Emerging Theranostics for Prostate Cancer and a Model of Prostate-specific Membrane Antigen Therapy.

There is increasing demand worldwide to develop diagnostic and therapeutic (theranostic) markers for prostate cancer. One target of interest is prostate-specific membrane antigen (PSMA), a protein which is overexpressed in prostate cancer cells. Over the past decade, a growing body of literature has demonstrated that radiolabeled ligands that target PSMA show favorable clinical response and survival outcomes in patients with advanced prostate cancer. This focused review provides background to the development of PSMA as a target, an overview of key studies informing our current approach to radioligand-based imaging and therapy for prostate cancer, and a model for real-world implementation of PSMA theranostics based on an Australian experience.

Assessment of perineural spread in advanced cutaneous squamous cell carcinomas treated with immunotherapy.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) has a propensity for perineural spread (PNS) which is associated with poorer treatment outcomes. Immunotherapy is the new standard of care treatment for advanced CSCC resulting in durable responses. PNS is not captured by traditional response assessment criteria used in clinical trials, e.g. RECIST 1.1, and there is limited literature documenting radiological PNS responses to immunotherapy. In this study we assess PNS responses to immunotherapy using a modified grading system. METHODS: This is an Australian single-center retrospective review of patients with advanced CSCC who were treated with immunotherapy between April 2018 and February 2022 who had evidence of PNS on pre-treatment magnetic-resonance imaging (MRI). The primary outcome was blinded overall radiological response in PNS using graded radiological criteria, post-commencement of immunotherapy. Three defined timepoints (< 5 months, 5-10 months, > 10 months) were reviewed. Secondary outcomes included a correlation between RECIST 1.1 and PNS assessments and the assessment of PNS on fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). RESULTS: Twenty CSCC patients treated with immunotherapy were identified. Median age was 75.7 years and 75% (n = 15) were male. All patients had locoregionally advanced disease and no distant metastases. Median follow-up was 18.5 months (range: 2-59). 70% (n = 14) demonstrated a PNS response by 5 months. Three patients experienced pseudoprogression. One patient had PNS progression by the end of study follow up. RECIST 1.1 and PNS responses were largely concordant at > 10 months (Cohen's Kappa 0.62). 5/14 cases had features suspicious for PNS on FDG-PET/CT. CONCLUSIONS: PNS response to immunotherapy can be documented on MRI using graded radiological criteria. High response rates were seen in PNS with the use of immunotherapy in this cohort and these responses were largely concordant with RECIST 1.1 assessments. FDG-PET/CT demonstrated limited sensitivity in the detection of PNS.

Clinical Trial Protocol for PRIMARY2: A Multicentre, Phase 3, Randomised Controlled Trial Investigating the Additive Diagnostic Value of [68Ga]Ga-PSMA-11 Positron Emission Tomography/Computed Tomography in Men with Negative or Equivocal Multiparametric Magnetic Resonance Imaging for the Diagnosis of Clinically Significant Prostate Cancer.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has an established role for the diagnosis of clinically significant prostate cancer (sPCa). The PRIMARY trial demonstrated that [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) was associated with a significant improvement in sensitivity and negative predictive value for sPCa detection. OBJECTIVE: To demonstrate that addition of prostate-specific membrane antigen (PSMA) radioligand PET/CT will enable some men to avoid transperineal prostate biopsy without missing sPCa, and will facilitate biopsy targeting of PSMA-avid sites. DESIGN, SETTING, AND PARTICIPANTS: This multicentre, two-arm, phase 3, randomised controlled trial will recruit 660 participants scheduled to undergo biopsy. Eligible participants will have clinical suspicion of sPCa with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 2 and red flags, or a PI-RADS score of 3 on mpMRI (PI-RADS v2). Participants will be randomised at a 1:1 ratio in permuted blocks stratified by centre. The trial is registered on ClinicalTrials.gov as NCT05154162. INTERVENTION: In the experimental arm, participants will undergo pelvic PSMA PET/CT. Local and central reviewers will interpret scans independently using the PRIMARY score. Participants with a positive result will undergo targeted transperineal prostate biopsies, whereas those with a negative result will undergo prostate-specific antigen monitoring alone. In the control arm, all participants undergo template transperineal prostate biopsies. Participants will be followed for subsequent clinical care for up to 2 yr after randomisation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: sPCa is defined as Gleason score 3 + 4 (≥10%) = 7 disease (grade group 2) or higher on transperineal prostate biopsy. Avoidance of transperineal prostate biopsy will be measured at 6 mo from randomisation. The primary endpoints will be analysed on an intention-to-treat basis. CONCLUSIONS: Patient enrolment began in March 2022, with recruitment expected to take 36 mo. PATIENT SUMMARY: For patients with suspected prostate cancer who have nonsuspicious or unclear MRI (magnetic resonance imaging) scan findings, a different type of scan (called PSMA PET/CT; prostate-specific membrane antigen positron emission tomography/computed tomography) may identify men who could avoid an invasive prostate biopsy. This type of scan could also help urologists in better targeting of samples from suspicious lesions during prostate biopsies.

