bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of palliative chemotherapy in advanced soft tissue sarcoma: Retrospective analysis of 488 patients
Authors: Karavasilis V. , Seddon B. , Al-Muderis O. , Ashley S. , Judson I. 
Published: March 2020

9520 Background: Advanced soft tissue sarcomas (aSTS) represent an incurable clinical entity of poor prognosis, in which chemotherapy is frequently viewed as relatively ineffective. We aimed to review the efficacy of palliative chemotherapy and investigate prognostic factors in a large group of patients treated on routine palliative protocols. Methods: Patients with STS who had first line chemotherapy for advanced and/or metastatic disease between 1991 and 2005 were identified from the Royal Marsden Hospital’s sarcoma database. Patients with Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumour and GIST were excluded from the study. Patients who were treated elsewhere more than 1 year before they come to our hospital were also excluded. Results: 488 patients (242M/286F) fulfilled the criteria. Median age at the time of treatment was 50 years (range 19–79). The main tumour types were leiomyosarcomas (35%) synovial sarcoma (13%), liposarcoma (10%) and malignant fibrous histiocytoma (10%). The majority of patients (83%) received chemotherapy for metastatic disease. 71% of patients had single organ involvement and 29% had multiple disease sites. Lung was the most common site of metastasis (56%). 54% were treated with single agent chemotherapy. Response rate to chemotherapy was 33% (53% for synovial sarcoma); 22% achieved stable disease for a median duration of 8 months; 45% progressed through chemotherapy. Median time to progression was 3 months, duration of response 9 months and post treatment survival (OS) 12 months. In multivariate analysis, age <60, liposarcoma and synovial histology were found as positive and bone involvement as negative independent prognostic factors. Patients treated with combination chemotherapy experienced longer survival (11 vs 14 months OS; p=0.001). Conclusions: This retrospective study of standard palliative chemotherapy in unselected patients with aSTS shows that more than half of patients benefit from treatment, indicating that this is a worthwhile treatment option. Synovial sarcoma and liposarcoma represent the most chemosensitive sarcoma subtypes. Nevertheless, continuing search for new agents is strongly warranted to improve the survival of these patients. No significant financial relationships to disclose.
A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma
Authors: D’Adamo D. R. , Scheu K. , Singer S. , Schwartz G. K. , Maki R. G. 
Published: March 2020

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.
Familial gastrointestinal stromal tumor with homo-/hemizygous kit exon 11 deletion: Genotypic, histopathologic, radiographic, and therapeutic findings
Authors: Kleinbaum E. P. , Chen L. L. , Lazar A. , Strong L. , Zhang W. , Choi H. , Benjamin R. , Patel S. , Trent J. C. 
Published: March 2020

9527 Background: Germ-line mutations in the kit receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). We describe a large kindred with multiple individuals with GIST and describe the genotype, clinical presentation, radiographic imaging, surgical findings, imatinib-sensitivity, and histopathologic appearance. Patients and Methods: A large kindred with multiple GISTs were identified after the proband patient was referred to our institution. The history of each affected and unaffected family member was obtained in person or via telephone. A medical questionnaire was sent to family members and appropriate medical records, tumor tissue and radiographic imaging was obtained. Histopathologic specimens from four of the family members with GIST was obtained, the diagnosis confirmed and three specimens were used to sequence kit exon 9, 11, 13, 15 and 17. Results: Fifteen members were identified in this family with histopathologic diagnosis of GIST or probable GIST. Surgical findings revealed multiple tumors arising from the submucosa of the small intestine. Histopathology revealed microscopic proliferation of the myenteric plexus with areas of microscopic tumor nodularity. Four patients in this kindred were treated with imatinib and had radiographic and clinical evidence of therapeutic benefit. A deletion of codon 579 in exon 11 of the kit gene was identified in tumor and normal tissue of this family. Evaluation of one GIST revealed loss of heterozygosity in kit exon 11 suggesting a homozygous mutation or loss of the wild-type locus. Conclusion: This study describes a kindred with a propensity to develop GIST in association with hyperpigmentation and melanocytic nevi, but not dysphagia. The germline deletion of codon 579 appears to confer proliferation and nodularity of the myenteric plexus, synchronous tumors at presentation, a metastatic phenotype, and in vivo sensitivivity to imatinib therapy. No significant financial relationships to disclose.
Combination of bevacizumab (A) and pegylated-liposomal doxorubicin (PLD) (PLD-A) in sarcoma (SAR)
Authors: Haddad P. A. , Skubitz K. M. 
Published: March 2020

