Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

Leiomyosarcoma of the great saphenous vein (vena saphena magna) with granular cell change: Report of a superficial neoplasm.

The great saphenous vein (GSV) corresponds to the main superficial large-caliber vessel affected by leiomyosarcoma (LMS). Given its superficial location and because signs of vascular origin may not be clinically apparent, LMS of the GSV may be misinterpreted clinically as superficial nonvascular soft tissue mass. Herein, we report a case on the distal portion of the right GSV of a 57-year-old man. The histopathological recognition of a large-caliber vein-associated LMS (with granular cell change) in an incisional biopsy specimen was crucial to guide radiological evaluation and confirmation of a superficial vascular LMS before surgical treatment. Recognizing this entity in small biopsies is important as its surgical treatment and prognosis differ substantially from nonvascular superficial (ie, subcutaneous and dermal) LMSs. In addition, because vascular LMSs can involve long vessel segments, underestimation of extent of disease is a risk. To the best of our knowledge, granular cell change has not been documented in LMS of the GSV.

Challenges and opportunities for sarcoma care and research in Latin America: a position paper from the LACOG sarcoma group.

As a developing region, Latin America faces unique cancer control and prevention challenges, which are intensified when considering rare cancers, including sarcomas. Sarcomas are a group of malignancies that arise in the connective tissues of the body-such as muscle, fat, nerves, blood vessels, and bones-accounting for a diverse range of tumours that, although rare, require specialized attention. Sarcoma care and research in Latin America require a comprehensive approach that includes deeper epidemiologic knowledge, diagnostic capacity building, access to innovative treatments, increased patient advocacy, and strengthening of clinical research capacity. This article will review current challenges and opportunities for treating patients with sarcoma in Latin America and outline a pathway toward improvement for regional collaborative groups.

Determinants of quality of life in advanced cancer patients with bone metastases undergoing palliative radiation treatment.

PURPOSE: Assessment of health-related quality of life (HRQOL) is critical to effective delivery of palliative care in patients with advanced cancer. The current study analyzes relationships between baseline social determinants of health and medical factors, and self-reported HRQOL in patients with bone metastases receiving palliative radiotherapy. METHODS AND MATERIALS: Advanced cancer patients referred for radiotherapy treatment of bone metastases completed the EORTC QLQ-C30 questionnaire in multiple outpatient clinics internationally. Demographics and social determinants were collected as baseline information. Univariate and Bonferroni-adjusted multivariate linear regression analyses were used to detect significant correlations between baseline determinants and different HRQOL domains. RESULTS: Karnofsky Performance Status (KPS) was correlated with better physical (p = 0.0002), role (p < 0.0001), emotional (p < 0.0001), and social (p < 0.0001) functioning, and global health scores (p = 0.0015) and predicted lower symptom scores for fatigue (p < 0.0001), pain (p < 0.0001), appetite loss (p < 0.0001), and constipation (p < 0.0001). Increased age was predictive of better social functioning (p < 0.0001) and less insomnia (p = 0.0036), higher education correlated with better global health status (p = 0.0043), and patients who were employed or retired had improved physical functioning (p = 0.0004 and p = 0.0030, respectively) and less financial challenges compared to patients who were unemployed (p = 0.0005). CONCLUSIONS: Baseline KPS had the greatest influence on EORTC QLQ-C30 domain scores. Age, education level, and employment status had significant impacts, although on fewer domains. Further studies that investigate baseline determinants are worthwhile to clarify relationships in order to care for patients more effectively at the end of life.

International field testing of the reliability and validity of the EORTC QLQ-BM22 module to assess health-related quality of life in patients with bone metastases.

