Corporal Skip Metastases in Penile Squamous Cell Carcinoma: An Unknown and Distinct Pattern of Spread with Poor Prognosis.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is characterised by stepwise lymphatic dissemination. Skip metastases (SkMs) are rare metastases in the corpus cavernosum or spongiosum without continuity to the primary tumour or its resection site. OBJECTIVE: To assess the distinct pattern of spread in SkM+ patients and the effect of SkM on prognosis. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of patients with SkM+ PSCC at ten high-volume international referral centres between January 2006 and May 2022. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated histopathological data, primary lymph node (LN) staging, and metastatic spread. We included a cohort of patients matched for pT stage, LN status, and grade who did not have SkM (SkM-) to compare the SkM prognosis and predictive value for cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Among the 63 SkM+ patients who met our inclusion criteria, the SkM diagnosis was synchronous in 54.0% and metastases were mostly located in the corpus cavernosum. SkM was symptomatic in 14% of cases, was detected on imaging in 32%, and was found incidentally on pathological examination in 27%. Fifty-one patients (81%) presented with positive LNs and 28 (44%) developed distant metastases. Seven patients (11%) presented with or developed distant metastasis without displaying any LN involvement. The 2-yr cancer-specific survival estimates were 36% (95% confidence interval [CI] 25-52%) for SkM+ and 66% (95% CI 55-80%) for matched SkM- patients (p < 0.001). On multivariable Cox regression analysis, SkM presence was an independent predictor for higher CSM (hazard ratio 2.05, 95% CI 1.06-4,12; p = 0.03). CONCLUSIONS: PSCC-related SkM is associated with aggressive disease behaviour and poor survival outcomes. Palpation of the entire penile shaft is essential, and distant staging is recommended in patients suspected of having SkM owing to the tendency for distant metastatic spread. PATIENT SUMMARY: We investigated outcomes for patients with cancer of the penis who had metastases in the tissues responsible for erection. We found that metastases in this location were associated with poor prognosis, even in the absence of more typical spread of cancer via the lymph nodes.

Risk of Local Recurrence in Men With Penile Intraepithelial Neoplasia in the Surgical Margin After Penile-sparing Surgery.

PURPOSE: Up to 90% of men with a positive surgical margin show remaining cancer in subsequent reresections. The risk of local recurrence in men with no penile cancer but the precancerous lesion penile intraepithelial neoplasia at the surgical margin is less well studied and was the aim of this analysis. MATERIAL AND METHODS: This was a retrospective analysis of men with distal penile cancer undergoing penile-sparing surgery. A competing risks survival analysis adjusted for grade, lymphovascular invasion, and stage was performed to assess local recurrence-free survival in patients with penile intraepithelial neoplasia-positive margins and completely negative surgical margins. RESULTS: A negative surgical margin was described in 319 men (85%), whereas penile intraepithelial neoplasia in the surgical margin was found in 59 men (15%). Local recurrence was observed in 30/319 men with a negative surgical margin compared to 11/59 men with penile intraepithelial neoplasia in the surgical margin. Adjusted for T stage and grade, patients with penile intraepithelial neoplasia at the surgical margin had a higher risk to develop a local recurrence than those with a negative surgical margin without penile intraepithelial neoplasia (HR 1.51, 95% CI 1.07-2.12, P = .019). CONCLUSIONS: Men with a penile intraepithelial neoplasia-positive surgical margin have an increased risk to experience local recurrence compared to men with a negative surgical margin and should undergo closer surveillance and/or adjuvant treatment.

Outcomes following radical inguinal lymphadenectomy for penile cancer using a fascial-sparing surgical technique.

PURPOSE: To describe our surgical technique and report the oncological outcomes and complication rates using a fascial-sparing radical inguinal lymphadenectomy (RILND) technique for penile cancer patients with cN+ disease in the inguinal lymph nodes. METHODS: Over a 10-year period, 660 fascial-sparing RILND procedures were performed in 421 patients across two specialist penile cancer centres. The technique used a subinguinal incision with an ellipse of skin excised over any palpable nodes. Identification and preservation of the Scarpa's and Camper's fascia was the first step. All superficial inguinal nodes were removed en bloc under this fascial layer with preservation of the subcutaneous veins and fascia lata. The saphenous vein was spared where possible. Patient characteristics, oncologic outcomes and perioperative morbidity were retrospectively collected and analysed. Kaplan-Meier curves estimated the cancer-specific survival (CSS) functions after the procedure. RESULTS: Median (interquartile range, IQR) follow-up was 28 (14-90) months. A median (IQR) number of 8.0 (6.5-10.5) nodes were removed per groin. A total of 153 postoperative complications (36.1%) occurred, including 50 conservatively managed wound infections (11.9%), 21 cases of deep wound dehiscence (5.0%), 104 cases of lymphoedema (24.7%), 3 cases of deep vein thrombosis (0.7%), 1 case of pulmonary embolism (0.2%), and 1 case of postoperative sepsis (0.2%). The 3-year CSS was 86% (95%Confidence Interval [95% CI] 77-96), 83% (95% CI 72-92), 58% (95% CI 51-66), respectively, for the pN1, pN2 and pN3 patients (p < 0.001), compared to a 3-year CSS of 87% (95% CI 84-95) for the pN0 patients. CONCLUSION: Fascial-sparing RILND offers excellent oncological outcomes whilst decreasing the morbidity rates. Patients with more advanced nodal involvement had poorer survival rates, emphasizing the need for adjuvant chemo-radiotherapy.

