Current treatment options for neuroendocrine tumors.

Neuroendocrine tumors are heterogeneous in their clinical behavior and require therapies specially tailored according to staging and grading, origin and expression of peptide receptors. Somatostatin analogues act as antisecretory and antiproliferative agents. Chemotherapy is mandatory for poorly differentiated neuroendocrine carcinomas and is also effective in neuroendocrine tumors of the pancreas and of the bronchial system. For localized neuroendocrine tumors, surgery should be performed with curative intent and is also an option in advanced or metastasized neuroendocrine tumors with the goal to debulk tumor masses. Local ablative therapies may be applied to decrease tumor load in the liver; however, results are often of short duration. Peptide receptor radiotherapy is a new treatment method applying radionuclide-targeted somatostatin receptor agonists for internal cytotoxic radiotherapy in somatostatin receptor-expressing neuroendocrine tumors. Retrospective and prospective clinical studies indicate prolonged progression-free survival and overall survival of patients responding by stable disease or any kind of remission with this innovative treatment, which is, however, available only in a few specialized centers. Finally, small-molecule inhibitors of vascular endothelial growth factor and serine/threonine-protein kinase mTOR pathways have been shown to delay progression in patients with neuroendocrine tumors. In summary, treatment options for neuroendocrine tumors have expanded considerably in the last years leading to prolonged overall survival.

Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer.

BACKGROUND: The study compared the efficacy of a first-line treatment with day 1 i.v. vinorelbine (NVBiv) and day 8 oral vinorelbine (NVBo) versus docetaxel (DCT) in a cisplatin-based combination in advanced non-small-cell lung cancer, in terms of time to treatment failure (TTF), overall response, progression-free survival (PFS), overall survival (OS), tolerance and quality of life (QoL). METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 (arm A) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks (arm B), for a maximum of six cycles in both arms. RESULTS: From 2 February 2004 to 1 January 2006, 390 patients were entered in a randomised study and 381 were treated. The patient characteristics are as follows (arms A/B): metastatic (%) 80.5/84.8; patients with three or more organs involved (%) 45.3/40.8; median age 59.4/62.1 years; male 139/146; squamous (%) 34.2/33.5; adenocarcinoma (%) 41.6/39.3; median TTF (arms A/B in months) [95% confidence interval (CI)]: 3.2 (3.0-4.2), 4.1 (3.4-4.5) (P = 0.19); overall response (arms A/B) (95% CI): 27.4% (21.2% to 34.2%), 27.2% (21.0% to 34.2%); median PFS (arms A/B in months) (95% CI): 4.9 (4.4-5.9), 5.1 (4.3-6.1) (P = 0.99) and median OS (arms A/B in months) (95% CI): 9.9 (8.4-11.6), 9.8 (8.8-11.5) (P = 0.58). The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B, respectively. Main haematological toxicity was grade 3-4 neutropenia: 24.4% (arm A) and 28.8% (arm B). QoL as measured by the Lung Cancer Symptom Scale was similar in both arms. CONCLUSIONS: Both arms provided similar efficacy in terms of response, time-related parameters and QoL, with an acceptable tolerance profile. In the current Global Lung Oncology Branch trial 3, NVBo was shown to be effective as a substitute for the i.v. formulation. This can relieve the burden of the i.v. injection on day 8 and can optimise the hospital's resources and improve patient convenience.

Depressed T cell-derived IFN-gamma following trauma-hemorrhage: a potential mechanism for diminished APC responses.

INTRODUCTION: Prolonged immunosuppression has been demonstrated after trauma-hemorrhage resulting in an increased susceptibility to sepsis. The contribution of antigen-presenting cells (APC) vs T cells to this diminished immune response, however, remains unknown. MATERIALS AND METHODS: To study this, male mice were trauma-hemorrhaged (35 +/- 5 mmHg for 90 min and resuscitation) or sham operated. At 24 h thereafter, spleens were harvested and T cells (via Microbeads) and APC (via adherence) were isolated. Cocultures of combined T cells and APC were established for 48 h, stimulated with ConA and LPS. The T cell-derived cytokine IFN-gamma and IL-12 for APC responses were measured in the supernatants by the multiplex assay. RESULTS: The release of IFN-gamma was suppressed by T cells after trauma-hemorrhage irrespective of whether sham or trauma-hemorrhage APC were added. Trauma-hemorrhaged APC did not affect T cells-derived IFN-gamma release by sham T cells. In contrast, trauma-hemorrhaged T cells depressed the release of IL-12 by APC. The release of IL-12 by trauma-hemorrhaged APC was not altered when sham T cells were cocultured. CONCLUSION: Prolonged immunosuppression after trauma-hemorrhage appears to be predominantly due to diminished T cell function. Thus, attempts to prevent immunodysfunction should be directed towards T cells.

