Adjuvant Radiation Field Extent and Sites of Failure in Node Positive Endometrioid Endometrial Cancer.

PURPOSE: In patients with node-positive endometrial cancer, adjuvant radiation therapy with chemotherapy decreases local-regional recurrence compared with chemotherapy alone. However, the optimal radiation field borders and extent of nodal coverage have not been well studied. In a multi-institutional cohort, survival outcomes and sites of failure were analyzed for patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIIC endometrioid endometrial cancer treated with pelvic radiation therapy (PRT) versus extended-field radiation therapy (EFRT), which encompassed high para-aortic lymph nodes. METHODS AND MATERIALS: In a multi-institutional retrospective study, 143 patients with FIGO stage IIIC1 or IIIC2 endometrioid endometrial cancer treated with adjuvant radiation therapy from 2000 to 2016 were identified. Patient subgroups were classified by substage and radiation field extent: stage IIIC1 received EFRT, stage IIIC1 received PRT, and stage IIIC2 received EFRT. Recurrence-free survival (RFS), overall survival (OS), and out-of-field recurrence were calculated by the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards model. Sites of failure were categorized as within or outside the radiation field. RESULTS: The median follow-up was 59 months; 87% of patients received chemotherapy. The 5-year RFS and OS rates were 73% and 87%, respectively. By subgroup, 5-year RFS rates were 79% for stage IIIC1 EFRT, 73% for stage IIIC1 PRT, and 69% for stage IIIC2 EFRT (P = .4). On multivariate analysis, the recurrence risk was highest for stage IIIC2 EFRT, although this result was not statistically significant (adjusted hazard ratio, 2.0; P = .4). In-field vaginal and nodal recurrences were observed in 2 patients (1%) and 4 patients (3%), respectively. Of 78 patients with stage IIIC1 cancer treated with PRT, 5 (6%) had isolated para-aortic nodal relapse outside the radiation field; 3 were long-term survivors (more than 6 years after salvage therapy). For patients with para-aortic recurrence, 86% had lymphovascular invasion, 71% had myometrial invasion of ≥50%, and 57% had grade 3 disease. CONCLUSIONS: Adjuvant chemoradiation therapy resulted in excellent survival outcomes for patients with FIGO stage IIIC endometrioid endometrial cancer. For patients with positive pelvic nodes, isolated para-aortic relapse outside the PRT field was uncommon and amenable to salvage therapy.

Pilot study on the impact of F18-labeled thymidine PET/CT on gross tumor volume identification and definition for pancreatic cancer.

PURPOSE: Accurate target definition for radiation therapy planning in localized pancreatic cancer is critical, particularly when using strategies that omit elective coverage. Standard imaging modalities such as computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasound have limited concordance with pathologic evaluation. Biologic imaging with [F18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can also be difficult to interpret because increased activity is indicative of increased glucose metabolism, rather than cellular proliferation. [F18]-3'-deoxy-3'-fluorothymidine labeled thymidine (FLT) is a proliferative marker which exploits the expression of pyrimidine-metabolizing enzymes. We evaluate the impact of FLT-PET on pancreatic target definition for radiation planning. METHODS AND MATERIALS: Patients with biopsy-proven, newly diagnosed, untreated pancreatic adenocarcinoma were enrolled on an institutional review board-approved prospective study. Patients were injected with FLT and scanned 20 to 30 minutes later. Two physicians (referred to as observer 1 and observer 2) independently contoured the gross tumor volume (GTV) and involved nodes on CT scan only and then again with the assistance of coregistered FLT-PET. Conformality index (CI), the ratio of the volumes of intersection and union, was used as the metric for volume comparison (where CI = 0 represents no overlap and CI = 1 represents perfect overlap). RESULTS: Nine patients were enrolled in this study. FLT-avidity was discerned in 8 of 9 patients. Average CT-GTV volume for observers 1 and 2 was 38.1 and 26.5 mL, respectively. Average FLT-GTV volume for observers 1 and 2 was 39.1 and 25.0 mL, respectively. For the 8 patients with FLT-avid tumors, addition of FLT data improved concordance of GTV definition between physicians in 6 of 8 tumors. Average CI for interobserver CT-GTV was 0.325. Addition of FLT-PET information improved the average CI to 0.400. CONCLUSIONS: FLT-PET improves interobserver concordance in GTV definition. Further studies will focus on verification of these findings, pathologic verification of the FLT-PET signal, and optimization of the FLT-PET signal threshold for autosegmentation.

