Hyaluronic acid and urology: a systematic review and meta-analysis.

INTRODUCTION: The use of hyaluronic acid as a nonsurgical treatment for various conditions within urology has been of great interest in recent literature. OBJECTIVES: In this study, we aimed to provide an updated review and analysis of the current state of hyaluronic acid use in urology, characterize its adverse effects, and briefly discuss future directions of research for hyaluronic acid in urology. METHODS: PubMed searches were run utilizing multiple terms, including "hyaluronic acid," "penile," "augmentation," "Peyronie disease," "premature ejaculation," and "cosmetic urology," among other related iterations. Relevant data extracted included International Index of Erectile Function score, intravaginal ejaculatory latency, glans circumference, penile girth, and plaque size. We also included studies which reported on complications of hyaluronic acid injections. Aggregated analysis was performed on studies with complete pre and post injection data at time closest to 6 months postinjection. RESULTS: A total of 33 studies met our inclusion criteria. Studies had marked heterogeneity in design, but most reported positive results. A total of 16 studies were included in our analysis. Intravaginal ejaculatory latency, penile girth, glans circumference, and International Index of Erectile Function were all increased on a fixed-effects model. Reduction in plaque size was not significant (P = .069). Complications were rare. CONCLUSION: Literature on hyaluronic acid for urologic issues demonstrates promising results; however, the quality of studies was variable. Our analysis of these studies largely corroborates these findings; however, the results are limited by the data available. Hyaluronic acid may be promising, but we highly implore standardization of study regimens in randomized controlled trials.

Synthesis and evaluation of anti-PD-L1-B11 antibody fragments for PET imaging of PD-L1 in breast cancer and melanoma tumor models.

There is a critical need to non-invasively assess the PD-L1 expression in tumors as a predictive biomarker for determining the efficacy of anti-PD-1/PD-L1 immunotherapies. Non-invasive imaging modality like positron emission tomography (PET) can be a powerful tool to assess the PD-L1 expression in the whole body including multiple metastases as a patient selection criterion for the anti-PD-1/PD-L1 immunotherapy. In this study, we synthesized B11-nanobody, B11-scFv and B11-diabody fragments from the full-length anti-PD-L1 B11 IgG. Out of the three antibody fragments, B11-diabody showed higher nM affinity towards PD-L1 antigen as compared to B11-scFv and B11-nanobody. All three antibody fragments were successfully radiolabeled with 64Cu, a PET radioisotope. For radiolabeling, the antibody fragments were first conjugated with p-SCN-Bn-NOTA followed by chelation with 64Cu. All three radiolabeled antibody fragments were found to be stable in mouse and human sera for up to 24 h. Additionally, all three [64Cu]Cu-NOTA-B11-antibody fragments were evaluated in PD-L1 negative and human PD-L1 expressing cancer cells and subcutaneous tumor models. Based on the results, [64Cu]Cu-NOTA-B11-diabody has potential to be used as a PET imaging probe for assessing PD-L1 expression in tumors as early as 4 h post-injection, allowing faster assessment compared to the full length IgG based PET imaging probe.

Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in lethal prostate cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. EXPERIMENTAL DESIGN: We applied targeted cell-free DNA sequencing to 126 mCRPC patients from three academic cancer centers, and separately performed genome-wide cell-free DNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome-positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 mCRPC patients, respectively, to develop and validate a stem-like signature, which we inferred from cell-free DNA. RESULTS: Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first-line ARSIs which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (p < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment for stemness-associated transcription factors in lethal mCRPC patients. The resulting stemness signature was then validated in a completely held-out cohort of 80 mCRPC patients profiled by tumor RNA sequencing. CONCLUSIONS: We analyzed a total of 220 mCRPC patients, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.

A rare case of chicken wishbone in Meckel's diverticulum causing partial perforation and diverticulitis.

Meckel's diverticulum (MD), a rare congenital abnormality, can lead to issues like diverticulitis and bleeding. Foreign bodies in MD are even rarer, causing vague symptoms and perforation, requiring urgent surgery. This case report highlights a patient with a foreign body in MD, focusing on clinical presentation and management. A 55-year-old male presented with abdominal pain, nausea, and vomiting. Computed tomography scan revealed a foreign body perforating the small bowel. Exploratory laparotomy found a partially perforated MD with a foreign body. Diverticulectomy was performed, and the patient recovered, discharged the next day. Foreign bodies in MD are exceedingly rare and can cause inflammation, infection, and perforation, mimicking appendicitis. Diagnosis is challenging due to nonspecific symptoms, with imaging and clinical evaluation crucial. Surgical intervention, like diverticulectomy, is primary. Early diagnosis and prompt surgery are critical in managing MD complicated by foreign bodies, ensuring favorable outcomes. This report underscores symptom recognition and effective management strategies.

