ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer.

Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

Single-Port Robotic-Assisted Excision of the Urachal Remnant in an Adult Female: A Case Report.

Urachal anomalies and their associated disease processes are quite rare in pediatric populations and even rarer in adults. Although often asymptomatic, patients with symptoms can be treated with a combination of surveillance, antibiotics, and sometimes surgical resection. In this case, we describe our experience using the single-port robotic approach for the excision of a symptomatic urachal remnant. The patient presented with a chief complaint of urinary frequency, dysuria, intermittent hematuria, and right flank pain. A CT scan of the abdomen and pelvis revealed a bladder wall thickening at the dome of the bladder measuring 2.6 x 3.6 x 1.5 cm with concerns for adenocarcinoma. The patient subsequently underwent a biopsy, which was benign. The patient's symptoms persisted, and she elected to undergo surgical resection. Postoperatively, her symptoms resolved, and she was satisfied with her treatment outcome. This case exemplifies the feasibility of the single-port robotic approach to urachal remnant excision, with further applicability to simple transabdominal robotic bladder surgery.

Current Expectations and Opinions on Single-port Robotic Surgery: A Survey Among European Experts by the SPARC Collaborative Group.

Single-port (SP) robotic surgery is a relatively new technology that is expected to become available on the European market within a year. We investigated the current expectations of robotic surgery experts and opinion leaders practicing in Europe. A 17-item online questionnaire was sent to 120 participants identified as "experts" on the basis of their general contributions to the field of robotic surgery. Overall, 90 responses were registered, with a response rate of 75%. Italy (30%), France (15%), and the UK (12%) provided the most participants, who worked mainly in academic-either public (60%) or private (20%)-hospitals. Most respondents (79%) had no previous experience with "single site" surgery, and attendance at scientific meetings (79%) and perusal of the literature (65%) were the sources of SP knowledge most frequently reported. The perceived advantages of SP robotic surgery included lower invasiveness (61%), easier access to the retroperitoneal or extraperitoneal space (53%), better cosmetic results (44%), and lower postoperative pain (44%). The most "appealing" SP procedures were retroperitoneal partial nephrectomy via an anterior approach (43%) and transvesical simple prostatectomy (43%). Within the limitations of this type of analysis, our findings suggest high interest and a positive attitude towards SP technology overall. Patient summary: Technology for single-port (SP) robotic surgery, in which just one skin incision is made in the abdomen to perform the operation, will soon be available in Europe. We conducted a survey on SP surgery among European experts in urological robotic surgery. The results show that there is high interest in and a positive attitude to SP surgery. The SP approach could result in better cosmetic results and lower postoperative pain for patients.

Recurrent MTOR Mutations in Renal Cell Carcinoma With Fibromyomatous Stroma: A Report of 2 Tumors.

Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations.

Association between Prostate Carcinoma and Multiple Myeloma.

Synchronous or sequential development of multiple myeloma and prostate carcinoma is rare. It is not sure whether these two occur independently or if one influences the development of the other. We reviewed the cases published in the English literature; eight cases of myeloma developing after diagnosis and treatment for prostate carcinoma, five cases of simultaneous occurrence of myeloma and prostate carcinoma, and five cases where the patient with multiple myeloma later developed prostate carcinoma were found. This short review attempts to analyze the occurrence of these two diseases in the same patient and dissect whether there is a close association or it is just a mere coincidence.

Does It Matter Whether a Psychiatric Intervention Is "Palliative"?

Palliative interventions are intended to alleviate suffering and improve quality, not quantity, of life and are not intended to cure illness. In psychiatry, uncertainty about which interventions count as palliative stems from the fact that psychiatry generally prioritizes symptom management irrespective of diagnosis or specific pathophysiology of illness. This commentary on a case considers how distinctions between palliative and other psychiatric interventions might not be all that helpful in resolving clinical and ethical questions about which interventions are-and when they are-appropriate.

Breathing, Obstruction, Restriction, and Gas Exchange: A Pulmonary Function Testing Interpretation Framework for Novice Learners.

