accesses a variety of nuclei, which can mediate the orexigenic effects of the hormone, even in the absence of an intact ARC.

A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report.

The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. Gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity. Semin Oncol 28 (suppl 10):57-61.

Localizing infection with a technetium-99m-labeled peptide: initial results.

In vitro-labeled leukocyte imaging is useful for the detection of infection, but an in vivo labeling method is preferable. This study sought to evaluate the safety and efficacy of a leukocyte-avid peptide for the detection of infection, to determine the effects of peptide dose on performance and to compare the peptide with in vitro-labeled leukocytes. A 23-amino acid peptide, P483, containing the platelet factor-4 heparin-binding sequence, was labeled with 99mTc and complexed with heparin (P483H). Thirty patients were injected with 29 microg (n = 11), 145 microg (n = 10) or 290 microg (n = 9) of labeled peptide, and imaged 15 min and 90-120 min later. Early and late images were interpreted individually and jointly. Twenty patients underwent (111)In-labeled leukocyte scintigraphy. Fourteen patients had infection: osteomyelitis (n = 7), vascular graft (n = 2), abscess (n = 2), joint replacement (n = 1), surgical wound (n = 1) and pneumonia (n = 1). There were 10 adverse events in six patients; all were mild and resolved spontaneously, and without any intervention. The sensitivity, specificity and accuracy were the same for both early and late imaging: 0.86, 0.81 and 0.83, respectively. Interpreting early and late images together did not improve the results. No relationship between peptide dose and study accuracy was found. In patients undergoing both examinations, the accuracies of the peptide and in vitro-labeled leukocyte imaging were identical: 0.80. In summary, 99mTc-P483H safely, rapidly and accurately detected focal infection, was comparable with in vitro-labeled leukocyte imaging and therefore merits further investigation.

Use of Sulesomab, a radiolabeled antibody fragment, to detect osteomyelitis in diabetic patients with foot ulcers by leukoscintigraphy.

Diabetic patients suspected of having osteomyelitis secondary to foot ulcers underwent scintigraphic imaging with Sulesomab, an anti-granulocyte antibody Fab' fragment labeled with technetium-99m. Among 122 patients who had osteomyelitis confirmed or excluded by histopathologic and/or microbiologic techniques, Sulesomab had a 91% sensitivity, a 56% specificity, and an accuracy of 80%. One planar imaging session was usually sufficient for diagnosis, typically requiring 20-30 minutes of camera time 1-2 hours after injection. Compared with ex vivo autologous white blood cell (WBC) scans, Sulesomab performed comparably but with significantly greater sensitivity (92% vs. 79%; P < .05). Sulesomab results were more sensitive than radiography (90% vs. 62%; P < .05) and more specific than bone scans (50% vs. 21%; P < .05) and would have altered management plans in most patients. No related adverse events occurred, and there was no induction of human anti-mouse antibody. Sulesomab is an effective and rapid imaging agent that is diagnostically comparable or superior to WBC scans in this setting, with significant advantages in safety and ease of use.

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity.

PURPOSE: Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkin's lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS: We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS: Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION: CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

Determination of glomerular filtration rate using technetium-99m-DTPA with differing degrees of renal function.

UNLABELLED: Glomerular filtration rate (GFR) is an important index of renal function. Twenty-four-hour creatinine clearance overestimates GFR in patients with poor renal function. Inulin and iothalamate clearances are accepted reference standards for determining GFR but are expensive and laborious. We have previously reported that GFRs obtained by measuring the disappearance of 99mTc-DTPA from ultrafiltered (protein-free) samples of plasma were virtually identical to those obtained by the iothalamate method. However, the subjects used in that study had normal to only moderately decreased renal function. METHODS: The accuracy of measuring GFR by plasma clearance of 99mTc-DTPA was determined in subjects where renal function varied from normal to severely impaired. In all subjects, GFR was established by clearance of 125I-iothalamate from urine and serum and was used as the standard of reference. RESULTS: For subjects with normal to moderately diminished renal function (GFR > 20 ml/min), the correlation between values of GFR obtained by the DTPA and iothalamate methods was high (n = 18, r = 0.966). The difference between the pairs of GFR values obtained by the two methods was not statistically significant (p > 0.1). In patients with severe renal insufficiency (GFR < 20 ml/min), the correlation between the DTPA and iothalamate methods was poor (n = 11, r = 0.236), and the GFR values obtained by the two methods were statistically different (p < 0.01). CONCLUSION: These results suggest that GFR can be determined accurately by plasma clearance of 99mTc-DTPA in all patients except those with severe renal insufficiency.