MegaAppendix: a rare case of mantle cell lymphoma in an appendix presented as volvulus.

Mantle cell lymphoma (MCL), representing 5% of cases, is an aggressive B-cell non-Hodgkin lymphoma. Rarely, it can spread to other areas. This case illustrates a unique occurrence of MCL involving the appendix, leading to obstructive symptoms. Additionally, its presentation as volvulus added complexity to diagnosis and treatment. A 72-year-old man with a history of MCL came to the ER with right lower quadrant abdominal pain and nausea for 7 days. A computed tomography scan showed a swirling sign, concerning for volvulus. The patient required emergent surgery for exploratory laparotomy. Intraoperatively, the patient was found to have an enlarged appendix measuring 16.5 cm in length and 5 cm in diameter. An appendectomy was performed, and the pathology was confirmed to be MCL. This is a rare case of MCL presenting in the appendix as a volvulus, resulting in obstructive symptoms. This distinctive manifestation posed significant challenges in diagnosis and management. Appreciating such cases is pivotal for accurate diagnosis and effective medical and surgical interventions for this aggressive lymphoma subtype.

Minibeam Radiation Therapy Treatment (MBRT): Commissioning and First Clinical Implementation.

PURPOSE: Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter-wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT. METHODS AND MATERIALS: A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3-, 4-, 5-, 8-, and 10-cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on the central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3-dimensional-printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT; both received 2 fractions. RESULTS: Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. The peak-to-valley ratios were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses in both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response. CONCLUSIONS: We report commissioning results, treatment processes, and the first 2 patients treated with MBRT using a clinical orthovoltage unit. While demonstrating the feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy.

Assessment of minimum target dose as a predictor of local failure after spine SBRT.

OBJECTIVES: Metastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. METHODS: Spine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20-24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27-36 Gy and 21-24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. RESULTS: 522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3-54.4). The cumulative incidence of local failure was 10.5 % (7.4-13.4) at 1 year and 16.3 % (12.6-19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 - 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6-9.4) vs. 14.2 % (8.3-19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). CONCLUSIONS: Spine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14-15.3 Gy with single fraction SBRT is recommended whenever possible.

Benign Adenomyoepithelioma: An Unrecognised Precursor of Ductal Carcinoma in Situ in Patient With Lynch Syndrome.

Currently, there is no robust evidence demonstrating a clear association between Lynch syndrome and non-malignant breast pathology such as adenomyoepithelioma. We report a case of benign breast adenomyoepithelioma, which after recurrence was associated with ductal carcinoma in-situ (DCIS) in a 41-year-old woman with Lynch syndrome, who lacked significant family history of breast or ovarian cancer. Both, the adenomyoepithelioma and DCIS were found to have nuclear loss of MSH2/MSH6 by immunohistochemistry, while germline testing confirmed MSH2 gene mutation. Concordant loss of MSH2 in both lesions in the context of a MSH2 pathogenic variant in this patient with Lynch syndrome illustrates that the benign adenomyoepithelioma behaved as a likely precursor of DCIS. Our report provides a novel perspective that in some patients with Lynch syndrome adenomyoepithelioma may represent a pre-malignant precursor lesion of DCIS.

Automated target placement for VMAT lattice radiation therapy: enhancing efficiency and consistency.