Localized Adult Ewing Sarcoma: Favorable Outcomes with Alternating Vincristine, Doxorubicin, Cyclophosphamide, and Ifosfamide, Etoposide (VDC/IE)-Based Multimodality Therapy.

BACKGROUND: In children with localized Ewing sarcoma (ES), addition of ifosfamide and etoposide to cyclophosphamide, doxorubicin, and vincristine (VDC/IE) improved 5-year overall survival (OS) to 70%-80%. Prior to delivery of VDC/IE in adults, 5-year OS was <50%. We reviewed our institutional outcomes for adults with ES who received VDC/IE-based treatment. MATERIALS AND METHODS: Between 1997-2013, 67 adults with localized ES were treated with curative intent. Local recurrence-free survival (LRFS), progression-free survival (PFS), and OS were determined using Kaplan-Meier method; comparisons were assessed with log-rank. Proportional hazard models were used to determine predictive factors. RESULTS: All patients received VDC/IE (median 14 cycles.) Local therapy was surgery for 33, radiation therapy for 17, or both for 17. Median follow-up for living patients was 5.2 years. Six patients had disease progression on therapy. Site of first failure was local for three, local and distant for two, and distant for ten. Five-year LRFS was 91%; 5-year LRFS was 96% for nonpelvic disease and 64% for pelvic disease (p = .003). Five-year PFS was 66%, and 5-year OS was 79%. On multivariate analysis, pelvic site had a 3.3 times increased risk of progression (p = .01). CONCLUSION: Survival for adults with localized ES treated with VDC/IE-based multimodality therapy appears to be better than historical data and similar to excellent outcomes in children. Pelvic site of disease remains a predictor of worse outcome. Given the paucity of literature for adult ES, these data help validate VDC/IE-based therapy as an appropriate treatment approach for this rare disease in adults. IMPLICATIONS FOR PRACTICE: Ewing sarcoma (ES) is rare in adults. Treatment approaches for adults have been extrapolated from the pediatric experience, and there is a sense that adults fare less well than children. We reviewed treatment outcomes in adults with localized ES treated with cyclophosphamide, doxorubicin, and vincristine in alternation with ifosfamide and etoposide (VDC/IE) as part of multimodality therapy. Survival outcomes appear to be better than historical data for adults and similar to the excellent outcomes for children. These data help validate VDC/IE-based therapy as an appropriate treatment approach for this rare disease in adults.

Dosimetric consequences of interobserver variability in delineating the organs at risk in gynecologic interstitial brachytherapy.

PURPOSE: To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy. METHODS AND MATERIALS: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD(TOT)) was calculated. RESULTS: The population mean ± 1 standard deviation of κ, CIgen, and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08, and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08, and 20% ± 5% for rectum; and 0.33 ± 0.20, 0.26 ± 0.17, and 82% ± 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% ± 19% (SD(TOT) = 72 ± 64 Gy) for D0.1cc and CV = 16% ± 10% (SD(TOT) = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SD(TOT) = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SD(TOT) = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SD(TOT) = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SD(TOT) = 4 ± 4 Gy) for D2cc. CONCLUSIONS: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.

ACR Appropriateness Criteria®-Anal Cancer.

The management of anal cancer is driven by randomized and nonrandomized clinical trials. However, trials may present conflicting conclusions. Furthermore, different clinical situations may not be addressed in certain trials because of eligibility inclusion criteria. Although prospective studies point to the use of definitive 5-fluorouracil and mitomycin C-based chemoradiation as a standard, some areas remain that are not well defined. In particular, management of very early stage disease, radiation dose, and the use of intensity-modulated radiation therapy remain unaddressed by phase III studies. The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Chemoradiation therapy: localized esophageal, gastric, and pancreatic cancer.