Bladder leiomyoma and the utility of 18F-Fluorodeoxyglucose-Positron Emission Tomography - a Case Report.

Bladder leiomyomas are rare neoplasms and various diagnostic methods are available to assist in confirming diagnosis preoperatively. Presented here is a case of bladder leiomyoma in a 41-year-old female who presented with urinary symptoms and right thigh pain. Imaging revealed a soft tissue density mass in the bladder wall. However concerns of a leiomyosarcoma remained. An 18F-fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) demonstrated low FDG uptake and absence of metastatic lesions. In combination with operative findings, the tumor allowed for localized resection instead of more invasive partial cystectomy. Therefore, FDG-PET might be used to support the diagnosis of leiomyoma and potentially facilitate a less aggressive surgical management.

Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography Maximum Standardized Uptake Value as a Predictor of Gleason Pattern 4 and Pathological Upgrading in Intermediate-Risk Prostate Cancer.

PURPOSE: Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA PET/CT) and the maximum standardized uptake value (SUVmax) may improve risk stratification within this population. MATERIALS AND METHODS: We reviewed men with International Society for Urological Pathology Grade Group (GG) 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per segment at surgery at 3 thresholds: >/<50% GP4, >/<20% GP4, and >/<10% GP4. SUVmax was compared by GP4, and multivariable logistic regression examined the relationship between SUVmax and GP4. Secondary outcome was association between SUVmax and pathological upgrading (GG 1/2 to GG ≥3 from biopsy to surgery). RESULTS: Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/<50% GP4 (p <0.001); 4.77 (3.31-7.00) vs 3.13 (2.64-4.41) >/<20% GP4 (p <0.001); and 4.54 (6.10-3.13) vs 3.03 (2.45-3.70) >/<10% GP4 (p <0.001). SUVmax remained an independent predictor of >50% (OR=1.39 [95%CI 1.18-1.65], p <0.001) and >20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathological upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value 75% and negative predictive value 72%. Threshold 5.4 predicted pathological upgrading with 91% specificity and negative predictive value 94%. CONCLUSIONS: SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

Do magnetic resonance imaging abnormalities of the non-dominant wrist correlate with ulnar-sided wrist pain in elite tennis players?