Pulmonary function testing (PFT) is a common method of assessing patients with respiratory symptoms, yet exposure to PFT is variable throughout medical training. Therefore, incorporating a dedicated approach to teaching PFT into the formal medical education curriculum can ensure that trainees become familiar with both the relevant physiologic principles involved in interpreting PFT results and the indications for performing PFT in clinical practice. In this "How I Teach" article, we present breathing, obstruction, restriction, and gas exchange (BORG), a novel, small-group workshop designed to teach novice learners a sequential framework for PFT interpretation. The BORG workshop comprises two segments: a whiteboard minilecture that illustrates the BORG framework and a case-based worksheet whereby learners apply this approach to sets of PFTs with increasing difficulty. Our workshop is grounded in two cognitive psychology frameworks: the cognitive theory of multimedia learning and the dual-process theory. We provide three figures and four supplementary videos to illustrate our workshop's design and delivery, as well as both learner and instructor versions of our BORG worksheet. Last, we address three PFT concepts that have challenged us as instructors and provide evidence-based teaching scripts. The BORG workshop can be used by medical educators working with medical students and residents as a means of helping learners progress along the continuum from a basic understanding of spirometry to independent analysis and interpretation of PFTs to application of PFT results to medical decision making.

A novel technique for subscapularis repair in total shoulder arthroplasty.

Anatomic total shoulder arthroplasty, when used for treatment of primary glenohumeral arthritis, is historically very successful. We propose a novel technique for subscapularis repair during closure of a deltopectoral approach to the shoulder with subscapularis peel. Our technique allows for early motion following surgery and also provides for improved subscapularis repair integrity and resilience during postoperative rehabilitation. Postoperatively, we allow passive and active assisted range of motion at week 1, limited active range of motion at week 2, and unrestricted external rotation range of motion beginning at week 6. The use of our technique has led to improved patient outcomes with regard to range of motion postoperatively following anatomic total shoulder arthroplasty and we recommend its adoption into practice.

Engineering prostate cancer in vitro: what does it take?

A key challenge in the clinical management and cause of treatment failure of prostate cancer (PCa) is its molecular, cellular and clinical heterogeneity. Modelling systems that fully recapitulate clinical diversity and resistant phenotypes are urgently required for the development of successful personalised PCa therapies. The advent of the three-dimensional (3D) organoid model has revolutionised preclinical cancer research through reflecting heterogeneity and offering genomic and environmental manipulation that has opened up unparalleled opportunities for applications in disease modelling, high-throughput drug screening and precision medicine. Despite these remarkable achievements of organoid technology, several shortcomings in emulating the complex tumor microenvironment and dynamic process of metastasis as well as the epigenome profile limit organoids achieving true in vivo functionality. Technological advances in tissue engineering have enabled the development of innovative tools to facilitate the design of improved 3D cancer models. In this review, we highlight the current in vitro 3D PCa models with a special focus on organoids and discuss engineering approaches to create more physiologically relevant PCa organoid models and maximise their translational relevance that ultimately will help to realise the transformational power of precision medicine.

Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles.

Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

Management of pediatric ureterolithiasis in the emergency room: A single institution review and new management pathway.