BACKGROUND: The objective of this international field study was to test the reliability, validity, and responsiveness of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BM22 module to assess health-related quality of life (HRQOL) in patients with bone metastases. METHODS: Patients undergoing a variety of bone metastases-specific treatments were accrued. The QLQ-BM22 was administered with the QLQ-C30 at baseline and at 1 follow-up time point internationally. A debriefing questionnaire was administered to determine patient acceptability and understanding. RESULTS: Large-scale field testing of the QLQ-BM22 in addition to the QLQ-C30 took place in 7 countries: Brazil, Canada, Cyprus, Egypt, France, India, and Taiwan. A total of 400 patients participated. Multitrait scaling analyses confirmed 4 scales in the 22-item module. The scales were able to discriminate between clinically distinct patient groups, such as between those with a poor and those with a better performance status. The QLQ-BM22 was well received in all 7 countries, and the majority of patients did not recommend any significant changes from the module in its current form. CONCLUSIONS: The final QLQ-BM22 module contains 22 items and 4 scales assessing Painful Sites, Painful Characteristics, Functional Interference, and Psychosocial Aspects. Results confirmed the validity, reliability, cross-cultural applicability, and sensitivity of the 22-item EORTC QLQ-BM22. It is therefore recommended that the QLQ-BM22 be used in addition to the QLQ-C30 in clinical trials to assess HRQOL in patients with bone metastases.

An international prospective study establishing minimal clinically important differences in the EORTC QLQ-BM22 and QLQ-C30 in cancer patients with bone metastases.

PURPOSE: Quality of life (QOL) is frequently an endpoint in clinical trials involving patients with advanced cancer. Statistical significance of minimal differences can be achieved with sufficient sample size, yet the actual clinical relevance is unknown. The purpose of this study was to establish the minimal clinically important difference (MCID) for the European Organisation for Research and Treatment of Cancer (EORTC) bone metastases module (EORTC QLQ-BM22). METHODS: Patients with bone metastases across seven countries were prospectively enrolled in a trial validating the EORTC QLQ-BM22 and completed the QLQ-BM22 and core measure (QLQ-C30) at baseline and 1-month follow-up. MCIDs were calculated for each QOL scale for both improvement and deterioration using both an anchor- (performance status) and distribution-based approach. RESULTS: A total of 93 patients completed both baseline and follow-up QOL and had recorded performance status at both intervals. Statistically significant meaningful differences were seen in seven scales. There were improvements of 30.5 (95 % confidence interval, 9.0 to 52.0), 20.1 (7.1 to 33.2), 30.5 (13.8 to 47.3) and 19.6 (5.0 to 34.3) in the pain, painful site, painful characteristic and functional interference scales, respectively, demonstrated clinical relevance. Decreases of 12.4 (0.3 to 24.6), 22.4 (11.8 to 32.9) and 13.5 (1.9 to 25.1) were required to represent clinically relevant deterioration in emotional functioning, global health status and financial issues, respectively. Minimal differences for improvement were closest to 0.5 standard deviations (SD) while for deterioration, closer to 0.3 SD on the QLQ-BM22. CONCLUSION: Identification of requirements for clinical significance can assist in determining the relevance of QOL changes after treatment and in sample size determination in future trials. Our study is limited by the small sample size. Future studies should continue to determine MCID and confirm our findings using a variety of appropriate anchors and in a larger sample.

Is PET-CT an accurate method for the differential diagnosis between chondroma and chondrosarcoma?