OBJECTIVE: Ulnar-sided injuries of the non-dominant wrist are common in elite tennis players that use the double-handed backhand technique. This study aimed to define the relationship between ulnar-sided wrist pain in symptomatic and asymptomatic elite tennis players, and the presence of abnormalities on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Fourteen symptomatic tennis players, 14 asymptomatic tennis players, and 12 healthy controls who did not play tennis, were analyzed prospectively, after undergoing MRI of their non-dominant wrist. Five anatomical regions were analyzed, thought to relate to ulnar-sided wrist pain. These consisted of the triangular fibrocartilage complex (TFCC), ulnar collateral ligament (UCL), extensor carpi ulnaris tendon (ECU), osseous-articular structures, and ganglia. Images were independently reviewed by two blinded musculoskeletal radiologists. RESULTS: Non-dominant, ulnar-sided, wrist pain in elite tennis players was not statistically significantly associated with an increased number of MRI abnormalities when compared with asymptomatic tennis players (p > 0.05). However, some evidence of statistical association was seen with an increased prevalence of ECU tendon abnormalities (OR = 8.0, 95% CI = (0.74, 20.00), p = 0.07). A statistically significant increase in MRI abnormalities of osseous structures (OR = 15.1, 95% CI = (1.56, 656.05), p = 0.02) and the dorsal radioulnar ligament (DRUL) (OR = 12.5, 95% CI = (2.15, 111.11), p = 0.03), was observed in symptomatic players compared with controls. CONCLUSIONS: Non-dominant, ulnar-sided, wrist pain in a subgroup of elite tennis players using a double-handed backhand technique is not associated with a statistically significant increased prevalence of MRI abnormalities when compared with asymptomatic tennis players, other than some evidence of statistical association with ECU tendon abnormalities. Therefore, significance of MRI abnormalities should be interpreted in the context of clinical findings.

Modulation of Immunity by Lymphatic Dysfunction in Lymphedema.

The debilitating condition known as secondary lymphedema frequently occurs after lymphadenectomy and/or radiotherapy for the treatment of cancer. These therapies can damage lymphatic vessels leading to edema, fibrosis, inflammation and dysregulated adipogenesis, which result in profound swelling of an affected limb. Importantly, lymphedema patients often exhibit impaired immune function which predisposes them to a variety of infections. It is known that lymphadenectomy can compromise the acquisition of adaptive immune responses and antibody production; however the cellular mechanisms involved are poorly understood. Here we discuss recent progress in revealing the cellular and molecular mechanisms underlying poor immune function in secondary lymphedema, which has indicated a key role for regulatory T cells in immunosuppression in this disease. Furthermore, the interaction of CD4+ T cells and macrophages has been shown to play a role in driving proliferation of lymphatic endothelial cells and aberrant lymphangiogenesis, which contribute to interstitial fluid accumulation in lymphedema. These new insights into the interplay between lymphatic vessels and the immune system in lymphedema will likely provide opportunities for novel therapeutic approaches designed to improve clinical outcomes in this problematic disease.

Radiologic Manifestations of Senile Lymph Nodes in the Popliteal Fossa.

PURPOSE: To determine the radiologic manifestations of senile lymph nodes in the popliteal fossa for radiologic and clinical application. METHODS: A total of six lower extremities from four unembalmed human cadavers were studied. Under a surgical microscope, 6% hydrogen peroxide was used to detect the lymphatic vessels commencing from the foot and leg. A 30-gauge needle was inserted into the vessels and injected with a radio-opaque lead oxide mixture. The specimens were radiographed and photographed to demonstrate the lymph nodes in the popliteal fossa. The final results were transferred to the computer for image analysis. RESULTS: An average of two lymph nodes (range 1 to 3) were found in the popliteal fossa of the lower extremity. They were divided into superficial and deep popliteal groups. The superficial group was located in the superficial layer of the popliteal fossa around the small saphenous vein (SSV). The deep group was close to the popliteal surface of the femur and always located next to the popliteal vein. All lymph nodes were transparent in appearance and contained coiled lymphatic tubules. The size and density of the tubules varied. CONCLUSION: The radiologic manifestations of senile lymph nodes in the popliteal fossa have been presented and discussed to upgrade our radiologic and anatomical knowledge. This will be of benefit for radiologic and clinical applications.

Divergent lymphatic drainage routes from the heel to the inguinal region: anatomic study and clinical implications.

