Interfraction interval in patients with stage III non-small-cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy: final results in 536 patients

We investigated the influence of interfraction interval (IFI) on treatment outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (Hfx RT) with or without concurrent chemotherapy (CHT). During 3 randomized phase III and 1 phase II study, a total of 536 patients were treated with Hfx RT alone or with concurrent carboplatin/etoposide. Two hundred eighty-five patients were treated with IFI of 4.5-5.0 hours, while 251 patients were treated with IFI of 5.5-6.0 hours. "Shorter" (4.5-5.0 hours) IFI led to better overall survival (OS) (P = 0.0000) and local recurrence-free survival (LRFS) (P = 0.0000). Multivariate analyses showed IFI to be an independent prognosticator of both OS and LRFS. These results were confirmed when we separated all patients (n = 536) into those treated with Hfx RT only (n = 127) and those treated with concurrent RT/CHT (n = 409). Various RT-related high-grade acute toxicity was not different between the 2 IFI, but patients treated with shorter IFI had a significantly higher incidence of hematological toxicity (P = 0.002). None of the late high-grade toxicities were different between the 2 interfraction intervals. Using regression analysis, it was shown that IFI was not a significant predictor of any of acute or late high-grade (> or =3) toxicity. IFI is an important prognosticator of OS and LRFS in patients with stage III NSCLC treated with Hfx RT with or without concurrent carboplatin/etoposide. IFI led to higher incidence only of hematological toxicity, but was not predictive of any acute or late high-grade (> or =3) toxicity. A carefully designed randomized trial seems necessary to give better insight into the issue of optimal IFI in this disease.     

Computed tomography of cystic lung diseases

A cystic lesion in the lung is defined as a well-demarcated epithel-lined cavity, that can be mostly filled with air, water, as well as solid material content. This definition includes a wide variety of diseases such as bronchogenic cyst, abscess formation, lymphangioleiomyomatosis, Langerhans cell histiocytosis, emphysema, bronchiectasis, and pneumatoceles. Despite the difficulties in differential diagnosis, there are some diagnostic criteria for CT-scanning helping the radiologist to differentiate between these cystic entities. Moreover, clinical informations are extremely important. The most important clinical parameters include age, sex, clinical history and symptoms. Thus, a better understanding of classic CT appearance of cystic lung disease will allow more definitive diagnosis and could, in some cases, avoid biopsy.     

The calcified ascending aorta in aortocoronary bypass

Heavily calcified ascending aorta significantly increased morbidity and lethality during open-heart surgery. Cannulation and clamping (partial or total) of severely atherosclerotic ascending aorta can easily cause damage and rupture of aortic wall, with consequential distal (often fatal) embolization with atheromatous debris (brain, myocardium). From June 1998. until June 2000, 11 of 2,136 (0.5%) patients who underwent coronary artery bypass grafting were with the severe atheromatous ascending aorta. The site of cannulation was in the aortic arch in three patients (aorta was occluded with Foley catheter in one case, and single clamp technique was used in the other two cases). The femoral artery was the cannulation site in other five cases. Profound hypothermia, ventricular fibrillation, and circulatory arrest, with no cross-clamping or cardioplegia, were used in three patients. Two patients were operated on with extracorporeal circulation, one in normothermia, on the beating heart, the other in moderate hypothermia, on fibrillating heart. In three patients myocardial revascularization was performed on the beating heart, in normothermia, without extracorporeal circulation. Postoperative course was uneventful in all 11 patients. Neither atheroembolism in the peripheral organs, nor atheroembolism of the extremities occurred. The proposed surgical approaches have the potential to reduce the prevalence of stroke and systemic embolization associated with coronary artery bypass grafting in patients with heavily calcified ascending aorta. This result was achieved due to the applied modifications of standard cardiosurgical technique.     

