Risk and Prognostics of Second Primary Cancer After Prostate Radiation Therapy.

INTRODUCTION: As overall survival in prostate cancer increases due to advances in early detection and management, there is a growing need to understand the long-term morbidity associated with treatment, including secondary tumors. The significance of developing radiation-associated secondary cancers in an elderly population remains unknown. METHODS: Patients diagnosed with prostate cancer between 1975 and 2016 in one of 9 Surveillance, Epidemiology, and End Results registries were included in this study. Risk of second primary pelvic malignancies (SPPMs) were assessed with death as a competing risk using the Fine-Gray model. Time-varying Cox proportional hazard models were employed to analyze risk to overall mortality based on secondary tumor status. RESULTS: A total of 569,167 primary prostate cancers were included in analysis with an average follow-up of 89 months. Among all prostate cancer patients, 4956 SPPMs were identified. After controlling for differences in age, year of diagnosis, and surgery at time of prostate cancer treatment, radiation receipt was associated with a significantly higher incidence of SPPMs (1.1% vs 1.8% at 25 years). Among those who received radiation during initial prostate cancer treatment (n = 195,415), developing an SPPM is significantly associated with worse survival (adjusted hazard ratio = 1.76), especially among younger patients (under age 63, adjusted hazard ratio = 2.36). CONCLUSIONS: While developing a secondary malignancy carries a detrimental effect on overall survival, the absolute risk of developing such tumors is exceedingly low regardless of radiation treatment.

A Tool to Integrate Electrophysiological Mapping for Cardiac Radioablation of Ventricular Tachycardia.

Purpose: Cardiac radioablation is an emerging therapy for recurrent ventricular tachycardia. Electrophysiology (EP) data, including electroanatomic maps (EAM) and electrocardiographic imaging (ECGI), provide crucial information for defining the arrhythmogenic target volume. The absence of standardized workflows and software tools to integrate the EP maps into a radiation planning system limits their use. This study developed a comprehensive software tool to enable efficient utilization of the mapping for cardiac radioablation treatment planning. Methods and Materials: The tool, HeaRTmap, is a Python-scripted plug-in module on the open-source 3D Slicer software platform. HeaRTmap is able to import EAM and ECGI data and visualize the maps in 3D Slicer. The EAM is translated into a 3D space by registration with cardiac magnetic resonance images (MRI) or computed tomography (CT). After the scar area is outlined on the mapping surface, the tool extracts and extends the annotated patch into a closed surface and converts it into a structure set associated with the anatomic images. The tool then exports the structure set and the images as The Digital Imaging and Communications in Medicine Standard in Radiotherapy for a radiation treatment planning system to import. Overlapping the scar structure on simulation CT, a transmural target volume is delineated for treatment planning. Results: The tool has been used to transfer Ensite NavX EAM data into the Varian Eclipse treatment planning system in radioablation on 2 patients with ventricular tachycardia. The ECGI data from CardioInsight was retrospectively evaluated using the tool to derive the target volume for a patient with left ventricular assist device, showing volumetric matching with the clinically used target with a Dice coefficient of 0.71. Conclusions: HeaRTmap smoothly fuses EP information from different mapping systems with simulation CT for accurate definition of radiation target volume. The efficient integration of EP data into treatment planning potentially facilitates the study and adoption of the technique.

Early-onset osteoradionecrosis following adjuvant volumetric-modulated arc therapy to an osteocutaneous free fibula flap with customized titanium plate.

BACKGROUND: Computerized surgical planning (CSP) in osseous reconstruction of head and neck cancer defects has become a mainstay of treatment. However, the consequences of CSP-designed titanium plating systems on planning adjuvant radiation remains unclear. METHODS: Two patients underwent head and neck cancer resection and maxillomandibular free fibula flap reconstruction with CSP-designed plates and immediate placement of osseointegrated dental implants. Surgical treatment was followed by adjuvant intensity modulated radiation therapy (IMRT). RESULTS: Both patients developed osteoradionecrosis (ORN), and one patient had local recurrence. The locations of disease occurred at the areas of highest titanium plate burden, possibly attributed to IMRT dosing inaccuracy caused by the CSP-designed plating system. CONCLUSION: Despite proven benefits of CSP-designed plates in osseous free flap reconstruction, there may be an underreported risk to adjuvant IMRT treatment planning leading to ORN and/or local recurrence. Future study should investigate alternative plating methods and materials to mitigate this debilitating outcome.

Ductal Carcinoma in Situ in Young Women: Increasing Rates of Mastectomy and Variability in Endocrine Therapy Use.

BACKGROUND: Young women with ductal carcinoma in situ (DCIS) represent a unique cohort given considerations for future risk reduction and treatment effects on fertility and quality of life. We evaluated national patterns of care in the treatment of young women and the impact of those treatments on overall survival (OS). METHODS: Women younger than 50 years of age diagnosed with pure DCIS from 2004 to 2016 in the National Cancer Database (NCDB) were identified. Clinical, demographic, and choice of local therapy are summarized and trended over time. OS was analyzed using Cox proportional hazard models. RESULTS: A total of 52,150 women were identified, and the most common surgical treatment was breast-conservation surgery (BCS; 59%). Bilateral mastectomy (BM) increased in frequency from 2004 to 2016 (11-27%; p < 0.001). In women < 40 years of age, BM (39%) surpassed BCS (35%) in 2010 with a continued upward trend. On multivariable analysis, no OS benefit of BM (hazard ratio [HR] 0.99, p = 0.90) or unilateral mastectomy (UM; HR 0.98, p = 0.80) was observed when compared with BCS + radiation therapy (RT). Inferior OS was seen with BCS, Black race, estrogen receptor (ER)-negative, and tumor ≥ 2.5 cm (p ≤ 0.006). In ER+ patients, there was a significant difference in endocrine therapy (ET) use between BM (11%), UM (33%), and BCS (28%) compared with BCS + RT (64%, p < 0.001). CONCLUSION: The use of BM for DCIS is increasing in younger patients and now exceeds breast-conservation approaches in women < 40 years of age with no evidence of improved OS. Among ER+ patients, the rates of ET are lower in the BM, UM, and BCS-alone groups compared with BCS + RT.

Modern Management of High-risk Soft Tissue Sarcoma With Neoadjuvant Chemoradiation: A Single-center Experience.

OBJECTIVE: Neoadjuvant chemoradiation (NA-CRT), followed by resection of high-risk soft tissue sarcoma (STS), may offer good disease control and toxicity outcomes. We report on a single institution's modern NA-CRT experience. MATERIALS AND METHODS: Delay to surgical resection, resection margin status, extent of necrosis, tumor cell viability, presence of hyalinization, positron emission tomography (PET)/computed tomography data, and treatment toxicities were collected. Using the Kaplan-Meier survival analysis, 5-year overall survival, disease-free survival, distant metastasis-free survival, and local control (LC) were estimated. Clinicopathologic features and PET/computed tomography avidity changes were assessed for their potential predictive impact using the log-rank test. RESULTS: From 2011 to 2018, 37 consecutive cases of localized high-risk STS were identified. Twenty-nine patients underwent ifosfamide-based NA-CRT to a median dose of 50 Gy before en bloc resection. At a median follow-up of 40.3 months, estimated 5-year overall survival was 86.1%, disease-free survival 70.2%, distant metastasis-free survival 75.2%, and LC 86.7%. Following NA-CRT, a median reduction of 54.7% was observed in tumor PET avidity; once resected, median tumor necrosis of 60.0% with no viable tumor cells was detected in 13.8% of the cases. Posttreatment resection margins were negative in all patients, with 27.6% having a margin of ≤1 mm. Delays of over 6 weeks following the end of radiation treatment to surgical resection occurred in 20.7% cases and was suggestive of inferior LC (92.8% vs. 68.6%, P=0.025). CONCLUSIONS: This single-institution series of NA-CRT demonstrates favorable disease control. Delay in surgical resection was associated with inferior LC, a finding that deserves further evaluation in a larger cohort. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Strict bladder filling and rectal emptying during prostate SBRT: Does it make a dosimetric or clinical difference?

BACKGROUND: To evaluate inter-fractional variations in bladder and rectum during prostate stereotactic body radiation therapy (SBRT) and determine dosimetric and clinical consequences. METHODS: Eighty-five patients with 510 computed tomography (CT) images were analyzed. Median prescription dose was 40 Gy in 5 fractions. Patients were instructed to maintain a full bladder and empty rectum prior to simulation and each treatment. A single reviewer delineated organs at risk (OARs) on the simulation (Sim-CT) and Cone Beam CTs (CBCT) for analyses. RESULTS: Bladder and rectum volume reductions were observed throughout the course of SBRT, with largest mean reductions of 86.9 mL (19.0%) for bladder and 6.4 mL (8.7%) for rectum noted at fraction #5 compared to Sim-CT (P < 0.01). Higher initial Sim-CT bladder volumes were predictive for greater reduction in absolute bladder volume during treatment (ρ = - 0.69; P < 0.01). Over the course of SBRT, there was a small but significant increase in bladder mean dose (+ 4.5 ± 12.8%; P < 0.01) but no significant change in the D2cc (+ 0.8 ± 4.0%; P = 0.28). The mean bladder trigone displacement was in the anterior direction (+ 4.02 ± 6.59 mm) with a corresponding decrease in mean trigone dose (- 3.6 ± 9.6%; P < 0.01) and D2cc (- 6.2 ± 15.6%; P < 0.01). There was a small but significant increase in mean rectal dose (+ 7.0 ± 12.9%, P < 0.01) but a decrease in rectal D2cc (- 2.2 ± 10.1%; P = 0.04). No significant correlations were found between relative bladder volume changes, bladder trigone displacements, or rectum volume changes with rates of genitourinary or rectal toxicities. CONCLUSIONS: Despite smaller than expected bladder and rectal volumes at the time of treatment compared to the planning scans, dosimetric impact was minimal and not predictive of detrimental clinical outcomes. These results cast doubt on the need for excessively strict bladder filling and rectal emptying protocols in the context of image guided prostate SBRT and prospective studies are needed to determine its necessity.

Immune Checkpoint Inhibitor-Associated Diabetes: A Single-Institution Experience.

OBJECTIVE: To characterize immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in a single-institution case series. RESEARCH DESIGN AND METHODS: Retrospective chart review of 18 patients with new-onset ICI-DM following anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death protein ligand 1 (PD-L1) therapy for advanced carcinomas. RESULTS: Of 18 patients, 9 had diabetic ketoacidosis (median glucose 27.92 mmol/L; median glucose before presentation 6.35 mmol/L). Median C-peptide at ICI-DM diagnosis was low, and it declined during follow-up. Median anti-PD-1/anti-PD-L1 duration before ICI-DM was 3.65 months (range 0.56-12.23 months). Time to ICI-DM onset was a median 1.4 months/3 ICI cycles and 6 months/10 cycles in those patients who were positive and negative for GAD65 autoantibodies, respectively. Time to ICI-DM onset was a median 2.5 months/3 ICI cycles and 4.8 months/8 cycles after anti-PD-L1 or anti-PD-1 therapy, respectively. Significant pancreatic atrophy was seen radiographically. CONCLUSIONS: ICI-DM presents abruptly, appears irreversible, is characterized by pancreatic atrophy, and may occur both earlier following PD-L1 blockade compared with PD-1 inhibition and in those who have positive GAD65 autoantibodies.

Prognostic potential of mid-treatment nodal response in oropharyngeal squamous cell carcinoma.

BACKGROUND: We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy. METHODS: In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1. RESULTS: At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND <43%. On multivariate analysis, D20 ≥43% was independently prognostic for LRC (HR 1.17, P = .05). CONCLUSION: Patients with low-risk oropharynx cancer with ND of ≥43% by treatment day 20 had significantly improved LRC. The prognostic benefit of ND may assist in identifying candidates for treatment de-escalation.

The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management.

Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint-related endocrinopathies.

Dorsal Wrist Pain in the Extended Wrist-Loading Position: An MRI Study.

Background The etiology of dorsal wrist pain associated with loading of the wrist in extension has not been clearly identified in the literature. Purpose Many exercise disciplines incorporate upper extremity weight-bearing exercises in an extended wrist posture, for example push-ups, plank position, and various yoga and Pilates poses. This study evaluates patients with dorsal wrist pain in the extended wrist-loading position and identifies anatomic abnormalities in the wrist using magnetic resonance imaging (MRI). Methods A retrospective chart review was performed comparing MRI of patients who complained of dorsal wrist pain while performing weight bearing in a wrist extension position with a control group of patients who complained of ulnar-sided wrist pain. The primary MRI outcome was dorsal wrist pathology, including occult dorsal ganglion cyst, scapholunate ligament tear or degeneration, and dorsal capsulitis. Results Dorsal wrist pathology was significantly more prevalent in patients with dorsal wrist pain (84%) than in the patient cohort with ulnar-sided wrist pain (12%). Occult dorsal ganglion cysts were the most common sources of pathology (76%). Conclusion MRI demonstrated an identifiable dorsal abnormality in 84% of patients with dorsal wrist pain associated with weight bearing on the extended wrist. Occult dorsal ganglion cysts are the most common cause of dorsal wrist pain, followed by partial scapholunate tears. When patients complain of dorsal wrist pain during specific extended loading wrist positions such as push-ups, yoga, or Pilates poses, an MRI may be warranted to help identify anatomic abnormalities that may help guide treatment choices. Level of Evidence Diagnostic, Level III.

Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies.

Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease. In this Review, we describe the current data regarding immune-related endocrinopathies, including hypophysitis, thyroid dysfunction and diabetes mellitus. We discuss the clinical management of these endocrinopathies within the context of our current understanding of the mechanisms of IRAEs.

The Effect of Smoking on 30-Day Complications Following Radical Prostatectomy.

OBJECTIVE: The purpose of this study was to determine if smoking status is associated with 30-day postoperative complications following radical prostatectomy. METHODS: From the American College of Surgeons National Surgical Quality Improvement Program's (NSQIP) 2005-2013 database, we identified patients who underwent prostatectomy for treatment of prostate cancer. The cohort was stratified into current smokers, former smokers, and never smokers. Bivariable and multivariable analysis was utilized to assess the association between smoking status and risk of complications. RESULTS: We identified 22,802 patients who underwent malignancy-related prostatectomy and met inclusion criteria. Based on reported smoking history, 2799 (12.3%) were current smokers, 1879 (8.2%) were former smokers, and 18,124 (79.5%) were never smokers. Current smokers had a higher rate of total complications (5.7%) in comparison with former (4.8%) and never smokers (4.6%; P = .050). Postoperative pneumonia was more frequent in current smokers (0.4%) compared with former smokers (0.2%) and never smokers (0.2%; P = .039). Unplanned intubation occurred more frequently in current smokers (0.4%) when compared with former smokers (0.3%) and never smokers (0.1%; P = .002). Multivariable analysis found that current smoking status was an independent predictor of an increased risk of unplanned intubation (odds ratio, 5.87; 95% confidence interval, 2.18-15.8; P < .001). CONCLUSION: Smoking status influences the risk of postoperative complications following prostatectomy. Specifically, current smoking status is an independent predictor of unplanned intubation within 30 days of the procedure.

Axon Counts Yield Multiple Options for Triceps Fascicular Nerve to Axillary Nerve Transfer.

PURPOSE: To evaluate the relative axonal match between potential donor and recipient nerves, so that maximal reinnervation potential may be reached with the least chance of donor site morbidity. METHODS: In 10 fresh-frozen cadaveric specimens, the main trunk and anterior, posterior, sensory and teres minor branches of the axillary nerve were identified, as were the radial nerve branches to the long, medial, and lateral heads of the triceps. The swing distances of the triceps fascicular nerve branches and the axillary nerve branches relative to the inferior border of the teres major muscle were recorded. Histomorphological analysis and axon counts were performed on sections of each branch. RESULTS: The median number of axons in the main axillary trunk was 7,887, with 4,052, 1,242, and 1,161 axons in the anterior, posterior, and teres minor branches, respectively. All specimens had a single long head triceps branch (median, 2,302 axons), a range of 1 to 3 branches to the medial head of the triceps (composite axon count, 2,198 axons), and 1 to 3 branches to the lateral head of the triceps (composite average, 1,462 axons). The medial and lateral head branches had sufficient swing distance to reach the anterior branch of the axillary nerve in all 10 specimens, with only 4 specimens having adequate long head branch swing distances. CONCLUSIONS: It is anatomically feasible to transfer multiple branches of the radial nerve supplying the medial, lateral, and sometimes, long head of the triceps to all branches of the axillary nerve in an attempt to reinnervate the deltoid and teres minor muscles. CLINICAL RELEVANCE: Understanding the axon counts of the different possible transfer combinations will improve operative flexibility and enable peripheral nerve surgeons to reinnervate for both abduction and external rotation with the highest donor/recipient axon count ratios.

Hybrid Russe Procedure for Scaphoid Waist Fracture Nonunion With Deformity.

PURPOSE: To assess the results of a hybrid Russe procedure using a corticocancellous strut, cancellous autologous nonvascularized bone graft, and cannulated headless compression screw to reduce the deformity reliably from a collapsed scaphoid nonunion, provide osteoinductive stimulus, and stabilize the fracture for predictable union. METHODS: A hybrid Russe procedure was performed for scaphoid waist fracture nonunions with humpback deformity and no evidence of avascular necrosis. A volar distal radius autologous bone graft was harvested and a strut of cortical bone was fashioned and placed into the nonunion site to restore length and alignment. We packed cancellous bone graft in the remainder of the nonunion site and fixed the scaphoid was with a headless compression screw. Union was determined by radiographs or computed tomography, and intrascaphoid, scapholunate, and radiolunate angles were calculated on final radiographs. We recorded wrist range of motion, grip strength, pinch strength, pain, and complications. RESULTS: Fourteen male and 3 female patients (average age, 32 years; range, 16-78 years), with a mean follow-up of 32 months, were examined clinically and radiographically. All 17 scaphoids united with a mean time for union of 3.6 months. The mean postoperative intrascaphoid angle was significantly reduced from 65° preoperatively to 35° postoperatively. The mean radiolunate angle was significantly improved from 20° from neutral (lunate tilted dorsally) preoperatively to 0° postoperatively. The scapholunate angle also demonstrated significant improvement from 70° preoperatively to 56° postoperatively. Grip strength improved from 70% of the contralateral hand to 89% after the procedure. All patients were satisfied with the functional outcome and no donor site morbidity or hardware issues were identified. CONCLUSIONS: This straightforward hybrid Russe technique predictably restored radiolunate, scapholunate, and intrascaphoid angles with a 100% union incidence. The technique provides excellent functional results in patients with a challenging clinical problem, and we recommend it for scaphoid fracture waist nonunions with dorsal intercalated segment instability deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Optimal axon counts for brachial plexus nerve transfers to restore elbow flexion.

BACKGROUND: Nerve transfer surgery has revolutionized the management of traumatic brachial plexus injures. However, the optimal size ratio of donor to recipient nerve has yet to be elucidated. The authors investigated the axon count ratios of ulnar and median fascicular transfers to restore elbow flexion. The authors hypothesized that donor nerve axon counts would be correlated with historical success of various nerve transfers used to restore elbow flexion. METHODS: Ten cadaveric specimens were used for a histomorphologic analysis of fascicular nerve transfers. Review of previously published axon counts and clinical results following transfer to the musculocutaneous nerve to restore elbow flexion was performed for the following donor nerves: medial pectoral, spinal accessory, intercostal, thoracodorsal, ulnar, and median fascicular. RESULTS: The average number of fascicles identified was 7.9 in the ulnar nerve and 8.0 in the median nerve. The mean fascicular axon count was 1318 for the ulnar nerve and 1860 for the median nerve. Mean recipient nerve axon count was 1826 for the musculocutaneous biceps branch and 1840 for the brachialis branch. A significant correlation between axon count and clinical results of transfers to restore elbow flexion was observed. Donor-to-recipient nerve axon count ratios below 0.7:1 were associated with a decreased likelihood of a successful outcome. CONCLUSIONS: In nerve transfers to restore elbow flexion, an appropriate size match between donor and recipient nerves appears to be a factor affecting clinical success. These data support a donor-to-recipient axon count ratio greater than 0.7:1 as the goal for brachial plexus nerve transfers to restore elbow flexion.

Preoperative donor nerve electromyography as a predictor of nerve transfer outcomes.

PURPOSE: We hypothesized that health of the donor nerve and corresponding muscle, as assessed by electromyography (EMG), could predict the outcome of nerve transfer surgery. METHODS: A retrospective review was performed to investigate outcomes of nerve transfers for elbow flexion and shoulder abduction. Motor strength was graded preoperatively and after a minimum 1-year follow-up. Preoperative EMG results were classified as functionally normal or affected based on motor unit recruitment pattern and correlated with follow-up motor strength and range of motion. RESULTS: Forty nerve transfers were identified: 27 were performed for elbow flexion and 13 for shoulder abduction. Overall, the 29 transfers in the normal EMG cohort showed significantly greater postoperative improvement in motor strength (Medical Research Council grade 0.2-4.1) than the 11 transfers in the affected EMG cohort (grade 0.0-3.0). In the shoulder cohort, normal donor nerves resulted in greater strength (grade 4.0 vs. 2.4) and active motion (83° vs. 25°) compared with affected donor nerves. Double fascicular transfers with 2 normal donor nerves demonstrated improved strength compared with double nerve transfers when 1 donor nerve was affected (grade 4.5 vs. 3.2). CONCLUSIONS: Our findings demonstrate that a simple EMG classification that describes the quality of donor nerves can predict outcome as measured by postoperative motor strength and range of motion. Preoperative EMG evaluation should be considered a valuable supplementary component of the donor nerve selection process when planning brachial plexus reconstruction. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.