9556 Background: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis (AG) in many tumors including SAR. A has demonstrated efficacy in several common solid tumors. Because of the known efficacy of PLD in SAR and the presumed importance of VEGF in SAR, we have treated SAR patients with PLD-A. It is possible that the addition of A to PLD might alter the toxicity profile. To our knowledge, the toxicities of this combination have not been previously described. Methods: To better define the toxicity of the combination of PLD-A in SAR, we reviewed our experience with PLD-A in patients with SAR treated between 2004 and 2005. Results: We identified 12 patients with SAR treated with PLD-A at our institution. There were 5 men and 7 women, with a median age of 43.5 years (range 27–57). Nine patients initiated therapy with PLD on a 28 day interval at a median dose of 45 mg/m2 (range 45–50), and 3 on a 14 day interval at a dose of 22.5 mg/m2, in combination with A at 5 mg/kg every 2 weeks. A median of 3 cycles was given (range 2–9). Standard CALGB response and NIH common toxicity criteria were used. Dose delay was required in 3 patients for the second cycle, and dose reduction was required in 5 patients by cycle 3. Of the 10 patients starting with monthly PLD, 6 were changed to q 2 week PLD by cycle 4. Mucositis and skin toxicity were the dose limiting toxicities (DLT) in 9/12 patients, and myelosuppression was the DLT in 1/12 patients. Conclusions: This report describes the toxicity profile of PLD-A in 12 patients with SAR. The toxicities observed were similar to those seen with PLD alone, however, there was a suggestion that these toxicities may be more pronounced with the addition of A, though this appears to vary among patients. Since VEGF is important for wound healing, the known effects of A on this process may contribute to more skin and mucosal toxicity of PLD at a given dose. Future studies of PLD-A should consider the potential of increased mucosal and skin toxicity, and the use of q2week PLD to allow more control over toxicity is suggested. [Table: see text]
HIV protease inhibitor (PI) therapy for liposarcoma
Authors: Chow W. A. , Guo S. , Valdes-Albini F. 
Published: March 2020

9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.
Extremity soft tissue sarcoma: The need for a differential surgical approach to primary tumor and local recurrence?
Authors: Gronchi A. , Miceli R. , Mariani L. , Fiore M. , Grosso F. , Collini P. , Olmi P. , Mussi C. , Casali P. G. 
Published: March 2020