Fasciocutaneous flaps in the treatment of soft tissue defects of the lower leg caused by explosive war injuries

The use of fasciocutaneous flaps for the reconstruction of lower leg soft-tissue defects inflicted during the bombing of our country is presented in this case report. The experience with 9 patients with soft-tissue defects of the lower leg is presented with the aim of examining the possibilities of war-wound reconstruction. The results of the earlier use of fasciocutaneous flaps in the lower leg reconstruction as well as the those obtained during the reconstruction of the lower leg soft-tissue defects in war wounds was proven to be safe and reliable method of the reconstructions of severe lower leg injuries, particularly of its distal segment and the malleolus region.     

Interleukin-3 promotes proliferation and differentiation of human hematopoietic stem cells but reduces their repopulation potential in NOD/SCID mice

In the present study we explored systematically the influence of human interleukin-3 (IL-3) on the cord blood (CB) cell-derived production of human hematopoietic cells in the bone marrow, blood, and spleen of chimeric nonobese/severe combined immunodeficient mice ((NOD/SCID) mice. CB mononuclear cells and MACS-enriched CB CD34(+) cells were injected into irradiated NOD/SCID mice. The mice were additionally transplanted with a stably transfected rat fibroblast cell line expressing the human IL-3 gene (Rat-IL-3) constitutively, or with the nontransfected rat fibroblast cell line as a control (Rat-1). Rat-IL-3 mice displayed a higher engraftment of human hematopoietic cells in bone marrow, spleen, and peripheral blood compared with mice with Rat-1 cotransplantation. When we transplanted their total bone marrow cell population into secondary mice, surprisingly, mice transplanted with bone marrow cells from Rat-1 mice displayed a higher proportion of human hematopoietic cells compared with Rat-IL-3 mice. As expected, bone marrow cultures (BMCs) from Rat-IL-3 mice contained a higher proportion of human cells than Rat-1 bone marrow cells. However, when BMCs were passaged to new flasks, we observed a higher proportion of human cells in BMCs from Rat-1 mice compared with BMCs from Rat-IL-3 mice. IL-3 promotes the proliferation and differentiation of hematopoietic stem cells in chimeric bone marrow. In addition, IL-3 may play a role in the depletion of hematopoietic stem cells in chimeric bone marrow. In the absence of IL-3, the hematopoietic stem cells may remain in a quiescent state and proliferation can be induced by stimuli, including secondary transplantation or cell passage.     

Ran's C-terminal,basic patch,and nucleotide exchange mechanisms in light of a canonical structure for Rab,Rho, Ras,and Ran GTPases

Proteins comprising the core of the eukaryotic cellular machinery are often highly conserved, presumably due to selective constraints maintaining important structural features. We have developed statistical procedures to decompose these constraints into distinct categories and to pinpoint critical structural features within each category. When applied to P-loop GTPases, this revealed within Rab, Rho, Ras, and Ran a canonical network of molecular interactions centered on bound nucleotide. This network presumably performs a crucial structural and/or mechanistic role considering that it has persisted for more than a billion years after the divergence of these families. We call these 'FY-pivot' GTPases after their most distinguishing feature, a phenylalanine or tyrosine that functions as a pivot within this network. Specific families deviate somewhat from canonical features in interesting ways, presumably reflecting their functional specialization during evolution. We illustrate this here for Ran GTPases, within which two highly conserved histidines, His30 and His139, strikingly diverge from their canonical counterparts. These, along with other residues specifically conserved in Ran, such as Tyr98, Lys99, and Phe138, appear to work in conjunction with FY-pivot canonical residues to facilitate alternative conformations in which these histidines are strategically positioned to couple Ran's basic patch and C-terminal switch to nucleotide exchange and effector binding. Other core components of the cellular machinery are likewise amenable to this approach, which we term Contrast Hierarchical Alignment and Interaction Network (CHAIN) analysis.     

