Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Lipid-lowering effects of lovastatin in CAPD patients.

Increased incidence of cardiovascular morbidity and mortality has been observed in continuous ambulatory peritoneal dialysis (CAPD) patients. Hyperlipemia is an important etiologic factor in the pathogenesis of coronary artery disease. Lovastatin has been shown to effectively lower both the serum total cholesterol and triglyceride levels, the most common abnormalities in these patients. In a retrospective study we assessed the lipid-lowering effects of lovastatin (20 mg/day) in 8 CAPD patients whose serum cholesterol and/or triglycerides remained greater than 240 mg/dL, despite a low cholesterol diet. At 6 months of lovastatin therapy, moderate reductions in total cholesterol and triglyceride levels were observed in 2 patients. Although 20 mg/day of lovastatin were well tolerated, the treatment was not universally effective in lowering the serum cholesterol and triglyceride levels.

Second malignancies in hairy cell leukemia.

Among 172 patients with hairy cell leukemia (HCL) seen at the University of Chicago over a 10-year period, 15 were found to have a second malignancy. Neoplasia of the skin was noted most frequently; there were three cases of basal cell carcinoma, one case of anaplastic squamous cell carcinoma, and one case of malignant melanoma. This was followed in frequency by three cases of carcinoma of the lung. The clinical characteristics of these 15 patients did not differ from those of the general population of patients with HCL. A variety of second hematologic malignant disorders and solid tumors were identified. In one case, the second neoplasm occurred before the diagnosis of HCL; six were diagnosed concurrently; and eight followed the diagnosis of HCL. Since HCL is a well-defined clinicopathologic entity, patients with HCL who exhibit unusual features of the disease should be investigated further for the presence of second malignancies.

Phase II study of carboplatin in previously untreated patients with metastatic small cell lung carcinoma.

Fourteen previously untreated patients with metastatic small cell lung carcinoma (SCLC) were treated with carboplatin, 400 mg/m2, given as a 1-hour infusion every 28 days. Eleven patients had a partial response to therapy [response rate, 79% (95% confidence limits, 57%-100%)]. The median duration of response was 8 weeks (range, 4-41) and the median survival was 29 weeks (range, 11-68+). Hematologic toxicity was limited to one patient who developed World Health Organization (WHO) grade IV thrombocytopenia; no patient developed infection due to granulocytopenia. Nonhematologic toxicity was limited to WHO grade I and II nausea and vomiting. This study demonstrates that carboplatin is a highly active drug in SCLC with minimal toxicity. Future studies should evaluate its use in combination with other chemotherapeutic drugs in SCLC.

Phase I study of pegylated liposomal doxorubicin, paclitaxel, and cisplatin in patients with advanced solid tumors.

BACKGROUND: The combination of doxorubicin, paclitaxel, and cisplatin has activity in gynecologic malignancies but requires colony stimulating factor (G-CSF) support. Moreover, there is concern about cardiotoxicity with doxorubicin/paclitaxel combinations. Pegylated liposomal doxorubicin may result in less myelosuppression and cardiac toxicity than free doxorubicin. The purpose of this study was to determine the maximal tolerated dose of pegylated liposomal doxorubicin with fixed doses of paclitaxel and cisplatin without using G-CSF support in advanced solid malignancies. PATIENTS AND METHODS: Twenty-three patients were enrolled; none of the patients had received prior doxorubicin. Patients received paclitaxel (90 mg/m2 for dose level one, escalating to 135 mg/m2 for all subsequent dose levels), with a fixed dose of cisplatin (60 mg/m2), followed by escalating doses of pegylated liposomal doxorubicin every 21 days. RESULTS: A total of 73 cycles was administered. Grade 4 neutropenia was seen after cycle one in two of eight patients receiving 30 mg/m2 of pegylated liposomal doxorubicin and three of seven patients receiving 40 mg/m2 of pegylated liposomal doxorubicin when combined with 135 mg/m2 of paclitaxel and 60 mg/m2 of cisplatin. Two additional patients at the 40 mg/m2 dose level developed grade 4 neutropenia following cycles 2 and 5. The mean decline in left ventricular ejection fraction (LVEF) after 2 cycles was 5 percentage points (P = 0.012). CONCLUSION: The combination of pegylated liposomal doxorubicin, paclitaxel and cisplatin is feasible without G-CSF support.

