New insights into IL-12-mediated tumor suppression.

During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

Distinguishing recovery from remission in a cohort of bulimic women: how should asymptomatic periods be described?

BACKGROUND: Empirical definitions of remission and recovery from eating disorders are needed to understand outcome data and compare results across studies. METHOD: 106 treatment-seeking women with bulimia nervosa, who had abstained from binging and purging for at least 4 weeks, were followed prospectively. Relapse was defined as at least 4 consecutive weeks of either binging and purging weekly or binging two or more times per week, regardless of purging. Recovery was differentiated from remission based on the probability of relapse. The minimum number of weeks after which the risk of relapse leveled off was used as the cut-off to distinguish between the two outcomes. Kaplan-Meier methods were used to estimate the weekly probability of relapse. RESULTS: When defining remission as at least 4 weeks of being asymptomatic, a quarter of the women relapsed within 11 weeks. By 37 weeks, only 49% of the women remained asymptomatic (95% CI, 41-61). The probability of relapse was substantial for approximately a year after a woman ceased to binge and purge. CONCLUSION: Bulimia nervosa is an episodic disorder. As a conservative approach, periods of being asymptomatic that last less than 1 year should be labeled as remissions, not recoveries.

Comorbidity and outcome in eating disorders.

This article reviews the data on comorbidity, course, and outcome in anorexia nervosa and bulimia nervosa. Recovery, relapse, the process of recovery, and predictors of outcome are reviewed. Although significant differences exist among outcome studies, the data suggest that patients with anorexia and bulimia tend to improve symptomatically over time. Anorexia nervosa and bulimia nervosa are associated with substantial rates of comorbidity. The relationship between eating disorders and depression, anxiety disorders, substance abuse, and personality disorders is discussed.

Liver metastases of breast cancer: results of liver resection.

BACKGROUND: In case of distant metastases breast cancer is generally regarded as incurable. Therefore liver surgery is withheld from those patients, even in cases of isolated liver metastases. MATERIALS AND METHODS: Over 11 years we performed 35 liver resections in 34 patients with liver metastases of breast cancer. The median age was 47 years. The median interval between the primary operation and the liver resection was 27.3 months. 59% of the patients had a solitary metastasis. RESULTS: Curative (R0) resection was possible in 86%. Operative mortality was 3% (n = 1). Overall 5-year survival was 18.4% (median 27 months). Prognosis was significantly (p < 0.001) better following R0-resection (22%, median 41.5 months) than after R1/2-resection (maximum 20 months, median 5 months). Beside the radicality an unfavorable influence on the prognosis could be demonstrated only for a prior local recurrence of the primary tumor (p < 0.05). Other factors like stage of the primary tumor and number and size of the metastases were without prognostic significance. CONCLUSIONS: Patients with isolated liver metastases of breast cancer may have a long lasting benefit from liver resection. In individual cases cure may be possible.

[Liver metastases in breast carcinoma. Results of partial liver resection]. / Lebermetastasen bei Mammacarcinom. Ergebnisse der Leberteilresektion.

Within 11 years we performed 35 liver resections in 34 patients with liver metastases of breast cancer. The median age was 47 years. The median interval between the primary operation and the liver resection was 27.3 months. 59% of the patients had a solitary metastases. A curative (R0) resection was possible in 86%. Operative mortality was 3% (n = 1). Overall 5-year survival was 18.4% (median 27 months). Prognosis was significantly (p < 0.001) better following R0-resection (22%, median 41.5 months) than after R1/2-resection (maximum 20 months, median 5 months). Beside the radicality an unfavorable influence on the prognosis could be demonstrated only for a prior local recurrence of the primary tumor (p < 0.05). If a R0-resection was possible stage of the primary tumor, number and size of the metastases, and extension of the operative procedure were without prognostic significance. We conclude that patients with isolated liver metastases of breast cancer can have a long lasting benefit from liver resection. In individual cases even cure may be possible.

[Liver resection for non-colorectal, non-neuroendocrine hepatic metastases]. / Ergebnisse der Resektion nichtcolorectaler nichtneuroendokriner Lebermetastasen.