Use of computer conferencing to allow view box-style teaching sessions with residents at outlying hospitals.

RATIONALE AND OBJECTIVES: Health care reform is placing new pressures on radiology faculty members to use their time more efficiently. We implemented a computer conferencing technique that allows one faculty member to perform a simultaneous view box-style teaching session with residents at local and outlying hospitals. METHODS: The system simultaneously displays digital images on computer screens at the local and outlying hospitals; an on-screen pen allows the instructor or the participants to point to findings on the images. Audio is provided either by a telephone conference call using speakerphones or over the wide-area network using microphones and speakers built into the computers. RESULTS: The technique has been in use for 1 year. A survey of the faculty and residents indicate that computer conferencing is equivalent to traditional face-to-face teaching sessions at the view box. CONCLUSION: Computer conferencing is possible and accepted. The technique is low-cost, using generic computers that are part of the picture archiving and communication system at both hospitals, and relatively inexpensive conferencing software.

Cefotaxima vs. cefalotina-gentamicina en el primer episodio febril de pacientes con tumores sólidos y neutropenia de corta duración / Cefotaxime vs Cephalotin-Gentamicin in the first febrile episode of patients having solid tumors and short-term neutropenia

Las infecciones no tratadas en un paciente neutropénico son rápidamente fatales y está plenamente justificado el uso de antibióticos en forma empírica. En el Instituto Nacional de Enfermedades Neoplásicas (INEN) el régimen de elección habitual para pacientes con el primer episodio febril con tumores sólidos y neutropenia de corta duración, es la asociación de gentamicina más cefalotina. Con el efecto de comparar la eficacia y toxicidad de un régimen de monoterapia con cefotaxima con este régimen combinado, llevamos a cabo un estudio prospectivo y randomizado comparando cefotaxima (1 g/8 h) versus la combinación de cefalotina (1 g/6 h) y gentamicina (4 mg/kg/día-dosis única-). Seleccionamos pacientes con tumores sólidos en el primer episodio febril que recibieron quimioterapia y desarrollaron neutropenia menor de 1000 neutrófilos/mm3. Con una duración esperada menor de 10 días. Se incluyeron 64 pacientes en el brazo de cefotaxima y 72 en el de cefalotina-gentamicina. El estudio se llevó a cabo entre mayo de 1993 hasta junio de 1994. La tasa de respuestas para el grupo de pacientes tratados con cefotaxima fue 75 por ciento y para el grupo tratado con cefalotina-gentamicina 69 por ciento. Las tasas de respuestas completas en los pacientes con infecciones microbiológicamente documentadas fueron 65.5 por ciento para el brazo de cefotaxima y 63.4 por ciento para el brazo de cefalotina-gentamicina. Los índices de falla fueron 23 por ciento para los pacientes incluidos en el brazo de cefotaxima y 30 por ciento para los pacientes tratados con cefalotina-gentamicina. No se demostró diferencias significativas en los índices de respuesta entre los dos brazos de tratamiento. No observamos efectos tóxicos secundarios que obligaran a suspender el tratamiento en ninguno de los dos esquemas. En conclusión: los índices de respueta obtenidos con los dos esquemas de tratamiento son adecuados en nuestro medio para la población de pacientes portadores de tumores sólidos que reciben quimioterapia y presenten un efecto infeccioso durante un período de neutropenia menor de 10 días. La combinación cefalotina-gentamicina requiere no sólo de un esquema posológico de mayor complejidad sino que también tiene una toxicidad potencialmente mayor y requiere de monitorización estrecha. La eficacia terapéutica fue mayor en el grupo que recibió cefotaxima, diferencia que no alcanzó significación estadística