Treatment of hairy cell leukemia with recombinant alpha 2 interferon.

Nine patients with progressive hairy cell leukemia were treated with subcutaneous injections of recombinant alpha 2 interferon (2 to 10 X 10(6) U/m2) three times weekly. Eight patients completed at least eight weeks of treatment and were evaluable; one patient with refractory thrombocytopenia died of an intracerebral hemorrhage after two doses of interferon. Seven of eight patients responded, with responses occurring as early as two weeks. Four patients also had resolution of their monocytopenia. No complete responses were seen with up to 30 weeks of treatment. Bone marrow biopsies demonstrated improvement in all eight patients. No unforeseen toxicity occurred, but most patients had transient myelosuppression during the first few weeks of treatment. Recombinant alpha 2 interferon is effective in the treatment of hairy cell leukemia, with acceptable toxicity.

Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes.

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

Prophylactic cranial irradiation in adenocarcinoma of the lung. A possible role.

Seventy-eight patients with modified Stage II or Stage IIIM0 adenocarcinoma of the lung were evaluated retrospectively with regard to the impact of prophylactic cranial irradiation (PCI) (30 Gy in 15 fractions) in preventing central nervous system (CNS) metastases. Twenty patients received PCI and 58 did not. There were no significant differences between these groups with respect to age, sex, stage, or median survival (17.4 months with PCI versus 16.9 months without PCI; P = 0.6). One (5%) of 20 patients receiving PCI developed CNS metastases, compared with 14 (24%) of 58 patients not receiving PCI (P = 0.06). The time from diagnosis to development of CNS metastases and survival after CNS involvement was 51 weeks and 14 weeks, respectively, for the patient who received PCI; and a median time of 50 weeks and 26 weeks, respectively, for the patients not receiving PCI. In nine (64%) of the 14 non-PCI patients the CNS was the first and only site of relapse. A Cox regression analysis demonstrated that nodal involvement was significantly associated with an increased risk of CNS metastases. These data suggest that PCI may decrease the incidence of CNS metastases, and that it may be beneficial in the management of patients with N1 or N2 disease.

A 10-year experience with combined modality therapy for stage III small cell lung carcinoma.

During the past 10 years, 240 patients with Stage III small cell lung carcinoma (SCLC) were treated with one of five chemotherapy programs plus thoracic irradiation. In addition, prophylactic cranial irradiation was administered concurrently with thoracic irradiation to 194 patients receiving CAML-HC, VCAM, or MOCA. Seventy-two patients had disease confined to the chest (Stage IIIM0), 30 patients had disease in the chest plus ipsilateral supraclavicular nodal involvement (Stage IIIM0SCN+), and 138 patients had distant metastatic disease (Stage IIIM1); the median survivals were 15.2 months, 12.6 months, and 8.4 months, respectively. The overall complete response rate was 30% and the overall response rate (complete and partial) was 76%. The overall response rates by stage were 86% for Stage IIIM0, 90% for Stage IIIM0SCN+, and 67% for Stage IIIM1. Eight patients (3%) were alive and free of disease at 24 months. Due to continued disease relapse in this group (four of eight patients), long-term survivors should not be identified for a minimum of 3.5 years from the time of initial therapy. Prophylactic cranial irradiation (PCI) effectively reduced the incidence of central nervous system (CNS) relapse in patients with a complete response to therapy (44% relapse without PCI versus 13% relapse with PCI, P less than 0.01). More effective chemotherapy is required for the successful treatment and improved long-term survival of patients with SCLC.