INTRODUCTION/BACKGROUND: Urolithiasis is an increasingly common condition seen in children with an annual incidence of 2-3% in children under 18, and up to 10% in adolescents. Treatment of stones varies including observation, IV hydration, pain management, medical expulsive therapy (MET), or surgery. Though well-studied and often used in adults, MET (alpha-adrenergic antagonists to facilitate passage of ureteral stones), is not routinely prescribed in pediatric patients. OBJECTIVE: The goals of this study were to review a quaternary children's hospital's emergency room frequency of MET utilization for ureterolithiasis as well as evaluate the clinical outcomes of children who were prescribed MET compared to those treated with pain control alone. STUDY DESIGN: A retrospective review was performed of children 2 months to 18 years with ureterolithiasis who presented to a quaternary children's hospital ED from 2011 to 2017. The primary outcome was the frequency of MET prescribed. Secondary outcomes included the following comparisons in patients who received MET and analgesics with those who received analgesics alone: hospital admission rate, length of hospitalization, emergency room re-presentation rate, surgical intervention, spontaneous stone passage, urology consultation, how the urology consult affected MET utilization, referral to outpatient urology and nephrology clinics, and CT utilization in the ED. Comparisons were performed utilizing Fischer's exact and t-tests. RESULTS: 139 patients were included with a mean age of 14 years (SD 4.14), 42% male. There was no difference between age, gender, stone size, return to the ED, serum creatinine, or length of hospitalization (if admitted) between patients who were and were not placed on MET. The rate of stone passage was significantly higher for those placed on MET (45%) versus not (20%) (p = 0.0022). Urology was consulted for 93% of the cases where children were prescribed MET, compared with only 52% of cases where MET was not prescribed (p = <0.0001). DISCUSSION: In our experience MET was significantly underutilized in patients where urology was not involved. This is similar to a study by Itano et al. which found urology consultation in the ED significantly increased use of tamsulosin for ureterolithiasis in adults. Children with ureterolithiasis placed on MET had a significantly higher rate of stone passage compared to children managed by pain control alone. CONCLUSION: Given the benefits of MET to increase the rate of spontaneous stone passage it may be considered first line therapy for treatment of children with ureterolithiasis.

Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol-Ene/Cyclization Sequence in Continuous Flow.

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.

Technical note: subscapularis-sparing approach to perform anatomic total shoulder arthroplasty using a multiplanar humeral osteotomy and angled glenoid instruments.

BACKGROUND: Anatomic total shoulder arthroplasty is typically performed through the deltopectoral approach followed by either a subscapularis tenotomy, tendon peel, or lesser tuberosity osteotomy to provide adequate exposure. These subscapularis-takedown methods have been associated with incomplete subscapularis healing, however, and as a result often lead to functional deficits and complications. Subscapularis-sparing approaches have been introduced to mitigate these complications, but thus far have either been limited to hemiarthroplasty or resulted in residual inferior humeral head osteophytes and humeral component size mismatch. The present technique demonstrates the possibility for surgeons to capitalize on the improved patient outcomes that are afforded by subscapularis-sparing approaches, while still utilizing the deltopectoral interval to perform a total glenohumeral joint arthroplasty. METHODS: This article describes in detail the placement of a stemless anatomic TSA with the use of angled glenoid instruments through a subscapularis-sparing deltopectoral approach. Postoperatively, patients are placed in a sling but are instructed to remove as tolerated, as early as the 1st postoperative week. Physical therapy is started at week 1 with a 4-phase progression. CONCLUSIONS: This technique using a TSA system with a polyaxial glenoid reamer and angled pegs on the backside of the glenoid allows the potential for maintenance of the strong postoperative radiographic and patient-reported outcomes that are achieved using traditional TSA approaches, with the advantage of accelerated rehabilitation protocols and decreased risk of subscapularis insufficiency that result from the use of subscapularis-sparing approaches.

Single-Port Robotic Inguinal Lymph Node Dissection for Penile Cancer.

OBJECTIVE: Inguinal lymph node dissection (ILND) is an essential component in the diagnosis, management, and treatment of penile cancer. Recent advances in minimally invasive surgery may play an important role in decreasing the adverse effects and complications of lymph node dissections. We present our technique utilizing a single-port (SP) robot assisted laparoscopic bilateral ILND in a patient with pT3N2Mx penile cancer s/p partial penectomy and sentinel lymph node biopsy. METHODS: We present a case of a 64-year-old man who underwent a radical penectomy for previously diagnosed penile cancer. Pathology report showed invasive squamous cell carcinoma of the penis. In accordance with NCCN guidelines, we performed a bilateral inguinal and pelvic lymph node dissection using robotic assisted SP laparoscopy with the DaVinci Single-Site platform. Our methods are detailed in this technical report. RESULTS: Total operative time was 3 hours and 38 minutes in duration with minimal blood loss (<20 mL). A 3 cm inguinal lymph node was excised and positive for malignancy without involvement of other nodes. The patient was discharged 90 minutes after recovery in PACU without narcotics and returned to normal bowel function within 6 hours. CONCLUSION: We present a successful surgical outcome of a SP robotic ILND in treating a patient with T3N2M0 penile cancer. At the time of publication, the patient is cancer-free with no palpable lymphadenopathy on exam. Utilization of the SP DaVinci system may soon become the standard of care in select cases as it is currently the least invasive approach and is associated with lower morbidity and mortality.

