Regional deep hyperthermia: quantitative evaluation of predicted and direct measured temperature distributions in patients with high-risk extremity soft-tissue sarcoma.

BACKGROUND: Temperature distributions resulting from hyperthermia treatment of patients with high-risk soft-tissue sarcoma (STS) were quantitatively evaluated and globally compared with thermal simulations performed by a treatment planning system. The aim was to test whether the treatment planning system was able to predict correct temperature distributions. METHODS: Five patients underwent computed tomography (CT) fluoroscopy-guided placement of tumor catheters used for the interstitial temperature measurements. For the simulations, five 3 D patient models were reconstructed by segmenting the patient CT datasets into different tissues. The measured and simulated data were evaluated by calculating the temperature change ( ΔT ), T90, T50, T20, Tmean, Tmin and Tmax, as well as the 90th percentile thermal dose (CEM43T90). In order to measure the agreement between both methods quantitatively, the Bland-Altman analysis was applied. RESULTS: The absolute difference between measured and simulated temperatures were found to be 2°, 6°, 1°, 4°, 5° and 4 °C on average for Tmin, Tmax, T90, T50, T20 and Tmean, respectively. Furthermore, the thermal simulations exhibited relatively higher thermal dose compared to those that were measured. Finally, the results of the Bland-Altman analysis showed that the mean difference between both methods was above 2 °C which is considered to be clinically unacceptable. CONCLUSION: Given the current practical limitations on resolution of calculation grid, tissue properties, and perfusion information, the software SigmaHyperPlan™ is incapable to produce thermal simulations with sufficient correlation to typically heterogeneous tissue temperatures to be useful for clinical treatment planning.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.

Inequalities in glycaemic control, hypoglycaemia and diabetic ketoacidosis according to socio-economic status and area-level deprivation in Type 1 diabetes mellitus: a systematic review.

AIM: The aim of this systematic review was to examine the associations of individual-level as well as area-level socio-economic status and area-level deprivation with glycaemic control, hypoglycaemia and diabetic ketoacidosis in people with Type 1 diabetes mellitus. METHODS: Ovid MEDLINE was searched to identify relevant cohort, case-control or cross-sectional studies published between January 2000 and June 2015. Search results were screened by title, abstract and keywords to identify eligible publications. Decisions on inclusion or exclusion of full texts were made independently by two reviewers. The Newcastle-Ottawa Scale was used to estimate the methodological quality of included studies. Quality assessment and extracted data of included studies were synthesized narratively and reported according to the PRISMA statement. RESULTS: Literature search in Ovid MEDLINE identified 1345 eligible studies. Twenty studies matched our inclusion and exclusion criteria. Two articles were additionally identified through hand search. According to the Newcastle-Ottawa Scale, most of the studies were of average quality. Results on associations of socio-economic status and area-level deprivation with glycaemic control and hypoglycaemia were contradictory between studies. By contrast, lower socio-economic status and higher area-level deprivation were associated with a higher risk for diabetic ketoacidosis in all except one study. CONCLUSIONS: Lower socio-economic status and higher area-level deprivation are associated with a higher risk of experiencing diabetic ketoacidosis in people with Type 1 diabetes mellitus. Access to care for socially deprived people needs to be expanded to overcome impairing effects on the course of the condition and to reduce healthcare disparities.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Impact of chemotherapy in uterine sarcoma (UtS): review of 13 clinical trials from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) involving advanced/metastatic UtS compared to other soft tissue sarcoma (STS) patients treated with first line chemotherapy.

OBJECTIVE: UtS are a group of uncommon tumors representing 1% of malignant neoplasms of the female genital tract, and 7% of sarcomas. The objective of this study was to evaluate the factors associated with the clinical behavior UtS. METHODS: Information on 269 patients with advanced or metastatic first line UtS treated by chemotherapy was available in a database containing information on 3270 patients with advanced soft tissue sarcomas (STS) entered in EORTC-STBSG clinical trials between 1977 and 2010. The chemotherapy was aggregated in 4 categories: anthracyclines alone, ifosfamide alone, the combination of doxorubicin and ifosfamide, and CYVADIC. RESULTS: Among the 269 UtS pts, there were 231 deaths (median OS 10.4months, 95% CI: 9.1-11.9) and 257 progressions and/or deaths (median PFS 4.1months, 95% CI: 3.5-4.9). Multivariate analyses reported PS (p<0.001) only to be a statistically significant prognostic factor for OS in UtS; for PFS, LMS histology (p=0.025) is associated with a better outcome. There was no relationship between the 4 groups of chemotherapy regimens and impact on clinical outcomes. Histological subtype was significantly correlated with response to chemotherapy (RR: LMS 19% vs other 33%, p=0.026). Ifosfamide single agent yielded only 5% of RR. CONCLUSIONS: Clearly, UtS are very aggressive neoplasms with poor outcome when treated with chemotherapy consisting of anthracyclines with or without ifosfamide or cyclophosphamide. New strategies are urgently needed.