[Significance of multiple organ failure for the prognosis of surgical intensive care patients]. / Bedeutung des Mehrfachorganversagens für die Prognose des chirurgischen Intensivpatienten.

BACKGROUND: The association of multiple organ failure and acute prognosis is an established fact in intensive care medicine. However, it is unclear whether the number of failing organs is an independent determinant of acute mortality, and whether there are additional effects on long-term outcome. METHODS: We performed a retrospective, observational cohort study using prospectively collected data from March 1993, through February 2005. Three different cohorts were analysed: patients with a short-term intensive care unit (ICU) stay (group I, ICU length of stay > 4 days), with a long-term ICU stay (group II, ICU length of stay > 28 days), and all patients requiring renal replacement therapy during ICU stay (group III). Organ failure was defined according to a modified Goris score. An independent effect of the number of failing organs on patient prognosis was evaluated after adjusting for more than 15 covariables. Acute prognosis was analysed in group I, whereas long-term prognosis was studied in groups II and III. RESULTS: The maximum number of failing organs was an independent determinant of acute prognosis in patients of group I, and of long-term prognosis in groups II and III. CONCLUSION: The effect of multiple organ failure on long-term prognosis emphasizes the importance of this variable for patient outcome. Therefore, multiple organ failure must be part of all therapeutic concepts in critical care. Within those, preventive measures are definitively preferable to keep the number of failing organs as small as possible.

[Trends in surgical intensive care. Experience in one centre over 12 years]. / Trends in der chirurgischen Intensivmedizin. Zwölf Jahre Erfahrung an einer einzelnen Institution.

BACKGROUND: For critically ill medical patients until the year 2000, increases in patient age and severity of disease but also acute prognosis have been described. Since then, further improvement appears possible. Several controlled studies have recently demonstrated that acute mortality may be further lowered by new adjuvant therapies such as aggressive glycemic control. However, it is still unknown whether demographic changes and progress in intensive care can be reproduced in surgical critically ill patients outside of a controlled trial setting. METHODS: We performed a retrospective, observational cohort study using data prospectively collected from the surgical intensive care unit (ICU) of the LMU Department of Surgery in Munich, Germany, Grosshadern Campus, from March 1 1993 through February 28 2005. Since 1999 we have successively introduced a variety of new therapies to daily routine. A cohort of 5,495 patients was analysed. RESULTS: We identified reduced ICU mortality during the observation period, although age rose simultaneously and disease severity remained constant. Results from multivariate analysis suggest that improvements in prognosis essentially result from the implementation of new therapies after 2001. After adjusting for more than 20 covariables, treatment received after 2001 was identified as an independent factor linked with reduced risk of death. CONCLUSIONS: General demographic trends and progress in intensive care can be demonstrated also in unselected surgical cohorts. Furthermore, the results here confirm the efficacy of new therapeutic modifications in routine therapy.

Pneumocystis carinii pneumonia as a complication of bendamustine monotherapy in a patient with advanced progressive breast cancer.

BACKGROUND: Bendamustine is an alkylator with anticipated antimetabolic activity. It has shown activity in malignant lymphoma, multiple myeloma, and breast cancer. Recognized side-effects are relatively mild with myelosuppression as the dose-limiting toxicity. The CD4/CD8 ratio may be reduced. To what extent the alteration of lymphocytes, especially CD4(+) lymphocytes, correlates with an increase in opportunistic infections cannot be definitively answered. CASE REPORT: The patient, female, aged 48 years, was suffering from an advanced progressive breast cancer. After initial treatment with several chemotherapies, a cytotoxic therapy was initiated, with bendamustine (150 mg/m(2)) administered on two consecutive days and repeated every 4 weeks. After five courses, the patient developed Pneumocystis carinii pneumonia (PCP), disclosed in the bronchoalveolar lavage. While receiving bendamustine therapy, the CD4(+) and CD8(+) lymphocyte counts in the peripheral blood were determined by flow cytometry. The next-to-normal CD4/CD8 ratio before therapy (0,82) had decreased to 0,05 during the therapy mainly due to a decline of CD4(+) lymphocyte. The patient was seronegative for human immunodeficiency virus. In spite of high-dose intravenous trimethoprim/sulfamethoxazole and methylprednisolone application, the patient died of a respiratory failure 3 days after PCP was diagnosed. CONCLUSION: Bendamustine is capable of inducing a reduction in CD4(+) lymphocyte counts causing a severe T-lymphocyte-mediated immunosuppression. Measuring CD4(+) lymphocyte counts may be helpful in determining the risk of PCP in patients treated with bendamustine.