Metopimazina en la prevención de la náusea y el vómito, inducido por quimioteapia a base de cisplatino en múltiples dosis / Metopimazine in prevention of nausea and vomiting chemoterapy induced (cisplatin)

Entre abril de 1993 y marzo 1994 llevamos a cabo el presente estudio con el fin de evaluar la eficacia de la metopimazina en la prevención de la emesis inducida por regímenes de platino administrados en cinco días. La metopimazina es un derivado fenotiacínico con moderada actividad antiemética. Este fue un estudio abierto, prospectivo y randomizado. Comparamos dos forma de administración de metopimazina: Régimen A: 25 mgr., 6 hr/días 1-5 EV, Régimen B: 50 mgr. antes y 4 horas después de la dosis de cisPlatino días 1-5 EV. Se utilizó además como parte de la antiemesis en ambos brazos de tratamiento: dexametasona 12 mgrs., clorfeniramina 8 mgr. y diazepán 10 mgrs. Todos los pacientes estuvieron hospitalizados. Ingresaron 70 pacientes de los cuales fueron evaluables 69. El promedio de edad fue 34.3 años (R: 16-63). La relación M/F 37/32. La distribución de neoplasias fue: testículo (40), cáncer de cérvix (21), tumores germinales del ovario (6), tumores germinales extragonadales (2). Ninguno tuvo metástasis hepática, ni al SNC; al ingreso 27 pacientes recibieron quimioterapia (Qt) por primera vez y el resto entre 2 a 5 cursos de Qt. Los esquema utilizados fueron: BEP (37 cursos), BIP (21 cursos), PEI (10 cursos). No encontramos diferencias en la distribución por edad, sexo, neoplasia, esquema de quimioterapia y número de cursos de quimioterapia recibidas entre los brazos de tratamiento. El 29 por ciento (95 por ciento CI 18.3-39.7) de los pacientes tuvieron control absoluto de las náuseas y el 24.6 por ciento tuvieron control absoluto de los vómitos durante los 5 días de tratamiento. Uno de nuestros pacientes incluido en el brazo B, fue retirado del estudio por haber presentado un evento de hipotensión y alteración de conciencia al iniciarse la administración de metopimazina. No se demostraron otros efectos adversos. Conclusión: metopimazina en la forma intravenosa puede ser una alternativa en la prevención de la náusea y el vómito inducidos por quimioterapia a base de cisPlatino. Se propone un estudio comparativo con otros regímenes considerados de uso estándar para comparar sus resultados

Comparison of methods for identifying early methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis.

Hepatotoxicity may complicate therapy with methotrexate in patients with rheumatoid arthritis. Prevention of cirrhosis may depend upon early identification of liver damage, usually accomplished by serial biopsy. To determine the adequacy of noninvasive methods for identifying hepatotoxicity, 22 sets of data were obtained in patients undergoing therapy with methotrexate for rheumatoid arthritis. Comparisons were made between liver biopsy, hepatocellular enzymes and two noninvasive radioisotopic methods that have been shown to be abnormal in hepatocellular disease: the rate constant of excretion of the 14C-aminopyrine and the time from injection to peak hepatic activity of 99mTc-diisopropylimidodiacetic acid. The hepatocellular enzymes and the time-to-peak-activity of diisopropylimidodiacetic acid were not useful predictors of methotrexate-induced hepatotoxicity. The aminopyrine breath test was abnormal in approximately half the patients with hepatotoxicity but showed poor specificity. Noninvasive methods remain inferior to biopsy for the detection of mild to moderate methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis.

Enthesopathy of the patellar tendon insertion associated with isotretinoin therapy.