[Hemato-oncological diseases]. / Hämatoonkologische Krankheitsbilder.

Acquired inhibitors of coagulation cause a life-threatening disease. Clinically newly occurring hemorrhagic diathesis combined with prolonged activated partial thromboplastin time (aPTT) time is diagnostically indicative and can be confirmed by a positive plasma exchange test. For thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP-HUS) the diagnosis of Coombs negative hemolytic anemia together with thrombocytopenia should lead to the detection of fragmentocytes in peripheral blood smears. Hairy cell leukemia is a rare subgroup of chronic B-cell neoplasia with the clinical signs of pancytopenia and splenomegaly which characteristically stain positive for CD103. The gastrointestinal stromal tumor (GIST) has nothing in common with classical soft tissue sarcoma based on the activating mutation of the KIT or PDGFRA gene (positivity for CD117). In all of these disorders the correct diagnosis has a major influence on patient outcome. For the case of acquired inhibitors of coagulation immunosuppressive therapy and substitution of coagulation factors (e.g. recombinant factor VIIa) or for TTP-HUS the immediate start of plasma exchange are mandatory. For hairy cell leukemia a very effective treatment exists with purine analogs (e.g. cladribine) and for metastatic inoperable GIST with tyrosine kinase inhibitors (e.g. imatinib).

Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS).

PURPOSE: We report data from phase II trials examining the efficacy of multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the extremities. PATIENTS AND METHODS: From 1991 to 2001 47 patients with high risk soft tissue sarcoma of the extremities were prospectively treated in two clinical trials with a treatment plan of four cycles of etoposide, ifosfamide and doxorubicin combined with regional hyperthermia followed by surgery, radiation and adjuvant chemotherapy. RESULTS: Objective response rate assessable in 39 patients was 21% (one complete and seven partial responses). A favourable histological response (>75% tumour necrosis) was observed in 34% of the 35 evaluable patients who had surgical resection. Median overall survival (OS) was 105 months. The five-year probability of local failure-free survival (LFFS), distant disease-free survival (DDFS), event-free survival (EFS) and OS were 48%, 55%, 35% and 57%, respectively. There were no significant differences between responders and non-responders of minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) at all measured tumour sites. Response to this neoadjuvant regimen predicted for prolonged LFFS (p = 0.0123), but not for OS (p = 0.2). Limb preservation was achieved in 37 patients (79%) and did not result in inferior DDFS (52% versus 50%) or OS (61% versus 50%) at five years (p = 0.8) in comparison to patients who underwent amputation. CONCLUSION: Response to combined modality treatment with RHT and neoadjuvant chemotherapy was predictive for an improved LFFS and led to limb preservation in 79% of patients with extremity sarcomas.

[Multimodal treatment of sarcomas: standards and new aspects in pharmacological and radio-oncological treatment]. / Multimodale Therapien bei Sarkomen: Standards und Neues in der medikamentösen und radioonkologischen Behandlung.

BACKGROUND: Patients with localized high-risk soft tissue sarcoma are at high risk for both local recurrence and distant metastases despite optimal surgical treatment. OBJECTIVE: Importance of preoperative or postoperative chemotherapy and hyperthermia. METHODS: Evaluation and overview of published study results. RESULTS: Preoperative or postoperative radiotherapy is considered as standard for patients with localized high-risk soft tissue sarcoma. The results of two randomized studies on neoadjuvant chemotherapy showed a survival benefit. As both studies did not have a control arm without chemotherapy but in one case the superiority of anthracycline/ifosfamide-based chemotherapy in combination with hyperthermia over chemotherapy alone and in the other case the superiority of anthracycline/ifosfamide-based chemotherapy over histology-specific chemotherapy were shown, the formal proof of the superiority of this treatment is still missing. Stratifying the patients treated in the so far largest randomized adjuvant chemotherapy trial according to current risk criteria ( http://www.sarculator.com ) revealed a significant survival benefit for patients at high risk of recurrence. CONCLUSION: For high-risk soft tissue sarcomas, multimodal treatment strategies involving perioperative chemotherapy, radiotherapy and, if possible, hyperthermia should be considered in addition to tumor resection. Preoperative chemotherapy should be given preference over postoperative chemotherapy based on available data.

Proton conductivity and proton dynamics in nanocrystalline cellulose functionalized with imidazole.

In the present study, we report the synthesis, electrical and dynamic properties of a new generation bio-based nanocomposite, that is a proton-exchange membrane based on nanocrystalline cellulose (CNC) and imidazole (Im). CNC serves as supporting material and imidazole acts as a proton donor and proton acceptor at the same time. The nanocomposite (1.3 CNC-Im) was synthesized as a film and shows proton conductivity equal to 4.0 × 10-1 S/m at 160 °C in anhydrous conditions. Analysis of impedance measurements and NMR spectra provided some insight into the macroscopic and microscopic processes involved in proton transport in 1.3 CNC-Im. Local processes such as reorientation of imidazole rings and breaking of hydrogen bonds are identified and their activation energies are calculated. The energies of the macroscopic and microscopic proton transport in CNC-Im film are correlated. The percolation model used confirmed the percolation nature of conductivity in cellulose composites with imidazole.