Chemoradiation plays an important role in management of locally advanced gastrointestinal tumors. This article reviews data regarding chemoradiation for tumors of the upper gastrointestinal tract. For esophageal and gastroesophageal junction cancers, chemoradiation is standard of care in the preoperative setting. In gastric cancer, 2 standards have emerged: definitively treating with perioperative chemotherapy alone and using chemoradiation postoperatively. For pancreatic cancer, the benefit of radiation is less well defined. The future of treatment sites lies in trials evaluating new chemotherapy regimens, alternative systemic therapies, and different radiation fractionation schema. Because care of these patients is complex, multimodality team evaluation before treatment is encouraged.

Emergency innovation: implications for the trauma surgeon.

BACKGROUND: Experimentation involving human subjects requires careful attention to the protection of their rights. Beginning with the Belmont Report in 1979, the United States has developed various sets of rules and regulations that identify the requirements for performing human subject research. In addition, these standards attempt to define the fundamental difference between what constitutes research versus clinical treatment versus innovation. We explore the intersection between two areas of independent bioethics, surgical innovation and emergency research; the point we refer to as emergency innovation. METHODS: A systematic literature review in each of the fields of emergency research and surgical innovation was completed. The ethical principles involved in each field were identified. In addition, a recent case of surgical innovation within the context of emergency treatment is evaluated for the ethics invoked. RESULTS: One of the great challenges in emergency innovation is that the main protection offered in innovation (heightened informed consent) is not possible in the emergency context where in fact informed consent is waived. Interestingly, the rest of the protections outlined for each field are not mutually exclusive. They can and should be utilized in any project that takes place at this intersection. However, as there are no strict regulations in place for the collision of these two fields, the possibility of having the majority of the involved ethical principles misinterpreted or ignored is very real. CONCLUSIONS: For emergency innovation, where it is unclear what ethical principles and regulatory powers apply, it is imperative to be unambiguous about the purpose of the investigation, to adhere to all applicable ethical principles, and to have utmost consideration for protection of the research subject. To determine intent, the goals of the study must be outlined precisely - and if those include the prospect of publication, institutional review board (IRB) approval should be involved early. If, however, the innovation is subtle and the goal geared toward improved patient care, a small feasibility trial would be an appropriate first step before transitioning to a formal larger study approved by an IRB. In either case, the degree of the change in practice must be carefully evaluated and the vulnerability of the research subjects respected. With careful attention paid to all applicable ethical principles at the emergency innovation intersection, medical progress can continue at minimized risk to the human subject participants.

An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone-responsive genes by microarray.

Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia, is a model disease for the study of erythroid differentiation but is poorly understood. RPS19 is the only gene yet to have been associated with DBA, but its relevance to erythroid differentiation is unclear. The molecular basis for the stimulation of erythropoiesis by glucocorticoids in patients with DBA has not been identified. We demonstrate that targeted degradation of the RPS19 transcript, through retroviral expression of short hairpin RNAs (shRNAs), blocks the proliferation and differentiation of erythroid progenitor cells in cultured human CD34(+) cells. Treatment of RPS19-deficient cells with dexamethasone restores erythroid differentiation to normal levels. We investigated the molecular basis of pharmacologic therapies for DBA using oligonucleotide microarrays to survey gene expression in CD34(+) cells treated with combinations of dexamethasone, erythropoietin, stem cell factor, and interleukin-3. Dexamethasone did not alter expression of RPS19 but activated a genetic program that includes a set of key hematopoietic regulatory genes. Genes specific to erythroid progenitor cells were up-regulated by dexamethasone, while genes specific to nonerythroid lineages were down-regulated. Deficiency of RPS19 therefore blocks proliferation of immature erythroid progenitor cells, and dexamethasone activates proliferation of the same cell population through mechanisms independent of RPS19.