Pericardial Disease in Pregnancy

Background: There is no evidence that pregnancy affects susceptibility to pericardial disease. However, when such a condition occurs, its proper diagnosis and management may be crucial for the outcome of the pregnancy. Incidence and Diagnosis: Hydropericardium is the most frequent form of pericardial involvement in pregnancy. It is typically a small, clinically silent pericardial effusion present in the third trimester in approximately 40% of healthy pregnant women. Small amounts of fetal pericardial fluid (< 2 mm in echocardiography, in diastole) can be detected after 20 weeks of gestation. Larger effusions should raise clinical concern for hydrops fetalis, Rh disease, hypoalbuminemia, and infectious or autoimmune disorder. Wide varieties of etiologic forms of pericardial diseases occur sporadically in pregnant women. Significant symptoms, electrocardiographic changes, or physiologic impairment warrant hospitalization. Treatment: Most pericardial disorders are managed during pregnancy as in nonpregnant patients (i.e., nonsteroidal antiinflammatory drugs for acute, antibiotics and drainage for purulent pericarditis, and corticosteroids for systemic autoimmune disorders). However, colchicine is contraindicated in pregnancy, and pericardiocentesis should be performed only for very large effusions causing clinical signs of cardiac tamponade or if presence of suppurative, tuberculous or neoplastic pericardial effusion is suspected. Echocardiographic guidance of pericardiocentesis is preferred to fluoroscopic guidance in order to avoid fetal X-ray exposure. Pericardiectomy should be reserved for significant pericardial constriction and resistant bacterial infections. Delivery of normal infants in term after pericardiocentesis or pericardiectomy is expected, whenever natural history of causative disease allows. Pericardiectomy itself is not a contraindication for subsequent successful pregnancies. Zusammenfassung. Hintergrund: Hinweise dafür, dass eine Schwangerschaft zur Entstehung von Perikarderkrankungen prädisponiert oder deren Ausbildung beeinflusst, gibt es nicht. Wenn aber während der Schwangerschaft eine Perikarderkrankung auftritt, sind eine schnelle Diagnose und die richtige Behandlung von großer Bedeutung. Inzidenz und Diagnose: Die häufigste Form eines Perikardergusses während der Schwangerschaft ist das "Hydroperikard". Es handelt sich typischerweise um das Auftreten eines kleinen, klinisch nicht relevanten Perikardergusses im dritten Trimenon der Schwangerschaft. Bei ca. 40% aller gesunden Schwangeren ist ein solcher minimaler Erguss nachweisbar. In der 20. Schwangerschaftswoche kann auch bei den Feten ein kleiner Perikarderguss nachgewiesen werden, der in der fetalen Echokardiographie eine Separation von < 2 mm zeigen sollte. Größere Ergüsse sind meist das erste klinische Zeichen für einen Hydrops fetalis, eine Rhesus-Blutgruppenunverträglichkeit, eine Hypoalbuminämie bzw. infektiöse oder autoimmune Erkrankungen des Fetus und/oder der Mutter. Die Ätiologie der Perikarderkrankungen der Mutter während der Schwangerschaft ist vielfältig, wobei die akute virale Perikarditis und Perikardergüsse im Rahmen systemischer autoimmuner Erkrankungen die häufigsten Ursachen darstellen. Selten findet man auch Perikardergüsse bei Schwangeren im Rahmen von Tumorerkrankungen oder einer Tuberkulose. Wenn starke präkordiale Schmerzen, Veränderungen im EKG und eine deutliche Beeinträchtigung der Belastungsfähigkeit auftreten, ist eine Klinikeinweisung unumgänglich. Therapie: Die meisten Perikarderkrankungen bei Schwangeren werden behandelt wie die von Nichtschwangeren, d.h. mit nichtsteroidalen antiinflammatorischen Medikamenten bei akuter Perikarditis, mit Antibiotika und ggf. einer Drainage bei eitrigen Perikardergüssen bzw. der Gabe von Kortikosteroiden bei autoimmunen Systemerkrankungen. Die Gabe von Colchicin ist während der Schwangerschaft kontraindiziert. Eine Perikardpunktion wird nur bei großen Perikardergüssen mit den klinischen Zeichen einer akuten Tamponade bzw. bei Verdacht auf Tuberkulose, infektiösen Erguss oder Tumorerkrankung durchzuführen sein. In diesen wenigen Fällen ist eine echokardiographisch gesteuerte Punktion angebracht, um eine Strahlenbelastung des Ungeborenen zu vermeiden. Eine Perikardektomie sollte nur bei perikardialer Konstriktion und schwerer bakterieller Infektion durchgeführt werden. Die Prozeduren Perikardpunktion und Perikardektomie allein haben, vom Interventions- bzw. Operationsrisiko abgesehen, keinen negativen, sondern eher einen günstigen prognostischen Einfluss auf die Schwangerschaft. Es gibt bislang keine ausreichenden Daten dafür, dass eine Perikardergussbildung in einer vorausgegangenen Schwangerschaft bei erneuter Gravidität zu einem Rezidiv führt. Liegen gleichzeitig allerdings eine linksventrikuläre Dilatation und Dysfunktion vor, ist, wie im Beitrag "Schwangerschaft und Kardiomyopathie" ausgeführt, nach den Empfehlungen der European Society of Cardiology (ESC) von einer erneuten Schwangerschaft abzuraten.     