9565 Background: To explore the prognostic implications of local recurrence in extremity adult soft tissue sarcoma (eSTS). Methods: From January 1983 to December 2002, 1,017 patients with localized eSTS were treated at Istituto Nazionale Tumori, Milan, Italy. First local recurrence, re-operated with a curative intent, was investigated as a predictor of further recurrence, distant metastasis and cause specific mortality. Such a task was carried out considering recurrent patients earlier operated for primary disease at our institution (Group A, N=88) or elsewhere (Group B, N=150). The follow up of the above patients after recurrence was compared to that of the overall group of 738 patients operated for primary disease at our institution. Analyses were performed by multiple Cox models, in which local recurrence was entered as a time dependent factor, and tumour size, depth, histotype, grade, margins, RT and CT as covariates for the purpose of adjustment. Event-times were computed from the date of diagnosis, with “left censoring” on the time when patients entered our cohort (date of surgery). Results: The hazard ratio estimates of second recurrence, distant metastases and disease-specific mortality in groups A and B were 5.39 vs 2.95 (p<0.001), 3.96 vs 1.54 (p<0.001), and 2.93 vs 1.43 (p<0.001), respectively. The prognostic effect of the covariates on mortality turned out to be not significantly affected by disease local relapse, but a trend for surgical margins in group A could be observed (HR 1.71). Conclusions: Local recurrence correlates with a worse prognosis, in terms of further local recurrence, distant metastases, and death. Such an effect is stronger following surgery at a referral center for eSTS if compared to local recurrence following surgery done elsewhere, i.e. at institutions less likely to perform adequate local treatment for this rare group of tumors. Possibly, this means that “true” local recurrences, not simply due to inappropriateness, single out pts carrying an inherently more aggressive disease. Consistently, these data cannot confirm, but neither rule out that more aggressive surgery (ie, at the cost of a higher amputation rate, in order to avoid contaminated surgical margins) may be needed in pts locally recurring after initial adequate surgery. No significant financial relationships to disclose.
Surgical and non-surgical treatment of pulmonary metastases of soft tissue sarcomas
Authors: Sade J. P. , Chacon M. , O′Connor J. M. , Pupareli C. , Varela M. , Chacon R. D. 
Published: March 2020

9582 Background: Several reports have shown a prolonged survival after surgery for lung metastases from soft tissue sarcomas (STS). This finding is in contrast with the results from chemotherapy. We performed a retrospective analysis to determine the impact of surgical and non surgical treatment in terms of time to progression (TTP) and disease specific survival (DSS). Methods: A review of 144 patients (pts) with STS treated at a single institution (december 1994-february 2005) was performed. Median age: 45 years old, female 53%. Extremity was the primary site in 54 pts and leiomyosarcoma was the most common histologic type (24%). In 42 pts pulmonary metastases were synchronous. The median disease free interval (DFI) was 11 months. Surgical treatment on the lung lesions was performed in 48 pts (group A), while 96 received medical treatment (group B). Results: Surgery was R0 in 90% of group A pts with only 4 lobectomies and 36 metastasectomies. Nine pts (19%) in this group received neo or adyuvant chemotherapy. The median TTP was 11 months (2–107) and 21 pts (44%) relapse in the lung (8 lung + other site). At the time of this analysis 13 pts (27%) are NED, with a DSS of 24 months for the surgical group. 28% remain alive at 5 years. In a univariate analysis only the number of lung metastases (1 vs 2 or more) was significant for DSS (p=0.05). Group B was treated primarily with chemotherapy being doxorubicin the most common drug used (89%). The RR was 23% with a median TTP of 3 months and a DSS of 12 months (1–98). Conclusions: The present results are similar with previous reports in terms of overall survival. Paliative chemotherapy showed modest activity and surgical treatment remains the only curative treatment modality for pts with lung metastases from STS. No significant financial relationships to disclose.
A Retrospective Study of Neurological Complications in Pediatric Patients With Moyamoya Disease Undergoing General Anesthesia
Authors: Lang Shih-Shan , Vollmer Emma , Wu Lezhou , Bathini Abhijith , Kanuga Bhavya , Ma Annie , Barrett Karyn , Galvez Jorge A. , Storm Phillip B. , Huh Jimmy , Simpao Allan F 
Published: March 2020

BACKGROUND:
Moyamoya disease is a condition with potentially devastating and permanent neurological sequelae. Adequate volume status and blood pressure, tight control of carbon dioxide to achieve normocarbia, and providing postoperative analgesia to prevent hyperventilation are typical goals that are used during anesthetic care in these patients. The purpose of this study was to assess postanesthesia neurological complications in moyamoya patients undergoing general anesthesia for imaging studies and surgical procedures excluding neurosurgical revascularization.

