Merkel cell carcinoma: An update and review: Current and future therapy.

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin associated with a high risk of local recurrence and distant metastases. It most commonly occurs on sun-exposed areas of white patients >65 years of age. The Merkel cell polyomavirus (MCV) is thought to be responsible for malignant transformation in approximately 80% of cases in the northern hemisphere, while ultraviolet radiation-induced DNA damage is implicated in MCV-negative tumors. The overall incidence of MCC is low, with approximately 1600 cases diagnosed annually in the United States. The rate is much higher in patients with lymphoproliferative malignancies, solid organ transplants, and HIV infection. The low overall incidence of this tumor makes it challenging to conduct prospective clinical trials with sufficient power. As a result, most management recommendations are based on case series, retrospective reviews, and expert opinion. The pathogenesis, diagnosis, and staging of MCC was discussed in the first article in this continuing medical education series. This article focuses on current management guidelines and promising new therapies in development. Because of the complexity, aggressive nature, and individuality of each case, MCC is best treated by a multidisciplinary team.

Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine cancer. It most commonly presents as an indurated plaque or nodule on sun-damaged skin in elderly patients and is characterized by high rates of local recurrence and nodal metastasis. Survival at 5 years is 51% for local disease and as low as 14% for distant disease, which underscores the aggressive nature of this tumor and challenges in management. Advances in immunology and molecular genetics have broadened our understanding of the pathophysiology of MCC and expanded our therapeutic arsenal. With this comprehensive review, we provide an update of MCC epidemiology, pathogenesis, clinical presentation, diagnostic evaluation and prognostic markers. The second article in this continuing medical education series explores the evolving landscape in MCC management.

Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) encompasses rare neoplasms that can arise either in the dermis or in the subfascial soft tissue. The behavior of UPS ranges from indolent to aggressive, but data predicting outcomes are limited. OBJECTIVE: Identify predictors of poor outcomes by analyzing a large collection of UPS cases. METHODS: We evaluated all available cases of UPS (including those termed atypical fibroxanthoma, malignant fibrous histiocytoma, pleomorphic dermal sarcoma, and subfascial UPS) across 3 tertiary care centers. RESULTS: Among the 319 patients, 45 experienced recurrence, 33 experienced metastasis, and 96 died of any cause. Risk factors for recurrence were clinical tumor size larger than 5 cm and invasion beyond subcutaneous fat. Risk factors for distant metastases were tumor site, tumor size larger than 2 cm, invasion beyond subcutaneous fat, and lymphovascular invasion. Risk factors for overall mortality were age, immunosuppression, tumor size larger than 2 cm, and lymphovascular invasion. History of skin cancer was associated with a lower risk of recurrence and metastasis. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Using the unbiased approach of pooling all UPS cases regardless of terminology, we identified clinical and histologic factors predicting poor outcomes. We propose subcategorization of UPS (into superficial versus deep UPS), which is consistent with the American Joint Committee on Cancer staging of soft-tissue sarcoma.

Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.

BACKGROUND: Total body irradiation (TBI) is an important component of hematopoietic stem cell transplant (SCT) for pediatric malignancies. With increasing survival rates, late effects of SCT become more important. Younger children may be at particular risk of late effects of radiation and SCT. METHODS: We retrospectively reviewed outcomes of children less than 3 years of age who received TBI as part of their preparative regimen for SCT at Children's Hospital Colorado. Clinical information including the date of last follow-up, most recent lab values, and physiologic tests were extracted from the medical record. RESULTS: Of 81 patients who underwent SCT, 19 received TBI and of those, 15 were long-term survivors available for review. Late effects occurring in greater than 50% of the children included abnormalities involving endocrine, metabolic, renal, cataracts, and neurocognitive systems. Other organs involved less commonly included liver, skeletal, and cardiac abnormalities. Solid tumors were a rare finding with only one patient developing a benign osteochondroma and no identified secondary malignancies. CONCLUSIONS: TBI has been shown to be an important part of the preparative regimen for patients undergoing SCT. Our results, similar to other studies, suggest TBI in patients less than 3 years of age will likely result in multi-organ dysfunction including endocrine, metabolic, renal, eye, and neurocognitive abnormalities. A longitudinal study with standardized testing of these systems would further clarify the late effects concerns in this patient population.

Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells.

Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant, embryonal CNS tumors with a poor prognosis. Therapy relies on highly toxic chemotherapy and radiotherapy. To improve outcomes and decrease morbidity, more targeted therapy is required. Gene expression analysis revealed elevated expression of multiple kinases in ATRT tissues. Aurora Kinase A was one of the candidate kinases. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in ATRT cell lines. Our analysis revealed that inhibition of Aurora Kinase A induces cell death in ATRT cells and the small molecule inhibitor MLN 8237 sensitizes these cells to radiation. Furthermore, inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways. These data indicate that inhibition of Aurora Kinase A is a promising small molecule target for ATRT therapy.

Local control of metastatic sites with radiation therapy in metastatic Ewing sarcoma and rhabdomyosarcoma.

Approximately 20% of children with Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) present with metastatic disease at initial diagnosis. Overall, the outcome is poor, with an event-free survival of < 20%. Local control at metastatic sites has not been previously reported. We reviewed control of metastatic sites in children with EWS and RMS that received curative intent radiation therapy to each metastatic site. In 13 children, at a median follow-up of 18 months, a single local failure was seen. Toxicity was minimal. Our data suggest that radiation therapy is effective and tolerable in children with metastatic EWS and RMS.

Rotational setup errors in pediatric stereotactic radiation therapy.

PURPOSE: Stereotactic radiation therapy (SRT) is an increasingly commonly used technique in children. The use of image guidance increases the ability to accurately position patients. With our robotic couch, rotational errors that can be corrected are limited to approximately 3 degrees. Given this limitation, we reviewed the rotational setup errors in our pediatric brain tumor population. METHODS AND MATERIALS: We reviewed the rotational corrections for all pediatric (age ≤21 years old) patients treated at our facility from 2009 to 2011. We compared children <5 years old treated to children between 5 and 21 years old (≥5 years old). Also, we analyzed the effect of steroid use and trends in rotational errors over the treatment period in each age group. RESULTS: The mean pitch, roll, and yaw rotational setup errors for younger children are -0.70 ± 2.60 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively; for children ≥5 years old, they are 0.46 ± 2.09 degrees, -0.06 ± 1.89 degrees, and 0.69 ± 2.42 degrees, respectively. The mean pitch corrections are larger for children <5 years old (P < .001) and the variance of the pitch, roll, and yaw corrections are all larger for children <5 years old (P < .001). The frequency of rotational errors above 3 degrees for pitch, roll, and yaw is 21.7%, 10.6%, and 20.9% for children <5 years old, and 15.6%, 2.1%, and 13.8% for children ≥5 years old. In both age groups, pitch and roll corrections were larger for children treated with steroids. CONCLUSIONS: Rotational errors in our pediatric population occur more frequently than previously reported, and are more common in younger children and in children treated with steroids. These rotational set up errors may not be fully correctable due to mechanical and safety limitations. We have altered our planning and treatment process to better account for rotational errors in children receiving SRT.

Future of acute care surgery: a perspective from the next generation.

BACKGROUND: Access to emergent surgical care has been identified as a crisis in the United States. To address this challenge, the American Association for Surgery of Trauma has developed a fellowship in acute care surgery (ACS) to reestablish broad-based surgical capabilities. But the viability of this new discipline will rest on the interests of the next generation of surgeons. The objective of this study was to determine key factors influencing the choice of surgical specialties among medical students with a focus on their interest in trauma/ACS (T/ACS). METHODS: An online questionnaire was distributed to students at four medical schools affiliated with Level I trauma centers, one of which also has an ACS fellowship. The survey was sent to medical students at all levels (first to fourth year). Students with an interest in surgery as a career were asked to complete the survey and rank factors and experiences influencing career selection on a scale of 1 (no influence) to 10 (critical). Students were also asked to select their top five surgical specialties. RESULTS: Three hundred thirty-seven students interested in surgery responded. Mean age was 26 years ± 0.2 years (range, 20-37 years), 58% were men, and 86% were single. Respondents were distributed evenly over medical schools and medical school years. The three most popular career choices were orthopedics (16%), T/ACS (12%), and pediatric surgery (8%). As students progressed through medical school, lifestyle factors such as predictable hours and family time became more important in influencing their career choice. Overall, 115 students (34%) selected emergent surgery (T/ACS) as one of their top three career choices. Factors that were ranked significantly higher by students interested in T/ACS were related to professional satisfaction. These students also placed less emphasis on lifestyle factors when choosing a surgical career. CONCLUSIONS: Our results indicate that there is a reassuring interest to address the growing demand for emergency surgery among current medical students exposed to a broad range of T/ACS patients in Level I trauma centers. The T/ACS model is in accordance with the drives of these students looking for a diverse and challenging profession. Academic societies should make further efforts to encourage medical students to pursue T/ACS.