Intermolecular interactions of gramicidin A' transmembrane channels incorporated into lysophosphatidylcholine lipid systems.

Fluorescence studies are reported on gramicidin A' incorporated into lysophosphatidylcholine phospholipid structures. The shift in the emission maximum during incorporation and the quenching of fluorescence by I- and by acrylamide of the incorporated state obtained after prolonged heating are consistent with the presence of the channel state comprised of two single-stranded beta 6 -helices associated head-to-head (formyl end-to-formyl end). The quantum yield for the incorporated state, when gramicidin A' is within the lipid matrix, is very low and indicates the occurrence of intermolecular Trp-Trp interactions. Possible interactions between channels within the lipid matrix are discussed utilizing Trp-Trp contacts.

Supramolecular organization of lysophosphatidylcholine-packaged Gramicidin A.

Heat derived gramicidin A'/L-alpha-lysophosphatidylcholine complexes were separated on a sucrose gradient to form two fractions: Fraction A which had an approximately constant Gramicidin A' to phospholipid ratio of 8 to 10 lipid molecules per Gramicidin A' molecule and Fraction B which had a larger but variable ratio. Fluorescence and circular dichroism studies confirmed Fraction A to be a lipid-incorporated channel state. Electron microscopic studies, using uranyl acetate negative staining, showed fraction A to be a membranous state with the formation of bilayer vesicles, that is, the interaction of peptide and phospholipid micelles causes the lipid to reorganize into a bilayer structure. Freeze-fracture replicas of the channel incorporated state demonstrated the presence of a supramolecular organization of particles exhibiting a tendency to form rows with a 50-60 A periodicity along the row and with 70-80 A distance between rows. An idealized working model for the incorporated state is presented.

Improvements in the silver-staining technique for nucleolar organizer regions (AgNOR).

The silver-staining technique for nucleolar organizer regions (AgNOR) of Ploton et al., as popularized by Crocker, is being widely used for evaluation of nucleolar function, especially in neoplasia. It suffers from limited reliability, background staining, precipitates, and fading of the sections. Factors were identified that affect these problems. The oxidation-reduction level and gelatin used are particularly important. An improved procedure is presented which incorporates pre-reduction of the sections, selection of an optimal gelatin, and post-treatment of the sections to produce a permanent preparation. It is compatible with many fixatives and with other stains used before or after the silver stain.

Hyaline casts in the urine: mechanism of formation and morphologic transformations.

Hyaline urinary casts have been examined primarily by scanning electron microscopy. Their appearance and their transformation with time are described. From this data, the mechanism of their formation and evolution has been deduced. These results permit more accurate identification and assessment of the types of urinary casts present and their significance.

Unsuitability of electron microscopic examination of urinary sediment for the diagnosis of amyloidosis.

Several recent reports suggest that amyloidosis can be diagnosed by ultrastructural identification of fibrillar proteins in the urinary sediment. However, the authors routinely identified similar fibrils in the urinary sediments of all patients with a wide variety of renal diseases who were producing urinary casts, as well as in those of stressed healthy individuals. They therefore conclude that electron microscopic examination of the urinary sediment alone has little value in the diagnosis of amyloidosis when unaccompanied by chemical or immunologic tests.

Identification and composition of types of granular urinary casts.

Granular urinary casts were analyzed by scanning electron microscopy and histochemistry. Three types were identified. They appear to have distinctly different origins and significance. Their clinical associations remain to be defined. One type can be misidentified by bright field microscopy. Bacterial casts also can be misidentified as granular casts unless the sediment is examined carefully.

A specific urinary cast in acute pyelonephritis.

A specific type of urinary cast has been demonstrated in the urine of patients who have acute pyelonephritis. This cast is characterized by the presence of bacteria in its matrix and appears to be specific for and diagnostic of pyelonephritis. It is easily demonstrated by routine urinalysis.

Identification of chlamydia in cervical smears by immunofluorescence: technic, sensitivity, and specificity.

Immunofluorescent staining was compared to cell culture for the diagnosis of Chlamydia trachomatis infections in the female genital tract. By culture, the incidence in the 496 patients in the study was 12.3%. Immunofluorescence demonstrated organisms in 90% of the culture-positive cases, with a specificity of 99.3%. This method appears to be a successful replacement for culture for general screening.

Comparison of scrape, swab, and cytobrush samples for the diagnosis of cervical chlamydial infection by immunofluorescence.

An endocervical swab, cytologic scraper, and endocervical cytobrush were used to prepare simultaneous full-slide smears for immunofluorescence for the diagnosis of cervical chlamydial infection. The cytobrush produced the best sample, with significantly higher numbers of organisms. Most of the false negative results were obtained with the cytologic scraper. The optimum technique appears to be to use a cytobrush sample; however, a swab should be used with pregnant patients.