Objective. An algorithm was developed for automated positioning of lattice points within volumetric modulated arc lattice radiation therapy (VMAT LRT) planning. These points are strategically placed within the gross tumor volume (GTV) to receive high doses, adhering to specific separation rules from adjacent organs at risk (OARs). The study goals included enhancing planning safety, consistency, and efficiency while emulating human performance.Approach. A Monte Carlo-based algorithm was designed to optimize the number and arrangement of lattice points within the GTV while considering placement constraints and objectives. These constraints encompassed minimum spacing between points, distance from OARs, and longitudinal separation along thez-axis. Additionally, the algorithm included an objective to permit, at the user's discretion, solutions with more centrally placed lattice points within the GTV. To validate its effectiveness, the automated approach was compared with manually planned treatments for 24 previous patients. Prior to clinical implementation, a failure mode and effects analysis (FMEA) was conducted to identify potential shortcomings.Main results.The automated program successfully met all placement constraints with an average execution time (over 24 plans) of 0.29 ±0.07 min per lattice point. The average lattice point density (# points per 100 c.c. of GTV) was similar for automated (0.725) compared to manual placement (0.704). The dosimetric differences between the automated and manual plans were minimal, with statistically significant differences in certain metrics like minimum dose (1.9% versus 1.4%), D5% (52.8% versus 49.4%), D95% (7.1% versus 6.2%), and Body-GTV V30% (20.7 c.c. versus 19.7 c.c.).Significance.This study underscores the feasibility of employing a straightforward Monte Carlo-based algorithm to automate the creation of spherical target structures for VMAT LRT planning. The automated method yields similar dose metrics, enhances inter-planner consistency for larger targets, and requires fewer resources and less time compared to manual placement. This approach holds promise for standardizing treatment planning in prospective patient trials and facilitating its adoption across centers seeking to implement VMAT LRT techniques.

A Novel Pre-Clinical Modeling of Massive Hemorrhagic Shock in Non-Human Primate: A Safe and Reproducible Method (Macaca fascicularis).

BACKGROUND: Although non-human primates are the closest animals to humans to simulate physiological and metabolic responses, there is a paucity of primate hemorrhagic shock models that are standardized and reproducible. Herein, we describe a model that is a clinical replica of extreme class IV hemorrhagic shock with a step-by-step description of the procedure in cynomolgus macaque monkeys. METHODS: The physiological changes that occurred during the process were evaluated using hemodynamic parameters, echocardiogram, and laboratory values. Five female monkeys were subjected to trauma laparotomy, followed by cannulation of the abdominal aorta to achieve graded hemorrhage. A central line was placed in the right internal jugular vein, which was subsequently used for laboratory sampling and volume resuscitation. The withdrawal of blood was ceased when a predefined cardiac endpoint with cardiac arrhythmia or bradycardia was reached. The animals were then immediately resuscitated with transfusion. The primary cardiac endpoint was consistently reached in all 5 animals during the fourth hemorrhage when more than 70% of the estimated total blood volume was lost. RESULTS: No mortality occurred during the process. The blood pressure, cardiac output measured from an echocardiogram, and hemoglobin correlated well with increasing loss of circulating volume, whereas the pulse pressure variation did not. The echocardiogram was also a useful predictor for urgent volume replacement. CONCLUSION: This model offers a safe and reproducible surgical hemorrhagic model in non-human primates and simulates clinical practice. This could provide a useful platform on which further studies can be carried out to address unanswered questions in trauma management.

Treatment modalities and survival outcomes in prostate cancer parenchymal brain metastasis.

BACKGROUND: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes. METHODS: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups. RESULTS: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022). CONCLUSIONS: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

Physician- and Patient-Reported Outcomes of the MC1635 Phase 3 Trial of Ultrahypofractionated Versus Moderately Hypofractionated Adjuvant Radiation Therapy After Breast-Conserving Surgery.

PURPOSE: Our aim was to report physician- and patient-reported outcomes of patients with localized breast cancer treated with moderate versus ultrahypofractionated whole breast irradiation (WBI) after breast-conserving surgery (BCS). METHODS AND MATERIALS: Between February 2018 and February 2020, patients with localized breast cancer (pT0-3 pN0-1 M0) were offered participation in a phase 3 randomized clinical trial assessing adjuvant moderate hypofractionation (MHF) to 40 Gy in 15 fractions versus ultrahypofractionation (UHF) to 25 Gy in 5 fractions after BCS, with an optional simultaneously integrated boost. Toxicities, cosmesis, and quality of life were assessed at baseline, end of treatment (EOT), and 3 months, 1 year, 2 years, and 3 years from irradiation using validated metric tools. RESULTS: One hundred seven patients were randomized to MHF (n = 54) or UHF (n = 53) adjuvant WBI. The median follow-up was 42.8 months. Grade 2 radiation dermatitis was experienced by 4 patients (7.4%) in the MHF arm and 2 patients (3.7%) in the UHF arm at EOT (P = .726). No grade 3 or higher toxicities were observed. Deterioration of cosmesis by physician assessment was observed in 2 (6.7%) patients treated in the UHF arm and 1 (1.9%) patient treated in the MHF arm at EOT (P = .534), whereas at 3 months, only 1 (1.8%) patient treated in the MHF arm demonstrated deterioration of cosmesis (P = .315). At EOT, 91% and 94% of patients reported excellent/good cosmesis among those treated with MHF and UHF regimens, respectively (P = .550). At 3 months, more patients within the MHF arm reported excellent/good cosmesis compared with those in the UHF arm (100% vs 91%; P = .030). However, the difference in patient-reported cosmesis disappeared at the 1-, 2-, and 3-year time points. CONCLUSIONS: UHF WBI showed similar treatment-related late toxicities and similar provider-scored cosmesis compared with MHF radiation in patients treated adjuvantly after BCS.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 up-regulation.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial.