Pediatric Urologic Surgery: Reducing Opioid Use.

Adequate pain management is important for successful postoperative recovery after any surgical procedure. Unfortunately, the USA and many other parts of the world are in the midst of an opioid epidemic, and healthcare providers are thus tasked with balancing the comfort and recovery of their patients after an operation against the individual and societal harms of the over-prescription of opioids. The goal of this article is to discuss the range of opioid formulations currently in use, examine why this may be problematic, and explore alternatives that provide similar efficacy and may improve overall safety in the pediatric population after urologic surgery. Improving the way opioids are prescribed through clinical practice guidelines as well as considering alternatives to opioids can ensure patients have access to safer and more effective pain treatments and potentially reduce opioid misuse.

Budget Impact of Adaptive Abiraterone Therapy for Castration-Resistant Prostate Cancer.

BACKGROUND: The use of a novel strategy known as adaptive abiraterone therapy based on mathematical modeling of evolutionary dynamics of tumor subpopulations was shown in a clinical trial to extend the time to disease progression in patients with metastatic castration-resistant prostate cancer (CRPC) and reduced the use of abiraterone therapy. Although the clinical impact of adaptive abiraterone treatment is clear, the economic impact of this strategy has not been investigated. OBJECTIVE: To compare the cost of care with adaptive abiraterone therapy versus standard continuous abiraterone therapy in patients with metastatic CRPC, using patient billing data. METHODS: We performed a retrospective review of billing data for patients with metastatic CRPC who received abiraterone treatment at a large cancer center between June 1, 2012, and August 31, 2018. Patients were divided into 2 groups based on whether they received adaptive abiraterone therapy (N = 15) or continuous abiraterone therapy (N = 21). All patients with refractory, metastatic prostate cancer after castration that was indicated for abiraterone therapy were eligible for this study. Each patient in the adaptive abiraterone therapy cohort received abiraterone plus prednisone treatment until the patient reached a target threshold of 50% or more reduction in prostate-specific antigen (PSA) level compared with his PSA level before abiraterone therapy; treatment was then suspended until the PSA level rose above the 50% of PSA before abiraterone therapy target threshold. The continuous therapy cohort received abiraterone plus prednisone daily until radiographic progression. The primary outcomes were the mean annual cost of care per patient, including and excluding the cost of abiraterone, and the cost of care, by clinical category. RESULTS: The median time to disease progression was 25.8 months for patients who received adaptive abiraterone therapy compared with 12.1 months for patients who received continuous abiraterone therapy. Overall, the mean total, including the cost of drug, annual cost per patient who received adaptive abiraterone therapy was $79,093 compared with $146,782 for patients who received continuous abiraterone therapy (P <.0001). The annual cost of care per patient, excluding the cost of abiraterone, was $13,883 for those who received adaptive therapy versus $22,322 for those who received continuous abiraterone therapy (P = .2757), which was not statistically significant. CONCLUSION: Practical precision medicine strategies, such as adaptive abiraterone treatment or pharmacogenomics-targeted dosing, can use known biomarkers, such as PSA, to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. The results of this study suggest that a large clinical study of adaptive abiraterone therapy is warranted to validate the potential of this strategy to extend the time to disease progression and reduce costs of treatment of metastatic CRPC.

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation.

Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.