The differential diagnosis between chondroma and intraosseous chondrosarcoma is based on imaging and clinical exams, but only a biopsy can confirm diagnosis. The aim of this study was to evaluate the value of PET-CT in differentially diagnosing chondroma and chondrosarcoma. From October 2009 to May 2015, 36 patients with cartilaginous bone lesions in the extremities, 12 (33.3 %) men and 24 (66.6 %) women, were prospectively included in the study. Patients ranged in age from 21 to 68 years, with a mean age of 44 years. Lesions were located in the long bones: in the proximal humerus in 26 (72.2 %) patients, in the femoral shaft in 1 (2.7 %), in the distal femur in 7 (19.4 %), and in the proximal tibia in 2 (5.5 %). The SUVmax value of 2.0 was used to separate between patients submitted to surgery and patients submitted to observation. Among the 36 patients studied, 17 (47.2 %) had SUVmax ≤ 2.0, and they were diagnosed as chondroma and they were treated conservatively. Follow-up ranged from 14 to 76 months, averaging 38 months. Nineteen (52.7 %) patients with SUVmax >2.0 were diagnosed as chondrosarcoma and underwent surgery. The area of the curve, calculated considering the SUV variable as numeric, is estimated in 0.966, with a 95 % confidence interval from 0.906 to 1.000. To evaluate the sensitivity, specificity and positive/negative predictive values, it was built a 2 × 2 table. Significance was set at p < 0.05. According the criteria of maximum sensitivity and specificity, the cut point suggested to SUVmax was 2.2. If we consider this point, it is possible to identify 19 of 36 positive cases to chondroma (52.8 %), it means, all chondrosarcomas of the series. We concluded that PET-CT can be used as an objective and quantitative method of differentiating between chondromas and chondrosarcomas located within the long bones. It represents a complementary examination to standard imaging (X-ray, scintigraphy, CT and MRI) and pathological exams. The SUVmax between 2.0 and 2.2 would be a range area between chondroma and chondrosarcoma and this range can be of value, among others exams, in decide the best treatment for patients with cartilaginous lesions in long bones. Level of evidence Level I-diagnostic study-prospectively investigating a diagnostic test using a universally applied "gold" standard.

Predictive factors of overall quality of life in advanced cancer patients using EORTC QLQ-C30.

OBJECTIVE: To identify which domains/symptoms from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were predictive of overall quality of life (QoL) in advanced cancer patients. METHODS: Four hundred and forty seven patients with brain metastases or bone metastases from seven countries were enrolled with regression analysis to determine the predictive value of the QLQ-C30 functional/symptom scores for patient reported overall QoL (question 30), overall health (question 29) and the global health status domain (questions 29 and 30). RESULTS: Worse role functioning, social functioning, fatigue and financial problems were the most significant predictive factors for worse QoL. In the bone metastases subgroup (n = 400), role functioning, fatigue and financial problems were the most significant predictors. In patients with brain metastases (n = 47), none of the EORTC domains significantly predicted worse QOL. CONCLUSION: Deterioration of certain QLQ-C30 functional/symptom scores significantly contributes to worse QoL, overall health and global health status.

Predictive factors of overall well-being using the EORTC QLQ-C15-PAL extracted from the EORTC QLQ-C30.

OBJECTIVE: The European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 15 Palliative (EORTC QLQ-C15-PAL) was developed to assess quality of life (QOL) for the palliative cancer population to decrease patient burden. The purpose of this study was to compare predictive factors for well-being in the QLQ-C15-PAL extracted from the EORTC Quality of Life Questionnaire - Core 30 (QLQ-C30) with the QLQ-C30 itself. METHODS AND MATERIALS: Patients with advanced cancer referred for treatment of bone metastases completed the QLQ-C30. Fifteen items from the QLQ-C15-PAL were extracted from the QLQ-C30. Univariate and multivariate analyses were used to determine predictive factors of the global QOL/health score in both tools. In the multivariate analyses, a p value of <0.003 indicated statistical significance. RESULTS: Overall, predictive factors were similar when analyzing data from both tools. Predictive factors for the QLQ-C30 were role functioning (p<0.0001), fatigue (p<0.0001), nausea/vomiting (p<0.0001), and financial problems (p<0.0001) and factors for the extracted QLQ-C15-PAL were physical functioning (p<0.0001) and fatigue (p<0.0001). CONCLUSIONS: Extraction of the QLQ-C15-PAL items from the QLQ-C30 resulted in similar predictive QOL domains for all patient subgroups analyzed individually. The QLQ-C15-PAL is reflective of the QLQ-C30 domains and is recommended for future studies involving patients in a palliative setting, as this shorter questionnaire reduces patient burden and may increase accrual and compliance, while maintaining a similar breadth of coverage and achieving the same predictive ability.