BACKGROUND: Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25-28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. METHODS: We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov, NCT02783690, and is closed to accrual. FINDINGS: Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44-64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5-61·2). The median mean heart dose was 0·54 Gy (IQR 0·30-0·72) for the conventional fractionation group and 0·49 Gy (0·25-0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. INTERPRETATION: After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. FUNDING: The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute.

A Comparison between the Use of Patient-worn Virtual Reality in Wound Care and Hand Surgery: How Does Virtual Reality Work?

As virtual reality (VR) technology becomes smaller and more affordable, it is gaining in popularity as a tool to address the patient experience of pain and anxiety during invasive procedures. In this study, we explore the effect of VR on the patient experience in two clinical environments of different anxiety levels to propose a possible mechanism of VR on pain and anxiety reduction. Method: Twenty-five wound care patients were randomly assigned to either a VR group or non-virtual reality (NVR) group, singly blinded. Pre-debridement, peri-debridement, and immediately postdebridement anxiety, fun, and pain scores were collected using a Likert scale (0 = least; 10 = most) from each group of patients. These measurements were compared among the VR versus NVR group in the setting of routine wound debridement procedures. The results are compared with our previously published data on patients who underwent wide awake local anesthesia no tourniquet (WALANT) hand surgery. Results: The WALANT surgery patients using VR experienced significant reduction in anxiety and increase in fun compared with the NVR group. In the wound debridement group with VR, there was improved fun, but no statistically significant reduction in pain or anxiety when compared with the NVR group. The mean score for anxiety was higher for awake hand surgery than for wound debridement cases (3.3 versus 1.7, P = 0.004). Conclusions: VR seems to be more effective in higher anxiety settings, could VR work via a neurological mechanism akin to the Melzack and Wall gate control theory of pain? VR may act primarily on the anxiety axis, providing negative feedback via cortical pathways to the amygdala.

Auxiliary liver xenotransplantation technique in a transgenic pig-to-non-human primate model: A surgical approach to prolong survival.

Xenotransplantation using pigs' liver offers a potentially alternative method to overcome worldwide donor shortage, or more importantly as a bridge to allotransplantation. However, it has been challenged by profound thrombocytopenia and fatal coagulopathy in non-human primate models. Here we suggest that a left auxiliary technique can be a useful method to achieve extended survival of the xenograft. Fifteen consecutive liver xenotransplants were carried out in a pig-to-cynomolgus model. Right auxiliary technique was implemented in two cases, orthotopic in eight cases, and left auxiliary in five cases. None of the right auxiliary recipients survived after surgery due to hemorrhage during complex dissection between the primate's right lobe and inferior vena cava. Orthotopic recipients survived less than 7 days secondary to profound thrombocytopenia and coagulopathy. Two out of five left auxiliary xenotransplants survived more than 3 weeks without uncontrolled thrombocytopenia or anemia, with one of them surviving 34 days, the longest graft survival reported to date. Left auxiliary xenotransplant is a feasible approach in non-human primate experiments, and the feared risk of thrombocytopenia and coagulopathy can be minimized. This may allow for longer evaluation of the xenograft and help better understand histopathological and immunological changes that occur following liver xenotransplantation.

Syringomatous adenoma of the nipple: A case series and systematic review.