PURPOSE: To determine routes of lymphatic drainage from the heel to the inguinal lymph nodes to assist in the clinical management of lower limb lymphatic disorders. METHODS: Six lower limbs from three unembalmed human cadavers were studied. Under a surgical microscope, 6% hydrogen peroxide was used to detect lymphatic vessels on the medial and lateral sides of the heel. The lymphatic vessel on either side was then injected with a radio-opaque mixture. The lymphatic vessels were traced, photographed, and radiographed to demonstrate the lymphatic pathways from the heel to the inguinal lymph nodes. The final results were transferred to computer for digital image analysis. RESULTS: Two groups of lymph collecting vessels were identified. The medial group, arising from the skin between the medial malleolus and the Achilles tendon, coursed along the medial side of the leg and thigh to the inguinal lymph nodes. The lateral group, arising from the skin between the lateral malleolus and the Achilles tendon, coursed along the postero-lateral side of the leg to the popliteal fossa. Alternative routes were then identified from the popliteal fossa to the inguinal lymph nodes. The number, size, type, and distribution of lymph vessels and nodes were variable from person to person. CONCLUSION: Two different lymphatic routes from the heel to the inguinal lymph nodes have been described. This information upgrades current anatomical knowledge and the results will be of benefit for the clinical management of lower limb trauma and malignancy.

Superficial lymphatic drainage of the lower extremity: anatomical study and clinical implications.

BACKGROUND: Knowledge of the lymphatic anatomy in the lower extremity is inadequate. A reevaluation is needed to assist in guiding clinical management. METHODS: A total of five lower extremities from three unembalmed human cadavers were studied. Under a surgical microscope, 6% hydrogen peroxide was used to detect the lymphatic vessels commencing from the foot, the leg, and the thigh. A 30-gauge needle was inserted into the vessels and injected with a radiopaque lead oxide mixture. The vessels were traced, photographed, and radiographed to demonstrate the superficial lymphatic pathways of the lower extremity. The final results were transferred to the computer for image analysis. RESULTS: Numerous lymph collecting vessels were identified in the subcutaneous tissue and the superficial femoral vascular bundle of the lower extremity. They originated beneath the dermis of each side of the toes, the foot, and the lateral side of the thigh. The diameters of the vessels varied from 0.2 to 2.2 mm. The vessels traveled in the subcutaneous tissue of the lower limb toward the popliteal, femoral, superficial, and deep inguinal lymph nodes. During their tortuous course, some vessels branched, diverged, and converged; sometimes, they anastomosed with neighboring vessels or crossed them. Most vessels converged to form larger collectors and then diverged into small branches before entering the lymph nodes. CONCLUSIONS: Accurate lymphatic distribution within the lower extremity has been described. This information upgrades our anatomical knowledge, and the results will be of benefit for clinical management.

Vascular endothelial growth factor-d modulates caliber and function of initial lymphatics in the dermis.

The lymphatic vasculature is important for skin biology as it maintains dermal fluid homeostasis. However, the molecular determinants of the form and function of the lymphatic vasculature in skin are poorly understood. Here, we explore the role of vascular endothelial growth factor-d (Vegf-d), a lymphangiogenic glycoprotein, in determining the form and function of the dermal lymphatic network, using Vegf-d-deficient mice. Initial lymphatic vessels in adult Vegf-d-deficient mice were significantly smaller than wild-type but collecting lymphatics were unaltered. The uptake/transport of dextran in initial lymphatics of Vegf-d-deficient mice was far less efficient, indicating compromised function of these vessels. The role of Vegf-d in modulating initial lymphatics was further supported by delivery of Vegf-d in skin of wild-type mice, which promoted enlargement of these vessels. Vegf-d-deficient mice were subjected to cutaneous wounding to challenge lymphatic function: the resulting wound epithelium was highly edematous and thicker, reflecting inadequate lymphatic drainage. Unexpectedly, myofibroblasts were more abundant in Vegf-d-deficient wounds leading to faster wound closure, but resorption of granulation tissue was compromised suggesting poorer-quality healing. Our findings demonstrate that Vegf-d deficiency alters the caliber of initial lymphatics in the dermis leading to reduced functional capacity.

Lymphatic drainage of the external ear.