Over a period of 11 years a total of 140 liver resections for non-colorectal, non-neuroendocrine hepatic metastases were performed in 127 patients (73 women, 54 men; median age 53 years). There were 120 first, 14 second and 6 third liver resections. Primary tumors were: breast cancer (n = 34), leiomyosarcoma (n = 20), pancreatic cancer (n = 16), renal cell carcinoma (n = 13), melanoma (n = 9), gastric cancer (n = 9), lung cancer (n = 6) and adrenal cancer (n = 6) and miscellaneous tumors (n = 14). Extrahepatic tumor manifestation (including synchronous primary tumors) was found in 69/140 cases (49%); 61 of 120 patients with a first liver resection had extrahepatic tumor (51%). In the 120 first liver resections, 82 (68%) R0, 13 (11%) R1 and 25 (21%) R2 excisions were possible. Median survival after first liver resection was 20 months; after R0 resection a median survival of 28 months and after R1/2 resection of 8 months was achieved. The 5-year survival rate was 16% for the total group, 24% in patients with R0 resection and 0% for R1/2 resections. After a second liver resection (n = 14) there was a median survival of 28 months (5-year-survival-rate of 21%) for all patients and of 41 months (5-year survival rate 38%) after R0 resection. Morbidity and mortality after the first liver resection were 32.5% and 5.8%, respectively. In patients without extrahepatic tumor at the time of the first liver resection a median survival of 32 months (5-year survival rate 25%) and 7 months was achieved after R0 resection and R1/2 resection, respectively. In case of extrahepatic tumor the median survival was 24 months (5-year survival rate 23%) for R0 resection compared to 8 months after R1/2 resection. These data suggest that not the presence of extrahepatic tumor but rather the possibility of a R0 resection is most decisive for the prognosis after liver resection. We conclude that patients with liver metastases of non-colorectal, non-neuroendocrine tumors may benefit from liver resection. Similar to colorectal metastases, a second or third liver resection can be worthwhile in selected cases. Even in more unfavorable tumor entities, several cases of long-term survival were observed after surgical therapy. Therefore, the indication for liver resection should be considered carefully in every single case.

Trypanosomatid parasites causing neglected diseases.

Parasitic diseases such as Kala azar (visceral leishmaniasis), Chagas disease human (American trypanosomiasis) and African sleeping sickness (African trypanosomiasis) are affecting more than 27 million people worldwide. They are categorized amongst the most important neglected diseases causing approximately 150,000 deaths annually. As no vaccination is available, treatment is solely dependent on chemotherapeutic drugs. This review provides a comprehensive insight into the treatment of Kala azar, Chagas disease and African sleeping sickness. In addition to established drugs, novel small molecule- based therapeutic approaches are discussed. Drugs currently used for the treatment of Kala azar include pentavalent antimonials, Amphotericin B, Miltefosine, and Paromomycin. Liposomal formulations such as AmBisome provide promising alternatives. Furthermore, antiproliferative compounds might open new avenues in Kala azar treatment. Regarding Chagas disease, chemotherapy is based on two drugs, Nifurtimox and Benznidazole. However, sequencing of T. cruzi genome in the year 2005 raises a hope for new drug targets. Proteases, sterols and sialic acids are potential promising drug targets. Suramin, Pentamidine, Melarsporol and Eflornithine are well-established drugs to treat African sleeping sickness. New treatment options include combination therapy of Eflornithine and Nifurtimox, a Chagas disease therapeutic.. However, all approved chemotherapeutic compounds for trypanosomatid diseases suffer from high toxicity. Further, increasing resistance limits their efficacy and compliance.

Abnormal mental phenomena in the prophets.

Abnormal mental phenomena of varying emotional depth are found frequently among the earlier, nonliterary, and literary prophets. Three levels are discerned: inspiration, i.e., a state of excitement with well-preserved reality controls; ecestasy, as a state in which reality control has been lost temporarily; and eidetic imagery characterized by dreams and visions. It is argued that the prophets were psychotics, or mystics, or poets, or endowed with psychic gifts. I have attempted to consider some of these phenomena from the psychiatric viewpoint, keeping in mind that such interpretations many centuries later must remain speculative.