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

Purpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200mg/m², and VP 16, 200mg/m², both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.     

The enhancement of riboflavin-mediated photo-oxidation of doxorubicin by histidine and urocanic acid

PURPOSE: Previously we have shown that doxorubicin (Adriamycin, ADR) can be inactivated by light-excited riboflavin. The inactivation of the drug results from its direct oxidation by the excited triplet riboflavin in a type I photosensitization reaction, and 3-methoxysalicyclic acid is an ADR breakdown product. In the present study, we investigated the enhancement of this process by histidine and some other imidazole analogs. METHODS: ADR solutions containing various concentrations of riboflavin and other agents were exposed to 365 nm light for various time periods and then the absorbance spectrum of ADR was measured by a double beam spectrophotometer. These measurement were used to calculate the half-time of the ADR degradation process. The degraded ADR solutions were analyzed by HPLC. RESULTS: The rate of bleaching of ADR by light-excited riboflavin was enhanced in the presence of histidine in a concentration-dependent manner. This enhancement was more pronounced at higher riboflavin concentrations. Histidine also enhanced the riboflavin-mediated photobleaching of N,N-dimethyl-4-nitrosoaniline (RNO), a compound known to be resistant to oxidation by singlet oxygen but sensitive to oxidation by the trans-annular peroxide of histidine. RNO was found to block the histidine enhancement of the riboflavin-mediated photobleaching of ADR in a competitive manner. Among the imidazole analogs of histidine tested, urocanic acid was found to be the most efficient enhancer of the riboflavin-mediated photobleaching of ADR. Superoxide anion radicals which retard the oxidation of ADR were quenched by urocanic acid but not by histidine. It was shown that the oxidation of ADR by the trans-annular peroxide of histidine resulted in the formation of 3-methoxysalicylic acid. CONCLUSIONS: In contrast to singlet oxygen, the trans-annular peroxide, formed by the interaction of histidine and the singlet oxygen produced by photoexcited riboflavin, is an efficient oxidizer of ADR. The enhancement of the riboflavin-mediated photobleaching of ADR by histidine analogs depends on the rate of their conversion to a trans-annular peroxide and on the efficiency of these products in oxidizing ADR. However, for some analogs of histidine, as shown for urocanic acid, other mechanisms could also be involved. The presence of urocanic acid in the skin suggests that significant degradation of ADR could occur in the presence of biologically relevant concentrations of riboflavin if patients treated with ADR are exposed to sunlight. The finding that histidine also enhanced the degradation of ADR to 3-methoxysalicylic acid, suggests that the process of ADR oxidation by the trans-annular peroxides is similar to the direct oxidation of ADR by excited triplet riboflavin.