A 99mTc-MDP bone scan performed on a 34-yr-old female for suspected osteomyelitis of the proximal tibia revealed focally increased activity in both tibial tuberosities due to enthesopathies secondary to chronic isotretinoin therapy. Physicians should be aware that isotretinoin therapy can cause abnormal bone scans and not mistake these abnormalities for other diseases such as osteomyelitis. Second, bone scans may be helpful in diagnosing and following isotretinoin bone toxicity.

Two years of cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for stage II and III breast carcinoma.

The results after 6 years of a prospective clinical trial of adjuvant chemotherapy with a regimen of two drugs--cyclophosphamide and 5-fluorouracil (CF)-- for 2 years in 97 women with stage II or III breast cancer are reported. Eligible patients were free from distant metastases. All patients began adjuvant therapy within 4 weeks of surgery; therapy consisted of radical, modified, or extended radical mastectomy. No postoperative radiotherapy was given. The results are compared with a historical control group from previous consecutive patients treated by surgery alone. Patients were stratified by age (younger than 50 or older than or equal to 50) and nodal status (one to three positive axillary nodes vs. four or more positive nodes). The estimated 6-year survival was 60% for CF patients vs. 31% for control patients (P = 0.001). The estimated 6-year disease-free survival was 53.6 and 30.3% for CF and control, respectively (P = 0.007). There was a trend toward longer disease-free survival (DFS) and survival (S) in patients treated with CF, but this was not significant in all the subgroups. Disease-free survival was statistically significant in the subgroup of women greater than or equal to 50 years old with one to three positive nodes (P = 0.038); survival in the patients less than or equal to 49 years old with four or more positive nodes (P = 0.0036); and in patients greater than or equal to 50 years old with one to three lymph nodes involvement (P = 0.038).

Radiotherapy in the management of locally advanced breast cancer.

A retrospective study of 484 patients with locally advanced cancer of the breast treated with irradiation alone revealed a partial or complete response in 64% of the patients, with a mean duration of 13 months. The 5-year survival was 21.9% for the entire group of patients; 32% for patients responding, and 5% for non-responding patients. The data suggests that the size of the tumor and the age of the patients influence the quality of response. The results indicate that radiotherapy adequately controls local disease in a significant number of patients but systemic treatment is needed for better disease control.

Postoperative whole lung irradiation with or without adriamycin in osteogenic sarcoma.

Thirty-six patients with histologically proven osteogenic sarcoma of the extremities, treated between September 1975 and April 1978, are the subject of this report. The primary tumor was treated with radical surgery. Patients received 2000 cGy whole lung irradiation postoperatively in an attempt to control micrometastases to the lung. Twenty-nine of the patients were given Adriamycin (60 mg/m2 IV every 6 weeks for a total dose of 550 mg/m2) in addition to the irradiation. The median, disease-free interval was 118 days for the seven patients treated with lung irradiation only. The median overall survival for these patients is 241 days, with one patient alive with disease. All patients developed lung metastasis. For the 29 patients treated with postoperative lung irradiation and Adriamycin, the median disease-free interval was 372 days, and the median overall survival is 843 days. Nineteen of the patients recurred (65.5%). The differences are statistically significant (p less than or equal to 0.003, median disease-free survival and p less than or equal to 0.03, median survival). This study supports the role of whole lung irradiation plus Adriamycin, in the control of micrometastases in osteogenic sarcoma of the extremities and suggests that additional clinical trials are warranted.

Local control of osteogenic sarcoma by radiation and chemotherapy.

Sixteen patients with osteogenic sarcoma of limbs were treated with high dose methotrexate followed by leucovorin rescue, adriamycin and radiotherapy to the primary tumor. A post-treatment surgical biopsy was performed in 15 of the 16 patients. In 12 of 15 patients (80%), the follow-up biopsy was negative for active tumor. Complications of treatment were myelosuppression (16 cases), moist desquamation (13 cases), soft tissue necrosis (2 cases) local infection (2 cases), fibrosis (9 cases) and bone fracture (4 cases). The mean survival time in this group of patients was 712 days.