Key Clinical Message: SAN should be considered in the setting of nipple discharge or morphology changes with typical histological findings. There are limited published cases of SAN, and workup of this pathology is still not clear to date. Abstract: Syringomatous adenoma of the nipple (SAN) is known to be a rare benign breast neoplasm. With a few cases documented in the literature, preoperatively diagnosing this tumor is a challenge, which often leads to invasive procedure such as mass excision with nipple removal. This study was aimed at presenting a case report of SAN and to conduct a review of published cases. Literature search was conducted through PubMed databases. Articles published from year 1983 to March of 2022 were included. Only histologically confirmed cases of SAN were included. The review was performed according to the PRISMA guidelines. Twenty-eight cases, including the newly reported case, were included in the review after going through inclusion criteria. The mean age at diagnosis was 44 ± 16 years. 7% were male. The most common presentation was palpable mass. Preoperative biopsy was done for 9 cases, out of which 7 did not indicate typical histopathological characteristic of SAN. Most common treatment was wide local excision with nipple removal. Immunohistochemical staining of the resected tumor was performed in 16 cases postoperatively. 32.1% (9/28) utilized p63 in constellation with histologic findings. Five cases that utilized staining also used Estrogen Receptor (ER) marker, while three used progesterone receptor (PR) marker. SAN should be considered in the setting of nipple discharge or morphology changes with typical histological findings. There are limited published cases of SAN, and workup of this pathology is still not clear to date. The case presented here and our comprehensive literature review suggest that pathohistological findings of SAN can be heterogeneous. Clinicians would also benefit from recognizing these variances. Further research and reported cases are needed to confidently diagnose SAN, which may open doors for less aggressive surgical treatment or surveillance option for asymptomatic patients.

Clinical aspects of spatially fractionated radiation therapy treatments.

PURPOSE: To provide clinical guidance for centers wishing to implement photon spatially fractionated radiation therapy (SFRT) treatments using either a brass grid or volumetric modulated arc therapy (VMAT) lattice approach. METHODS: We describe in detail processes which have been developed over the course of a 3-year period during which our institution treated over 240 SFRT cases. The importance of patient selection, along with aspects of simulation, treatment planning, quality assurance, and treatment delivery are discussed. Illustrative examples involving clinical cases are shown, and we discuss safety implications relevant to the heterogeneous dose distributions. RESULTS: SFRT can be an effective modality for tumors which are otherwise challenging to manage with conventional radiation therapy techniques or for patients who have limited treatment options. However, SFRT has several aspects which differ drastically from conventional radiation therapy treatments. Therefore, the successful implementation of an SFRT treatment program requires the multidisciplinary expertise and collaboration of physicians, physicists, dosimetrists, and radiation therapists. CONCLUSIONS: We have described methods for patient selection, simulation, treatment planning, quality assurance and delivery of clinical SFRT treatments which were built upon our experience treating a large patient population with both a brass grid and VMAT lattice approach. Preclinical research and patient trials aimed at understanding the mechanism of action are needed to elucidate which patients may benefit most from SFRT, and ultimately expand its use.

Effect of pre-operative radiation therapy on surgical outcome in retroperitoneal sarcoma.

Background: A high rate of locoregional recurrence is one of the major difficulties in successful treatment of retroperitoneal sarcoma (RPS). Although pre-operative radiation therapy (RT) is considered a potential way to improve local recurrence, concerns about the associated treatment toxicity and risk of peri-operative complications need to be addressed. Hence, this study investigates the safety of pre-operative RT (preRTx) for RPS. Methods: A cohort of 198 patients with RPS who had undergone both surgery and RT was analyzed for peri-operative complications. They were divided into three groups according to the RT scheme: (1) preRTx group, (2) post-operative RT without tissue expander, and (3) post-operative RT with tissue expander. Results: The preRTx was overall well tolerated and did not affect the R2 resection rate, operative time, and severe post-operative complications. However, the preRTx group was associated with higher incidence of post-operative transfusion and admission to intensive care unit (p = 0.013 and p = 0.036, respectively), where preRTx was an independent risk factor only for the post-operative transfusion (p = 0.009) in multivariate analysis. The median radiation dose was the highest in preRTx group, although no significant difference was demonstrated in overall survival and local recurrence rate. Conclusion: This study suggests that the preRTx does not add significant post-operative morbidity to the patients with RPS. In addition, radiation dose elevation is achievable with the pre-operative RT. However, a meticulous intra-operative bleeding control is recommended in those patients, and further high-quality trials are warranted to evaluate the long-term oncological outcomes.