BACKGROUND: Lymphoscintigraphy reveals inconsistencies in our knowledge of the lymphatic anatomy of the external ear. METHODS: Fifteen external ears from 9 unembalmed human cadavers were studied. Six percent hydrogen peroxide was used to find the lymphatic vessels using a surgical microscope. They were injected with a radio-opaque mixture, dissected, photographed, and radiographed to demonstrate lymphatic vessels in the tissue. Final results were transferred to the computer for analysis. RESULTS: Four groups of lymph collecting vessels were found. The anterior branch, in all specimens, drained directly or indirectly (having merged with a vessel descending from the scalp) into the preauricular lymph nodes. The superior, middle, and inferior (lobule) branches drained to their multiple first tier lymph nodes. CONCLUSION: An accurate lymphatic map of the external ear is described to upgrade our anatomic knowledge. It will be of benefit for the clinical management of malignancies in this region.

Alternative lymphatic drainage routes from the lateral heel to the inguinal lymph nodes: anatomic study and clinical implications.

BACKGROUND: The route of lymphatic drainage from the heel to the inguinal lymph nodes is required to be accurately evaluated for clinical needs. METHODS: Seven lower limbs from four unembalmed human cadavers were studied. Under a surgical microscope, 6% hydrogen peroxide was used to detect the lymphatic vessel on the lateral side of the heel. The vessel was then injected with a radio-opaque lead oxide mixture. The vessel was traced, photographed and radiographed to demonstrate the lymphatic pathways from the lateral heel to the inguinal lymph nodes. The final results were transferred to the computer for image analysis. RESULTS: The lymph collecting vessel arising from the skin of the fossa between the lateral malleolus and the Achilles tendon ran along the posterolateral side of the leg, deep to the superficial fascia. From the popliteal fossa to the inguinal lymph nodes, three lymphatic routes were found: (i) via the superficial tissue of the medial side of the thigh; (ii) running with the superficial femoral blood vessels; (iii) running between the sciatic nerve and the profunda femoral vessels. The number and type of lymph nodes found in the popliteal fossa and femoral triangle were different from person to person. CONCLUSION: Actual and accurate lymphatic routes from the skin above the posterolateral heel to the inguinal lymph nodes have been described. This information upgrades our anatomical knowledge and the results will be of benefit for the clinical management of trauma and malignancies in the lower limb.

The morphology of the human lymphatic vessels in the head and neck.

Previously little has been written about the morphology of the human lymphatic vessels since Sappey (Sappey [1874] Anatomie, Physiologie, Pathologie des Vaisseaux Lymphatiques, Paris: Adrien Delahaye) over 100 years ago. There needs to be an accurate re-evaluation of scientific observations to aid clinical management. Forty-nine combinations of tissue from the head and neck of 20 unembalmed human cadavers were studied. Six percent hydrogen peroxide was used to find the vessels. They were injected with radio-opaque mixture, dissected, photographed, and radiographed. Final results were transferred to the computer for analysis. Different sized lymphatic valves were found in the precollecting and collecting lymph vessels, the lymphatic trunks, and ducts. The intervals between the valves were of various lengths. Diverse lymphatic ampullae and diverticula were seen in precollecting and collecting lymph vessels. Initial lymph vessels arose from the dermis, the galea, and the mucosal membrane. The vasculature of the direct and indirect precollecting and collecting lymph vessels, lymphatic trunks, and ducts was recorded. The morphology of the human lymphatic vessels in the head and neck has been described and recorded using radiographs and photographs.

Angiosomes of the brachial plexus: an anatomical study.

This anatomical study analyzed the neurovascular relationships of the brachial plexus. Ten fresh cadaveric brachial plexuses were examined after injection of the arterial system. The vascular anatomical features of the brachial plexus were documented with microdissection after lead oxide/gelatin injection. The specimens were analyzed by using radiography (including digital subtraction techniques) and light-microscopic, macroscopic, and digital photography. Four angiosomes, based on the subclavian, axillary, vertebral, and dorsal scapular arteries, were observed. As noted in previous angiosome studies, connections between angiosome territories lay within tissues, in this case, nerve trunks. Nutrient vessels penetrated nerve trunks at points of branching within the brachial plexus, with a Y-shaped mode of division on entry. The vascular supply was markedly rich, often with true anastomotic connections occurring within the nerves. There was much variation in supply, depending on the vascular anatomical features of the subclavian artery.