Faculty Bibliography

BACKGROUND:Colorectal cancer is the third most prevalent cancer in the world, preceded by prostate and lung cancers in men (10%) and breast and lung cancers in women (9.4%). Colorectal cancer is the fourth leading cause of death in men (7.6%) and the third in women (8.6%). A multidisciplinary approach has radically changed the way we deal with this disease among all specialist fields. PURPOSE/OBJECTIVE:In this study, we propose comparing the multidisciplinary experience group (started in 2012) of S. Anna Hospital (University of Ferrara) with the previous approach to rectal cancer before the advent of the multidisciplinary program. RESULTS:We find that more study depth of neoplastic disease as well as of each individual patient leads to more accurate staging and to a weighted therapy based on the needs of the individual. All the studies were performed in accordance with the guidelines established by the European and Italian associations.

PURPOSE/OBJECTIVE:This study was designed to compare the observed risk of femoral fracture in primary soft-tissue sarcoma (STS) of the thigh/groin treated with intensity-modulated radiation therapy (IMRT) to expected risk calculated using the Princess Margaret Hospital (PMH) nomogram. METHODS:Expected femoral fracture risk was calculated by using the PMH nomogram. Cumulative risk of fracture was estimated by using Kaplan-Meier statistics. Prognostic factors were assessed with univariate and multivariate analysis using Cox's stepwise regression. RESULTS:Between February 2002 and December 2010, 92 consecutive eligible patients were assessed. Median follow-up was 73 months (106 months in surviving patients). IMRT was delivered preoperatively (50 Gy) in 13 (14%) patients and postoperatively in 79 (86%) patients (median dose, 63 Gy; range, 59.4-66.6 Gy). The observed crude risk of fractures was 6.5% compared with 25.6% expected risk from the nomogram; the cumulative risk of fracture using IMRT at 5 years was 6.7% (95% CI 2.8-16.0%). The median time to fracture was 23 months (range, 6.9-88.6). Significant predictors of fracture on univariate analysis were age ≥ 60 years (p = 0.03), tumor location in the anterior thigh (p = 0.008), and periosteal stripping to > 20 cm (p < 0.0001). On multivariate analysis, age ≥ 60 years and periosteal stripping > 20 cm retained significance (p = 0.04 and p = 0.009, respectively). CONCLUSIONS:In this study, the cumulative risk of femur fracture in patients treated with IMRT (6.7%) is less than the expected risk using the PMH nomogram (25.6%). Established predictors of femur fracture, such as gender, tumor size, and dose of RT, seem to have less impact on fracture risk when using IMRT.

BACKGROUND:Biologic agents may prolong survival of patients with certain kidney and lung adenocarcinomas that have metastasized to bone, and patient response to these agents should be considered when choosing between an endoprosthesis and internal fixation for surgical treatment of femoral metastases. QUESTIONS/PURPOSES:Among patients undergoing surgery for femoral metastases of lung or renal cell carcinoma, (1) Does survival differ between patients who receive only cytotoxic chemotherapy and those who either respond or do not respond to biologic therapy? (2) Does postsurgical incidence of local disease progression differ between groups stratified by systemic treatment and response? (3) Does implant survival differ among groups stratified by systemic treatment and response? METHODS:From our institutional longitudinally maintained orthopaedic database, patients were identified by a query initially identifying all patients who carried a diagnosis of renal cell carcinoma or lung carcinoma. Patients who underwent internal fixation or prosthetic reconstruction between 2000 and 2016 for pathologic fracture of the femur and who survived ≥ 1 year after surgery were studied. Patients who received either traditional cytotoxic chemotherapy or a biologic agent were included. Patients were classified as responders or nonresponders to biologic agents based on whether they had clinical and imaging evidence of a response recorded on two consecutive office visits over ≥ 6 months. Endpoints were overall survival from the time of diagnosis, survival after the femoral operation, evidence of disease progression in the femoral operative site, and symptomatic local disease progression for which revision surgery was necessary. Our analysis included 148 patients with renal (n = 26) and lung (n = 122) adenocarcinoma. Fifty-one patients received traditional chemotherapy only. Of 97 patients who received a biologic agent, 41 achieved a response (stabilization/regression of visceral metastases), whereas 56 developed disease progression. We analyzed overall patient survival with the Kaplan-Meier method and used the log-rank test to identify significant differences (p < 0.05) between groups. RESULTS:One-year survival after surgery among patients responsive to biologic therapy was 61% compared with 20% among patients nonresponsive to biologics (p < 0.001) and 10% among those who received chemotherapy only (p < 0.009). With the number of patients we had to study, we could not detect any difference in local progression of femoral disease associated with systemic treatment and response. Radiologic evidence of periimplant local disease progression developed in three (7%) of 41 patients who responded to biologic treatment, two (3%) of 56 patients nonresponsive to biologics, and one (2%) of 51 patients treated with traditional chemotherapy. With the numbers of patients we had, we could not detect a difference in patients who underwent revision. All three patients responsive to biologics who developed local recurrence underwent revision, whereas the two without a response to biologics did not. CONCLUSIONS:Biologic therapy improves the overall longevity of some patients with lung and renal metastases to the femur in whom a visceral disease response occurred. In our limited cohort, we could not demonstrate an implant survival difference between such patients and those with shorter survival who may have had more aggressive disease. However, an increased life expectancy beyond 1 year among patients responsive to biologics may increase risk of mechanical failure of fixation constructs. LEVEL OF EVIDENCE:Level III, therapeutic study.

BACKGROUND:Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. OBJECTIVE:To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. DESIGN, SETTING, AND PARTICIPANTS:mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. RESULTS AND LIMITATIONS:Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p=0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p=0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. CONCLUSIONS:Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. PATIENT SUMMARY:Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti-vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.

Surgical management of primary musculoskeletal tumors of the shoulder girdle is cognitively and technically demanding. Over the last decades, advances in the medical treatments, imaging and surgical techniques have fostered limb salvage surgery and reduced the need for amputation. Despite well-accepted general principles, an individualized approach is often necessary to accommodate tumor extension, anatomical challenges and patient characteristics. A combination of techniques is often required to achieve optimal oncologic and durable functional outcome. Goal of this article is to review approach and management of patients with locally advanced sarcomas of the shoulder girdle requiring major tumor surgery, to illustrate principles of surgical strategy, outcome and complications, and to provide useful guidelines for the treating physicians.

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ER^lo/Notch^hi feed-forward loop responsible for the generation of CD133^hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221^hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133^hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133^hi CSCs. Conversely, in models of CD133^neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133^hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR.