Focal Application of Neurotrophic Factors Augments Outcomes of Nerve-Muscle-Endplate Grafting Technique for Limb Muscle Reinnervation.

BACKGROUND: We have developed a novel muscle reinnervation technique called "nerve-muscle-endplate grafting (NMEG) in the native motor zone (NMZ)." This study aimed to augment the outcomes of the NMEG-NMZ (NN) by focal application of exogenous neurotrophic factors (ENFs) for limb reinnervation. METHODS: Adult rats were used to conduct NN plus ENF (NN/ENF) and autologous nerve grafting (ANG, technique control). The nerve innervating the left tibialis anterior (TA) muscle was resected and the denervated TA was immediately treated with NN/ENF or ANG. For NN procedure, an NMEG pedicle was taken from the lateral gastrocnemius muscle and transferred to the NMZ of the denervated TA. For ANG, the nerve gap was bridged with sural nerve. Three months after treatment, the extent of functional and neuromuscular recovery was assessed by measuring static toe spread, maximal muscle force, wet muscle weight, regenerated axons, and innervated motor endplates (MEPs). RESULTS: NN/ENF resulted in 90% muscle force recovery of the treated TA, which is far superior to ANG (46%) and NN alone (79%) as reported elsewhere. Toe spread recovered up to 89 and 49% of the control for the NN/ENF and ANG groups, respectively. The average wet muscle weight was 87 and 52% of the control for muscles treated with NN/ENF and ANG, respectively. The mean number of the regenerated axons was 88% of the control for the muscles treated with NN/ENF, which was significantly larger than that for the ANG-repaired muscles (39%). The average percentage of the innervated MEPs in the NN/ENF-treated TA (89%) was higher compared with that in the ANG-repaired TA (48%). CONCLUSION: ENF enhances nerve regeneration and MEP reinnervation that further augment outcomes of NN. The NN technique could be an alternative option to treat denervated or paralyzed limb muscles caused by traumatic nerve injuries or lesions.

Prostate MRI percentage tumor involvement or "PI-RADS percent" as a predictor of adverse surgical pathology.

BACKGROUND: This study assesses magnetic resonance imaging (MRI) prostate % tumor involvement or "PI-RADs percent" as a predictor of adverse pathology (AP) after surgery for localized prostate cancer (PCa). Two separate variables, "All PI-RADS percent" (APP) and "Highest PI-RADS percent" (HPP), are defined as the volume of All PI-RADS 3-5 score lesions on MRI and the volume of the Highest PI-RADS 3-5 score lesion each divided by TPV, respectively. METHOD: An analysis was done of an IRB approved prospective cohort of 557 patients with localized PCa who had targeted biopsy of MRI PIRADs 3-5 lesions followed by RARP from April 2015 to May 2020 performed by a single surgeon at a single center. AP was defined as ISUP GGG ≥3, pT stage ≥T3 and/or LNI. Univariate and multivariable analyses were used to evaluate APP and HPP at predicting AP with other clinical variables such as Age, PSA at surgery, Race, Biopsy GGG, mpMRI ECE and mpMRI SVI. Internal and External Validation demonstrated predicted probabilities versus observed probabilities. RESULTS: AP was reported in 44.5% (n = 248) of patients. Multivariable regression showed both APP (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04-1.14, p = 0.0007) and HPP (OR: 1.10; 95% CI: 1.04-1.16; p = 0.0007) were significantly associated with AP with individual area under the operating curves (AUCs) of 0.6142 and 0.6229, respectively, and AUCs of 0.8129 and 0.8124 when incorporated in models including preoperative PSA and highest biopsy GGG. CONCLUSIONS: Increasing PI-RADS Percent was associated with a higher risk of AP, and both APP and HPP may have clinical utility as predictors of AP in GGG 1 and 2 patients being considered for AS. PATIENT SUMMARY: Using PIRADs percent to predict AP for presurgical patients may help risk stratification, and for low and low volume intermediate risk patients, may influence treatment decisions.

Clinical characteristics and oncological outcomes in negative multiparametric MRI patients undergoing robot-assisted radical prostatectomy.

BACKGROUND: Efforts are ongoing to try and find ways to reduce the number of unnecessary prostate biopsies without missing clinically significant prostate cancers (csPCa). The utility of multiparametric magnetic resonance imaging (mpMRI) in detecting prostate cancer (PCa) shows promise to be used as triage test for systematic prostate biopsy. Our aim is to Study clinical parameters and oncological outcomes in men with negative mpMRI (nMRI; PI-RADS v2 scores of ≤ 2) who underwent robot-assisted radical prostatectomy (RARP) to evaluate nMRI's practicality as a biopsy triage test. METHODS: Retrospective analysis of 331 men with nMRI who underwent RARP between 2014 and 2020 compared with men with positive mpMRI (pMRI; PI-RADS v2 scores ≥ 3, N = 1770). csPCa was defined as Gleason score ≥ 3 + 4 and biochemical recurrence (BCR) was defined as PSA > 0.2 ng/ml on two occasions. Biopsies were graded with the International Society of Urologic Pathology [ISUP] grade. Descriptive statistics for nMRI and pMRI were performed. Mann-Whitney U test was used for continuous variables and χ 2 for categorical variables. Univariable and multivariable regression analyses were performed. RESULTS: Univariable analysis shows statistically significant difference (p < .05) between median age (nMRI-61 years vs. pMRI 63 years), race (higher incidence of nMRI in African American men), use of 5-alpha reductase inhibitors (higher rate in nMRI). While incidence rates of family history of PCa, suspicious digital rectal examination (DRE) findings, median PSA levels and 4Kscore, were lower in nMRI versus pMRI. Rates of positive surgical margins and BCR were comparable in nMRI versus pMRI. Biopsy ISUP Grades I and II upgraded by 51% and 12%, respectively in final pathology. African American race and no history of the prior negative biopsy were significant predictors for upgrading. CONCLUSION: Men with nMRI pose diagnostic challenges as they tend to be younger patients with lower rates of suspicious DRE findings and lower 4K scores, yet comparable oncological outcomes in csPCa rates, positive surgical margins, and BCR rates.

De-Escalated Adjuvant Therapy After Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Carcinoma: The Sinai Robotic Surgery (SIRS) Trial.

BACKGROUND: Treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity. METHODS: This study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin). RESULTS: Fifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease. CONCLUSION: The results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC. IMPLICATIONS FOR PRACTICE: Transoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.

Staging Accuracy of Multiparametric Magnetic Resonance Imaging in Caucasian and African American Men Undergoing Radical Prostatectomy.

PURPOSE: We compared the performance of multiparametric magnetic resonance imaging for the prediction of extraprostatic extension in African American and Caucasian American men and evaluated racial disparities in pathological outcomes after radical prostatectomy. MATERIALS AND METHODS: We identified 975 patients who underwent radical prostatectomy with preoperative multiparametric magnetic resonance imaging between January 2013 and April 2019 at our institution. Multivariable logistic regression analysis was performed predicting pathological extraprostatic extension, high grade prostate cancer (final pathology GGG [Gleason Grade Group] 3 or greater) in the overall population and pathological upgrading (final pathology GGG 3 or greater) in patients with a diagnosis of GGG 1-2 prostate cancer. Adverse pathology was defined as pT3 and/or GGG 3 or greater. RESULTS: A total of 221 (23%) patients were African American. Preoperatively 594 (60.9%) were GGG 1-2 (low risk group) and 381 (39.1%) GGG 3 or greater (high risk group). In the low risk group rates of pathological extraprostatic extension (18% vs 12.8%, p=0.14), adverse pathology (18% vs 13.4%, p=0.2) or upgrading (9.4% vs 12.1%, p=0.4) were similar between races. Similarly, in the high risk group there was no difference in rates of pathological extraprostatic extension. On multivariable analysis multiparametric magnetic resonance imaging predicted the presence of extraprostatic extension (OR 1.80, 95% CI 1.29-2.50) and high grade prostate cancer (OR 1.82, 95% CI 1.25-2.67) on final pathology. Conversely, race did not predict the outcomes of interest (all values p >0.05). Multiparametric magnetic resonance imaging showed comparable sensitivity (22.22% vs 27.84%), specificity (89.2% vs 79.2%), positive predictive value (89.2% vs 83.4%) and negative predictive value (89.2% vs 83.4%) between African American and Caucasian America men, respectively. CONCLUSIONS: The accuracy of multiparametric magnetic resonance imaging in staging prostate cancer was similar in African American and Caucasian American patients and no difference was found between races in pathological outcomes after radical prostatectomy. These findings suggest that access to and use of advanced diagnostic tests may help mitigate prostate cancer racial disparities.

Prediction of biochemical recurrence in prostate cancer patients who underwent prostatectomy using routine clinical prostate multiparametric MRI and decipher genomic score.

BACKGROUND: Biochemical recurrence (BCR) affects a significant proportion of patients who undergo robotic-assisted laparoscopic prostatectomy (RALP). PURPOSE: To evaluate the performance of a routine clinical prostate multiparametric magnetic resonance imaging (mpMRI) and Decipher genomic classifier score for prediction of biochemical recurrence in patients who underwent RALP. STUDY TYPE: Retrospective cohort study. SUBJECTS: Ninety-one patients who underwent RALP performed by a single surgeon, had mpMRI before RALP, Decipher taken from RALP samples, and prostate specific antigen (PSA) follow-up for >3 years or BCR within 3 years, defined as PSA >0.2 mg/ml. FIELD STRENGTH/SEQUENCE: mpMRI was performed at 27 different institutions using 1.5T (n = 10) or 3T scanners and included T2 w, diffusion-weighted imaging (DWI), or dynamic contrast-enhanced (DCE) MRI. ASSESSMENT: All mpMRI studies were reported by one reader using Prostate Imaging Reporting and Data System v. 2.1 (PI-RADsv2.1) without knowledge of other findings. Eighteen (20%) randomly selected cases were re-reported by reader B to evaluate interreader variability. STATISTICAL TESTS: Univariate and multivariate analysis using greedy feature selection and tournament leave-pair-out cross-validation (TLPOCV) were used to evaluate the performance of various variables for prediction of BCR, which included clinical (three), systematic biopsy (three), surgical (six: RALP Gleason Grade Group [GGG], extracapsular extension, seminal vesicle invasion, intraoperative surgical margins [PSM], final PSM, pTNM), Decipher (two: Decipher score, Decipher risk category), and mpMRI (eight: prostate volume, PSA density, PI-RADv2.1 score, MRI largest lesion size, summed MRI lesions' volume and relative volume [MRI-lesion-percentage], mpMRI ECE, mpMRI seminal vesicle invasion [SVI]) variables. The evaluation metric was the area under the curve (AUC). RESULTS: Forty-eight (53%) patients developed BCR. The best-performing individual features with TLPOCV AUC of 0.73 (95% confidence interval [CI] 0.64-0.82) were RALP GGG, MRI-lesion-percentage followed by biopsy GGG (0.72, 0.62-0.82), and Decipher score (0.71, 0.60-0.82). The best performance was achieved by feature selection of Decipher+Surgery and MRI + Surgery variables with TLPOCV AUC of 0.82 and 0.81, respectively DATA CONCLUSION: Relative lesion volume measured on a routine clinical mpMRI failed to outperform Decipher score in BCR prediction. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1075-1085.

Nerve growth factor and basic fibroblast growth factor promote reinnervation by nerve-muscle-endplate grafting.

INTRODUCTION: This study was designed to test whether exogenous application of nerve growth factor (NGF) and basic fibroblast growth factor (FGF-2) to muscles reinnervated with nerve-muscle-endplate band grafting (NMEG) could promote specific outcomes. METHODS: The right sternomastoid muscle in adult rats was experimentally denervated and immediately reinnervated by implanting an NMEG pedicle from the ipsilateral sternohyoid muscle. A fibrin sealant containing NGF and FGF-2 was focally applied to the implantation site. Maximal tetanic force, muscle weight, regenerated axons, and motor endplates were analyzed 3 months after treatment. RESULTS: Mean tetanic force, wet muscle weight, and number of regenerated axons in the treated muscles were 91%, 92%, and 84% of the contralateral controls, respectively. The majority of endplates (86%) in the treated muscles were reinnervated by regenerated axons. DISCUSSION: Focal administration of NGF and FGF-2 promotes efficacy of the NMEG technique. Muscle Nerve 57: 449-459, 2018.

Immunohistochemical Detection of Motor Endplates in the Long-Term Denervated Muscle.

BACKGROUND: We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. METHODS: Sternomastoid (SM) muscles of adult female Sprague-Dawley rats (n = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation. The values obtained from the ipsilateral normal side served as control. RESULTS: The denervated SM muscles exhibited a progressive reduction in muscle weight (38%, 31%, and 19% of the control) and fiber diameter (52%, 40%, and 28% of the control) for 3-, 6-, and 9-month denervation, respectively. The denervated MEPs were still detectable even 9 months after denervation. The mean number of the denervated MEPs was 79%, 65%, and 43% of the control in the 3-, 6-, and 9-month denervated SM, respectively. Degenerated axons in the denervated muscles became fragmented. CONCLUSIONS: Persistence of MEPs in the long-term denervated SM suggests that some surgeries targeting the MEPs such as NMEG-NMZ technique should be effective for delayed reinnervation. However, more work is needed to develop strategies for preservation of muscle mass and MEPs after denervation.

Outcomes of Muscle Reinnervation with Direct Nerve Implantation into the Native Motor Zone of the Target Muscle.

Background Our recent work has demonstrated that the native motor zone (NMZ) within a given skeletal muscle is the best site for muscle reinnervation. This study was designed to explore the outcomes of direct nerve implantation (DNI) into the NMZ of denervated sternomastoid (SM) muscle in a rat model. Methods The right SM muscle was experimentally denervated by transecting its innervating nerve. The proximal stump of the severed SM nerve was immediately implanted into a small muscle slit made in the NMZ of the muscle where denervated motor endplates were concentrated. The outcomes of DNI-NMZ reinnervation were evaluated 3 months after surgery. Specifically, the degree of functional recovery was examined with muscle force measurement. The extent of nerve regeneration and endplate reinnervation was assessed using histological and immunohistochemical methods. Results This study showed that the mean muscle force of the treated muscles was 64% of the contralateral control. Reinnervated SM muscles weighed 71% of the weight of the control muscles. Abundant regenerated axons were identified in the NMZ of the target muscle. The mean number and area of the regenerated axons in the treated muscles was computed to be 62% and 51% of the control muscles, respectively. On average, 66% of the denervated endplates in the treated muscles were reinnervated by regenerated axons. Conclusion Our results suggest that the NMZ within a muscle is an ideal site for endplate reinnervation and satisfactory functional recovery. Further studies are needed to promote the efficacy of DNI-NMZ technique for muscle reinnervation.

Muscle reinnervation with nerve-muscle-endplate band grafting technique: correlation between force recovery and axonal regeneration.

BACKGROUND: This study was designed to determine the correlation between functional recovery and the extent of axonal regeneration after muscle reinnervation with our recently developed nerve-muscle-endplate band grafting (NMEG) technique in a rat model. MATERIALS AND METHODS: The right experimentally paralyzed sternomastoid (SM) muscle by nerve transection was immediately reinnervated with an NMEG pedicle harvested from a neighboring sternohyoid muscle. The NMEG pedicle contained a muscle block (6 × 6 × 3 mm), a donor nerve branch with nerve terminals, and a motor endplate band. Three months after surgery, the tetanic force of the SM muscle was measured and the regenerated axons in the muscle were detected using neurofilament immunohistochemistry. RESULTS: The results showed that the maximal tetanic force (a measure of muscle functional recovery) of the NMEG-reinnervated SM muscle reached up to 66.0% of the normal control. The wet weight of the reinnervated SM muscle (a measure of muscle mass recovery) was 87.2% of the control. The area fraction of the regenerating axons visualized with neurofilament staining within the NMEG-reinnervated SM muscle (a measure of muscle reinnervation) was 42.3%. A positive correlation was revealed between the extent of muscle reinnervation and maximal muscle force. CONCLUSIONS: Our newly developed NMEG technique results in satisfactory functional outcomes and nerve regeneration. Further improvement in the functional recovery after NMEG reinnervation could be achieved by refining the surgical procedure and creating an ideal environment that favors axon-endplate connections and accelerates axonal growth and sprouting.

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

Comparison of muscle force after immediate and delayed reinnervation using nerve-muscle-endplate band grafting.

BACKGROUND: Because of poor functional outcomes of currently used reinnervation methods, we developed novel treatment strategy for the restoration of paralyzed muscles-the nerve-muscle-endplate band grafting (NMEG) technique. The graft was obtained from the sternohyoid muscle (donor) and implanted into the ipsilateral paralyzed sternomastoid (SM) muscle (recipient). METHODS: Rats were subjected to immediate or delayed (1 or 3 mo) reinnervation of the experimentally paralyzed SM muscles using the NMEG technique or the conventionally used nerve end-to-end anastomosis. The SM muscle at the opposite side served as a normal control. RESULTS: NMEG produced better recovery of muscle force as compared with end-to-end anastomosis. A larger force produced by NMEG was most evident for small stimulation currents. CONCLUSIONS: The NMEG technique holds great potential for successful muscle reinnervation. We hypothesize that even better muscle reinnervation and functional recovery could be achieved with further improvement of the environment that favors axon-end plate connections and accelerates axonal growth and sprouting.

Force recovery and axonal regeneration of the sternomastoid muscle reinnervated with the end-to-end nerve anastomosis.

BACKGROUND: End-to-end nerve anastomosis (EEA) is a commonly used nerve repair technique. However, this method generally results in poor functional recovery. This study was designed to determine the correlation of functional recovery to the extent of axonal reinnervation after EEA procedure in a rat model. MATERIALS AND METHODS: Seven adult rats were subjected to the immediate reinnervation of an experimentally paralyzed sternomastoid (SM) muscle. The SM nerve was transected and immediately repaired with EEA. The SM muscle at the opposite side, without nerve transection, served as a control. Three months after EEA nerve repair, the muscle force of the SM muscle was measured and the regenerated axons in the muscle were detected using neurofilament immunohistochemistry. RESULTS: Three months after surgery, the reinnervated SM muscle produced limited anatomical and functional recovery (calculated as the percentage of the control). Specifically, the wet weight of the operated SM muscle (a measure of muscle mass recovery) was 78.0% of the control. The maximal tetanic force (a measure of muscle functional recovery) was 56.7% of the control. The area fraction of the neurofilament stained intramuscular axons (a measure of axonal regeneration and muscle reinnervation) was measured to be only 13.4% of the control. A positive correlation was revealed between the extent of muscle reinnervation and maximal muscle force. CONCLUSIONS: The EEA reinnervated SM muscle in the rat yielded unsatisfactory muscle force recovery as a result of mild to moderate nerve regeneration. Further work is needed to improve the surgical procedure, enhance axonal regeneration, and/or develop novel treatment strategies for better functional recovery.

Reinnervation of Paralyzed Limb Muscle by Nerve-Muscle-Endplate Grafting Technique.

BACKGROUND: We have developed a novel reinnervation technique called nerve-muscle-endplate grafting in the native motor zone (NMEG-NMZ). However, it remains unknown whether the NMEG-NMZ is effective for limb reinnervation. OBJECTIVE: To evaluate the efficacy of the NMEG-NMZ in limb muscle reinnervation. METHODS: Forty-five adult rats were divided into 3 groups: NMEG, end-to-end anastomosis (EEA, technique control), and denervation control (DC). The left tibialis anterior muscle was denervated by resecting its nerve. For NMEG-NMZ, the denervated tibialis anterior was reinnervated by transferring a NMEG pedicle from the lateral gastrocnemius muscle. Three months after surgery, static toe spread analysis was performed for all rats and muscle force was measured for the rats treated with NMEG and EEA. Muscle weight, myofiber morphology, regenerated axons, and reinnervated motor endplates in the treated muscles were also quantified and compared with those in the DC group. RESULTS: NMEG-NMZ technique resulted in better muscle force recovery (79% of the control) compared with EEA (51% of the control, P = .048). Toe spread analysis in NMEG-NMZ reinnervated muscles showed static sciatic index = -16.8, whereas -41.4 in EEA, P < .0001). The average weight of the NMEG-NMZ reinnervated muscles (86%) was greater than those of the EEA treated (71%) and DC (26%) muscles (all P < .0001). The mean count of the regenerated axons in the muscles with NMEG-NMZ was 76% of the control, which was larger than that in the muscles with EEA (46%), P < .0001. CONCLUSION: NMEG-NMZ technique has unique advantages and is superior to EEA for muscle reinnervation and functional recovery.

Morphometric and Immunohistochemical Characteristics of the Adult Human Soft Palate Muscles.

The soft palate is the only structure that reversibly separates the respiratory and gastrointestinal systems. Most species can eat and breathe at the same time. Humans cannot do this and malfunction of the soft palate may allow food to enter the lungs and cause fatal aspiration pneumonia. Speech is the most defining characteristic of humans and the soft palate, along with the larynx and tongue, plays the key roles. In addition, palatal muscles are involved in snoring and obstructive sleep apnea. Considering the significance of the soft palate, its function is insufficiently understood. The objectives of this study were to document morphometric and immunohistochemical characteristics of adult human soft palate muscles, including fiber size, the fiber type, and myosin heavy chain (MyHC) composition for better understanding muscle functions. In this study, 15 soft palates were obtained from human autopsies. The palatal muscles were separated, cryosectioned, and stained using histological and immunohistochemical techniques. The results showed that there was a fast type II predominance in the musculus uvulae and palatopharyngeus and a slow type I predominance in the levator veli palatine. Approximately equal proportions of type I and type II fibers existed in both the palatoglossus and tensor veli palatine. Soft palate muscles also contained hybrid fibers and some specialized myofibers expressing slow-tonic and embryonic MyHC isoforms. These findings would help better understand muscle functions.

Development and External Validation of a Prediction Model to Identify Candidates for Prostate Biopsy.

PURPOSE: Prostate biopsies are associated with infectious complications and approximately 80% are either benign or clinically insignificant prostate cancer. Our aim is to develop and independently validate prediction model to avoid unnecessary prostate biopsies by predicting clinically significant prostate cancer (csPCa) Materials and Methods: Retrospective analysis of single-center cohort (Mount Sinai Hospital, NY) of 1632 men who underwent systematic or combined systematic and Magnetic Resonance Imaging (MRI)/ultrasound fusion targeted prostate biopsy between 2014-2020. External cohort (University of Miami) included 622 men that underwent biopsy. Outcome for predicting csPCa was defined as International Society of Urologic Pathology (ISUP) Gleason grade ≥ 2 on biopsy. Multivariable logistic regression analysis was performed to build nomogram using coefficients of logit function. Nomogram validation was performed in external cohort by plotting receiver operating characteristics (ROC). We also plotted decision curve analysis (DCA) and compared nomogram-predicted probabilities with actual rates of csPCa probabilities in external cohort. RESULTS: Of 1632 men, 43% showed csPCa on biopsy. PSA density, prior negative biopsy, and Prostate Imaging and Reporting Data System (PI-RADS) scores 3, 4, and 5 were significant predictors for csPCa. ROC for prediction of csPCa was 0.88 in external cohort. There was agreement between predicted and actual rate of csPCa in external cohort. DCA demonstrated net benefit using the model. Using the prediction model at threshold of 30, 35% of biopsies and 46% of diagnosed indolent PCa could be avoided, while missing 5% of csPCa. CONCLUSION: Using our prediction model can help reduce unnecessary prostate biopsies with minimal impact on csPCa detection rates.

Unified model involving genomics, magnetic resonance imaging and prostate-specific antigen density outperforms individual co-variables at predicting biopsy upgrading in patients on active surveillance for low risk prostate cancer.

BACKGROUND: Active surveillance (AS) is the reference standard treatment for the management of low risk prostate cancer (PCa). Accurate assessment of tumor aggressiveness guides recruitment to AS programs to avoid conservative treatment of intermediate and higher risk patients. Nevertheless, underestimating the disease risk may occur in some patients recruited, with biopsy upgrading and the concomitant potential for delayed treatment. AIM: To evaluate the accuracy of mpMRI and GPS for the prediction of biopsy upgrading during active surveillance (AS) management of prostate cancer (PCa). METHOD: A retrospective analysis was performed on 144 patients recruited to AS from October 2013 to December 2020. Median follow was 4.8 (IQR 3.6, 6.3) years. Upgrading was defined as upgrading to biopsy grade group ≥2 on follow up biopsies. Cox proportional hazard regression was used to investigate the effect of PSA density (PSAD), baseline Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score and GPS on upgrading. Time-to-event outcome, defined as upgrading, was estimated using the Kaplan-Meier method with log-rank test. RESULTS: Overall rate of upgrading was 31.9% (n = 46). PSAD was higher in the patients who were upgraded (0.12 vs. 0.08 ng/ml2 , p = .005), while no significant difference was present for median GPS in the overall cohort (overall median GPS 21; 22 upgrading vs. 20 no upgrading, p = .2044). On univariable cox proportional hazard regression analysis, the factors associated with increased risk of biopsy upgrading were PSA (HR = 1.30, CI 1.16-1.47, p = <.0001), PSAD (HR = 1.08, CI 1.05-1.12, p = <.0001) and higher PI-RADS score (HR = 3.51, CI 1.56-7.91, p = .0024). On multivariable cox proportional hazard regression analysis, only PSAD (HR = 1.10, CI 1.06-1.14, p = <.001) and high PI-RADS score (HR = 4.11, CI 1.79-9.44, p = .0009) were associated with upgrading. A cox regression model combining these three clinical features (PSAD ≥0.15 ng/ml2 at baseline, PI-RADS Score and GPS) yielded a concordance index of 0.71 for the prediction of upgrading. CONCLUSION: In this study PSAD has higher accuracy over baseline PI-RADS score and GPS score for the prediction of PCa upgrading during AS. However, combined use of PSAD, GPS and PI-RADS Score yielded the highest predictive ability with a concordance index of 0.71.

Association between Incidental Pelvic Inflammation and Aggressive Prostate Cancer.