Impairment severity in seizure disorders: some suggestions for reliable assessment.

Severity of impairment in seizure disorders is typically difficult to assess because of the existence of seizure-free intervals of varying duration, often in the absence of neurological or other clinical signs. For purposes of determining degree of severity, clear documentation and description of seizures, as well as of any associated phenomena such as loss of sphincter control and the side effects of medication, are needed. Differentiation between primary and secondary seizure disorders is also important because the latter frequently are associated with other impairments. The approach to assessment advocated is based on the incidence and intensity of seizures remaining after maximum therapeutic control has been achieved. An assessment form has been developed which concisely summarizes salient case features. A composite case report is appended for the purpose of demonstrating use of the form. Instructions are in the Appendix.

Hepatic metastases from leiomyosarcoma: A single-center experience with 34 liver resections during a 15-year period.

OBJECTIVE: To describe a large single-center experience with hepatic resection for metastatic leiomyosarcoma. SUMMARY BACKGROUND DATA: Liver resection is the treatment of choice for hepatic metastases from colorectal carcinoma. In contrast, the role of liver resection for hepatic metastases from leiomyosarcoma has not been defined. METHODS: The records of 26 patients who between 1982 and 1996 underwent a total of 34 liver resections for hepatic metastases from leiomyosarcoma were reviewed. There were 23 first, 9 second, and 2 third liver resections. The records were analyzed with regard to survival and predictive factors. RESULTS: In the 23 first liver resections, there were 15 R0, 3 R1, and 5 R2 resections. Median survival was 32 months after R0 resection and 20.5 months after R1/2 resection. The 5-year survival rate was 13% for all patients and 20% after R0 resection. In 10 patients with extrahepatic tumor at the time of the first liver resection, 6 R0 and 4 R2 resections were achieved. After R0 resection, the median survival was 40 months (range 5-84 months), with a 5-year survival rate of 33%. After repeat liver resection, the median survival was 31 months (range 5-51 months); after R0 resection, median survival was 31 months and after R1/2 resection it was 28 months. There was no 5-year survivor in the overall group after repeat liver resection. CONCLUSIONS: Despite frequent tumor recurrence, the long-term outcome after liver resection for hepatic metastases from leiomyosarcoma is superior to that after chemotherapy and chemoembolization. Although survival after tumor debulking also seems to be more favorable than after nonoperative therapy, these data indicate that only an R0 resection offers the chance of long-term survival. The presence of extrahepatic tumor should not be considered a contraindication to liver resection if complete removal of all tumorous masses appears possible. In selected cases of intrahepatic tumor recurrence, even repeated liver resection might be worthwhile. In view of the poor results of chemoembolization and chemotherapy in hepatic metastases from leiomyosarcoma, liver resection should be attempted whenever possible.

Pregnancy: outcome and impact on symptomatology in a cohort of eating-disordered women.

OBJECTIVE: This study investigates both the impact of eating disorders (ED) on pregnancy outcome and the impact of pregnancy on cognitive and behavioral symptoms of EDs. METHOD: Data on pregnancy outcome (live birth [LB], therapeutic abortion [TAB], and spontaneous abortion [SAB]) and ED symptomatology were collected as part of a large, prospective longitudinal study of anorexia nervosa (AN) and bulimia nervosa (BN). Data were gathered using a semistructured interview administered every 6 months to 246 subjects. RESULTS: We identified 54 women who reported 82 pregnancies (46 LB, 25 TAB, and 11 SAB). Pregnancy outcome was not significantly related to any of the clinical variables studied. Women with BN showed a significant decrease in the severity of their ED symptoms during pregnancy, and this decrease was sustained through 9 months postpartum. Women with AN also demonstrated a significant reduction in ED symptoms, however, these symptoms returned to prepregnancy levels by 6 months postpartum. CONCLUSIONS: Our prospective findings reveal an elevated TAB rate for ED women along with a general reduction in the severity of ED symptoms during pregnancy.