METHODS:
We performed a retrospective cohort study examining moyamoya patients who received general anesthesia for imaging studies and nonneurosurgical-revascularization procedures between January 1, 2001 and December 1, 2016 at our quaternary care pediatric hospital. A general anesthetic encounter was excluded if it occurred within 30 days after a revascularization surgery. The electronic medical records of study patients were analyzed for perioperative management, and neurological outcomes within 30 days of an anesthetic were assessed.

RESULTS:
A total of 58 patients undergoing 351 anesthesia exposures were included in the study. Three patients experienced neurological complications, which included focal neurological weakness, seizure, and altered mental status. The incidence of complications during anesthesia encounters was 0.85% (3/351) with a 95% confidence interval of 0.28–2.62.

CONCLUSIONS:
Over a 16-year period at our hospital, 3 children with moyamoya disease who underwent anesthesia for nonneurosurgical-revascularization purposes demonstrated postanesthesia neurological symptoms. The symptoms were consistent with transient ischemic attacks and all resolved without long-term sequelae.
A ÁGUA E O SEU VALOR ECONÔMICO: UMA ANÁLISE SOBRE OS CONFLITOS E AS DIFERENTES FORMAS DE ACESSO À ÁGUA
Authors: Agostinho Luane Lemos Felício , Santos Diogo De Almeida Viana dos , Façanha Josanne Cristina Ribeiro Ferreira 
Published: March 2020

O objetivo deste artigo é examinar a evolução do direito de acesso à água, desde a perspectiva internacional global, passando pela regulação comparada na América do Sul, até o surgimento e a implementação do arcabouço regulatório brasileiro. Para atingir tal objetivo, analisou-se a formação do direito internacional de acesso à água, ressaltando o seu aspecto predominantemente econômico, bem como as políticas de privatização e monetarização da água enquanto bem de consumo, dotado de valor financeiro, apesar de já despontar no cenário internacional o reconhecimento do acesso à água como um direito humano. Visitaram-se os casos de Bolívia e Brasil, lugares onde o valor econômico da água redundou em privação do direito humano de acesso à água e de seus consectários, como dignidade humana e vida. Conclui-se que há dois macro-movimentos globais paralelos: o hegemônico, que defende o valor econômico da água e que tende à privatização do recurso, dificultando seu acesso aos mais vulneráveis e possibilitando futuros conflitos pelo direito à água; e o movimento que defende o acesso à água como um direito humano, ou mesmo como sujeito de direito e destinatário da norma, que tem embasado uma postura contra-hegemônica à comoditização dos “recursos” naturais. O presente artigo caracteriza-se como descritivo, exploratório e de natureza bibliográfica.
Recent advances in understanding and managing resistant/refractory hypertension
Authors: Doumas Michael , Imprialos Konstantinos P , Kallistratos Manolis S , Manolis Athanasios J 
Published: March 2020

The management of resistant hypertension presents several challenges in everyday clinical practice. During the past few years, several studies have been performed to identify efficient and safe pharmacological and non-pharmacological options for the management of such patients. The Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2) trial demonstrated significant benefits with the use of spinorolactone as a fourth-line drug for the treatment of resistant hypertension over doxazosin and bisoprolol. In addition, recent data support that spironolactone may demonstrate superiority over central acting drugs in such patients, as well. Based on the European guidelines, spironolactone is recommended as the fourth-line drug option, followed by amiloride, other diuretics, doxazosin, bisoprolol or clonidine. Among several device-based approaches, renal sympathetic denervation had fallen into hibernation after the disappointing results of the Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN) 3 trial. However, the technique re-emerged at the epicenter of the clinical and research interest after the favorable results of three sham-controlled studies, which facilitated novel catheters and techniques to perform the denervation. Significant results of iliac anastomosis on blood pressure levels have also been demonstrated. Nevertheless, the technique-related adverse events resulted in withdrawal of this interventional approach. Last, the sympatholytic properties of the carotid baroreceptor activation therapy were associated with significant blood pressure reductions in patients with resistant hypertension, which need to be verified in larger controlled trials. Currently device-based approaches are recommended only in the setting of clinical trials until more safety and efficacy data become available.