The impact of pelvic inflammation on prostate cancer (PCa) biology and aggressive phenotype has never been studied. Our study objective was to evaluate the role of pelvic inflammation on PCa aggressiveness and its association with clinical outcomes in patients following radical prostatectomy (RP). This study has been conducted on a retrospective single-institutional consecutive cohort of 2278 patients who underwent robot-assisted laparoscopic prostatectomy (RALP) between 01/2013 and 10/2019. Data from 2085 patients were analyzed to study the association between pelvic inflammation and adverse pathology (AP), defined as Gleason Grade Group (GGG) > 2 and ≥ pT3 stage, at resection. In a subset of 1997 patients, the association between pelvic inflammation and biochemical recurrence (BCR) was studied. Alteration in tumor transcriptome and inflammatory markers in patients with and without pelvic inflammation were studied using microarray analysis, immunohistochemistry, and culture supernatants derived from inflamed sites used in functional assays. Changes in blood inflammatory markers in the study cohort were analyzed by O-link. In univariate analyses, pelvic inflammation emerged as a significant predictor of AP. Multivariate cox proportional-hazards regression analyses showed that high pelvic inflammation with pT3 stage and positive surgical margins significantly affected the time to BCR (p ≤ 0.05). PCa patients with high inflammation had elevated levels of pro-inflammatory cytokines in their tissues and in blood. Genes involved in epithelial-to-mesenchymal transition (EMT) and DNA damage response were upregulated in patients with pelvic inflammation. Attenuation of STAT and IL-6 signaling decreased tumor driving properties of conditioned medium from inflamed sites. Pelvic inflammation exacerbates the progression of prostate cancer and drives an aggressive phenotype.

The Mount Sinai Prebiopsy Risk Calculator for Predicting any Prostate Cancer and Clinically Significant Prostate Cancer: Development of a Risk Predictive Tool and Validation with Advanced Neural Networking, Prostate Magnetic Resonance Imaging Outcome Database, and European Randomized Study of Screening for Prostate Cancer Risk Calculator.

Background: The European Association of Urology guidelines recommend the use of imaging, biomarkers, and risk calculators in men at risk of prostate cancer. Risk predictive calculators that combine multiparametric magnetic resonance imaging with prebiopsy variables aid as an individualized decision-making tool for patients at risk of prostate cancer, and advanced neural networking increases reliability of these tools. Objective: To develop a comprehensive risk predictive online web-based tool using magnetic resonance imaging (MRI) and clinical data, to predict the risk of any prostate cancer (PCa) and clinically significant PCa (csPCa) applicable to biopsy-naïve men, men with a prior negative biopsy, men with prior positive low-grade cancer, and men with negative MRI. Design setting and participants: Institutional review board-approved prospective data of 1902 men undergoing biopsy from October 2013 to September 2021 at Mount Sinai were collected. Outcome measurements and statistical analysis: Univariable and multivariable analyses were used to evaluate clinical variables such as age, race, digital rectal examination, family history, prostate-specific antigen (PSA), biopsy status, Prostate Imaging Reporting and Data System score, and prostate volume, which emerged as predictors for any PCa and csPCa. Binary logistic regression was performed to study the probability. Validation was performed with advanced neural networking (ANN), multi-institutional European cohort (Prostate MRI Outcome Database [PROMOD]), and European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC RC) 3/4. Results and limitations: Overall, 2363 biopsies had complete clinical information, with 57.98% any cancer and 31.40% csPCa. The prediction model was significantly associated with both any PCa and csPCa having an area under the curve (AUC) of 81.9% including clinical data. The AUC for external validation was calculated in PROMOD, ERSPC RC, and ANN for any PCa (0.82 vs 0.70 vs 0.90) and csPCa (0.82 vs 0.78 vs 0.92), respectively. This study is limited by its retrospective design and overestimation of csPCa in the PROMOD cohort. Conclusions: The Mount Sinai Prebiopsy Risk Calculator combines PSA, imaging and clinical data to predict the risk of any PCa and csPCa for all patient settings. With accurate validation results in a large European cohort, ERSPC RC, and ANN, it exhibits its efficiency and applicability in a more generalized population. This calculator is available online in the form of a free web-based tool that can aid clinicians in better patients counseling and treatment decision-making. Patient summary: We developed the Mount Sinai Prebiopsy Risk Calculator (MSP-RC) to assess the likelihood of any prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. MSP-RC is applicable to all patient settings and accessible online.