Phase I clinical and pharmacokinetic study of combination chemotherapy with topotecan and ifosfamide in patients with progressive or relapsed solid tumors.

PURPOSE: Topotecan and ifosfamide are effective in the treatment of various solid tumors. Up to the time of this study, the two drugs have been combined just once (Smith et al. 1998). Due to its hematotoxicity, topotecan has been used predominantly within monochemotherapy protocols. However, the combination of topotecan and alkylating agents is supra-additive in many preclinical models. This phase-I trial was primarily performed to evaluate the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) of a combination chemotherapy with topotecan and ifosfamide using a 5-day schedule. A secondary goal was to estimate the response rate in a group of heavily pretreated patients with advanced solid tumors. METHODS: The pharmacokinetics of topotecan were preliminarily determined in some of the patients. A total of 12 patients (three female/nine male), median age 49 years (range 19-69), 11 with prior chemotherapy, received a total of 24 courses of chemotherapy at three dose-levels of topotecan. Ifosfamide was administered by intravenous infusion over 3 h immediately followed by a 30-min infusion of topotecan. Mesna (3 x 300 mg x m(2) x day) was given routinely during chemotherapy as a uroprotector. G-CSF (filgrastim) was permitted only in cases of febrile neutropenia (FN). RESULTS: The major toxicity was non-hematologic; severe liver and renal toxicity were observed in three out of 11 patients. Two treatment-related deaths occurred. No clinical remissions occurred in 11 evaluable patients. The pharmacokinetics of topotecan were relatively similar in our patients and supported findings in recent literature. The MTD of this combination was defined at dose-level 2 (1.0 mg/m(2) of topotecan and 750 mg/m(2) of ifosfamide). CONCLUSIONS: Further trials should not exceed this dose. The pharmacological causes for the pronounced toxicity have to be clarified.

Resistance of macrophages to the suppressive effect of interleukin-10 following thermal injury.

The activation of a macrophage (Mphi)-dependent proinflammatory cascade following thermal injury plays an important role in the development of immunosuppression and increased susceptibility to subsequent sepsis in burn patients. In contrast, although interleukin (IL)-10, an anti-inflammatory cytokine that can downregulate M phi activity, has also been implicated in postburn immune dysfunction, its role in the regulation of M phi function postburn remains unclear. To study this, C57BL/6 female mice were subjected to a 25% total body surface area third-degree scald burn, and splenic Mphis were isolated 7 days later. Lipopolysaccharide (LPS)-stimulated IL-10, IL-6, tumor necrosis factor (TNF)-alpha, and nitric oxide (NO) production were significantly increased in the burn group compared with shams. Blockade of endogenous IL-10 activity enhanced IL-6 and TNF-alpha release, but not NO release, in both groups. The addition of exogenous IL-10 to the M phi cultures dose dependently suppressed production of these inflammatory mediators in both groups. The timing of IL-10 addition to the cultures in relation to LPS stimulation, however, was critical. The suppressive effect of exogenous IL-10 was attenuated in both groups when the cells were exposed to IL-10 at 4-6 h after LPS stimulation; however, Mphis from injured mice were significantly better able to maintain inflammatory mediator-productive capacity. The resistance of Mphis from injured mice to IL-10-mediated suppression correlated with decreased IL-10 receptor (IL-10R) expression and increased CD11b expression. These findings suggest that Mphis, following thermal injury, display resistance to suppression by IL-10 due in part to downregulation of IL-10R expression.

The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis.

Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses. Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30+/-5 mmHg for 90 min) followed by adequate fluid resuscitation. 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resuscitation. At 2 h after resuscitation, the mice were killed, and spleens were harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed. In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days. A significant decrease in splenocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-gamma release, and decreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-alpha and -beta expression was observed in the vehicle-treated group after TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH. ER-alpha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER-beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.

Gastric cancer in very young adults: apropos four patients and a review of the literature.

Whether gastric cancer in young adults differs from gastric cancer in older patients has been a controversial issue. It has long been suspected that young patients with gastric cancer have different biological features with a more aggressive course of disease and a poorer prognosis than older patients. This, however, has not been firmly substantiated. We report on the clinical course of four patients (three female and one male) with locally advanced (n = 1) or metastasized (n = 3) non-resectable gastric cancer diagnosed under the age of 29 years (23, 25, 27, 28 years). Prior to diagnosis, all three women had recently been pregnant (1-22 months). Diagnosis was endoscopically biopsy-proven and staging work-up was performed by primary explorative surgery (n = 1), laparoscopy and explorative surgery (n = 1) or CAT scan and ultrasound (n = 2). The delay between initial symptoms and diagnosis was 8-22 weeks (median, 10 weeks). The histology was signet-ring cell (n = 2) or undifferentiated (n = 2) gastric cancer. All patients had the diffuse type of gastric cancer according to Lauren. Patients were treated with the FLAP polychemotherapy regimen consisting of leucovorin, 5-fluorouracil, doxorubicin and cisplatinum, as previously reported. The best response after chemotherapy was partial in two patients. Two patients showed progressive disease. Secondary surgery was performed in three responding patients (one of them responded only locally). One patient achieved no evidence of disease after complete tumor resection (R0). In two patients surgery was palliative (R2/exploration). Three patients died 6, 4 and 8 months after diagnosis. One patient is still alive. In our series, very young adults with gastric cancer had adverse clinical and pathological features. In accordance with other reports, we observed a predominance of female patients and a possible association with recent pregnancies. Though the delay between the first symptoms and diagnosis in our patients was no different from that reported for older patients, special emphasis should be given to prompt referral and diagnostic investigations, ensuring the diagnosis of gastric cancer early in the course of disease.

Severe non-haematological toxicity after treatment with gemcitabine.

The authors report that 4 out of a series of 56 patients (7.1%) treated with gemcitabine developed an unexplained non-cardiogenic pulmonary distress syndrome most likely related to gemcitabine. One further patient developed ventricular arrhythmia immediately after gemcitabine exposure, leading to cardiac arrest. Between 1995 and 1998 56 patients with locally advanced or metastatic carcinoma were treated with gemcitabine. The patients suffered from breast cancer (n = 17), pancreatic cancer (n = 17), lung cancer (n = 12), cancer of unknown primary (n = 5), ovarian cancer (n = 2), oral cavity cancer (n = 2) and cancer of the bladder (n = 1). Their median age was 55 years, and there were 33 female and 23 male patients. Fifteen patients had been pretreated with radiation therapy: 2 had received radiation therapy involving the mediastinum as treatment for non-small-cell lung cancer and cancer of unknown origin respectively, 11 patients had had prior neoadjuvant or adjuvant radiation therapy of the chest wall for breast cancer and 2 patients had received radiation therapy for head/neck cancer. All patients received gemcitabine on days 1, 8 and 15 and this was repeated on day 29 at a dose of 1000 mg/m(2) as a 30-min infusion in 250 ml isotonic NaCl. In 4 patients gemcitabine treatment was combined with cisplatinum, in 7 patients with a somatostatin analogue and in 1 patient with epirubicin. All other patients received gemcitabine as a single agent. We assume that the pulmonary or cardiac toxicity of 5 patients was related to gemcitabine. In 3 patients re-exposure resulted in repeated toxicity. One patient did not receive gemcitabine again because of the life-threatening nature of the primary response. Two patients had received prior radiation to the mediastinum with 62 Gy and 50 Gy respectively, 3 years and 1 year before gemcitabine application. In our experience pulmonary toxicity after gemcitabine treatment is more common than initially anticipated. Gemcitabine should be used with caution in patients who have received prior radiation to the mediastinum.

[CT-assisted transthoracic puncture of pulmonary lesions and mediastinal infiltrations. A retrospective study of 300 patients]. / CT-gestützte transthorakale Punktion pulmonaler Herde und mediastinaler Infiltrationen. Eine retrospektive Untersuchung bei 300 Patienten.

With this retrospective study we evaluated the results and the complications of our 343 CT-guided transthoracic biopsies, which we performed in 300 patients with localised and infiltrative lesions of the lung and the mediastinum during 4 years, using the VacuCut-needle in 96% of our cases. In 256 pts. bronchoscopy without final diagnosis was performed before transthoracic biopsy. In 219 pts. (73.0%) we had positive results. In 209 pts. with malignancies the positive rate was 73.7%. In patients with benign processes the positive rate was less (67.8%). Out of 32 pts, suffering from mediastinal lesions 29 had malignancies. In 79.3% positive results were obtained. The rate of complications was low (9%) in 311 biopsies of pulmonary lesions, most were pneumothoraces (7.7%). Haemorrhages occurred in 4 pts. (1.3%) 5 pts. (1.6%) required drainage because of pneumothorax. On the base of our good results and the low complication rate we recommend CT-guided transthoracic aspiration biopsy with the VacuCut-needle as a useful and accurate diagnostic technique.

Intrauterine torsion of an intra-abdominal testis.

Intra-abdominal torsion of an undescended testis is a rare surgical problem in the neonate. However, one must consider the possibility of intrauterine torsion in a neonate who presents with an undescended testis and an abdominal mass.