Impact of COVID-19, gender, race, specialty and seniority on mental health during surgical training: an international study.

BACKGROUND: Superior patient outcomes rely on surgical training being optimized. Accordingly, we conducted an international, prospective, cross-sectional study determining relative impacts of COVID-19, gender, race, specialty and seniority on mental health of surgical trainees. METHOD: Trainees across Australia, New Zealand and UK enrolled in surgical training accredited by the Royal Australasian College of Surgeons or Royal College of Surgeons were included. Outcomes included the short version of the Perceived Stress Scale, Oxford Happiness Questionnaire short scale, Patient Health Questionnaire-2 and the effect on individual stress levels of training experiences affected by COVID-19. Predictors included trainee characteristics and local COVID-19 prevalence. Multivariable linear regression analyses were conducted to assess association between outcomes and predictors. RESULTS: Two hundred and five surgical trainees were included. Increased stress was associated with number of COVID-19 patients treated (P = 0.0127), female gender (P = 0.0293), minority race (P = 0.0012), less seniority (P = 0.001), and greater COVID-19 prevalence (P = 0.0122). Lower happiness was associated with training country (P = 0.0026), minority race (P = 0.0258) and more seniority (P < 0.0001). Greater depression was associated with more seniority (P < 0.0001). Greater COVID-19 prevalence was associated with greater reported loss of training opportunities (P = 0.0038), poor working conditions (P = 0.0079), personal protective equipment availability (P = 0.0008), relocation to areas of little experience (P < 0.0001), difficulties with career progression (P = 0.0172), loss of supervision (P = 0.0211), difficulties with pay (P = 0.0034), and difficulties with leave (P = 0.0002). CONCLUSION: This is the first study to specifically describe the relative impacts of COVID-19 community prevalence, gender, race, surgical specialty and level of seniority on stress, happiness and depression of surgical trainees on an international scale.

Surgical management of chronic high-grade acromioclavicular joint dislocations: a systematic review.

BACKGROUND: To date, no gold-standard technique exists for the treatment of chronic acromioclavicular joint (ACJ) instability. We systematically reviewed the clinical results of 3 main categories of ACJ reconstruction for high-grade chronic instability. METHODS: A literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The inclusion criteria were clinical studies involving patients with ACJ instability (Rockwood grades III-VI) for at least 6 weeks, managed with ACJ stabilization, with a minimum 1-year follow-up. Depending on the surgical technique, patients were divided into 1 of 3 groups: nonbiological fixation between the coracoid and clavicle, for example, suture loops and synthetic ligaments (group 1); biological reconstruction of the coracoclavicular ligaments, for example, allograft or autograft ligament reconstruction (group 2); and ligament and/or tendon transfer, for example, the Weaver-Dunn procedure (group 3). Patient demographic characteristics, functional scores, radiographic outcomes, and complications were compared. RESULTS: Two independent investigators reviewed 960 articles. A total of 27 studies met the inclusion criteria, comprising 590 patients divided into 1 of 3 groups. The complication rates were similar among the 3 groups: 15% for nonbiological fixation, 15% for biological reconstruction, and 17% for ligament and/or tendon transfer, with failure rates of 8%, 7%, and 5%, respectively. In terms of functional results, the mean Constant score was 87.2 points for nonbiological fixation (n = 89), 92.4 points for biological reconstruction (n = 86), and 87.4 points for ligament and/or tendon transfer (n = 49). CONCLUSION: On comparison of the results of 3 different ACJ reconstruction methods, all techniques showed similar complication rates. Among the level II studies, ACJ reconstruction with a tendon graft showed superior results.

The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience.

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is focused on developing new tools and neurotechnologies to transform our understanding of the brain, and neuroethics is an essential component of this research effort. Coordination with other brain projects around the world will help maximize success.

The State of the NIH BRAIN Initiative.

The BRAIN Initiative arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.

The clinical academic workforce in Australia and New Zealand: report on the second binational summit to implement a sustainable training pathway.

There has been a decline in the proportion of clinical academics compared with full-time clinicians, since 2004. A Working Party was established to help develop and implement a model for the training of clinical academics. After a highly successful first summit in 2014 that summarised the challenges faced by clinical academics in Australia and New Zealand, a second summit was convened late in 2015 to report on progress and to identify key areas for further action. The second summit provided survey results that identified the varied training pathways currently offered to clinical academics and the institutions willing to be involved in developing improved pathways. A literature review also described the contributions that clinical academics make to the health sector and the challenges faced by this workforce sector. Current training pathways created for clinical academics by Australasian institutions were presented as examples of what can be done. The perspectives of government and research organisations presented at the summit helped define how key stakeholders can contribute. Following the summit, there was a strong commitment to continue to work towards developing a sustainable and defined training pathway for clinical academics. The need for a coordinated and integrated approach was highlighted. Some key objectives were agreed upon for the next phase, including identifying and engaging key advocates within government and leading institutions; publishing and profiling the contributions of successful clinical academics to healthcare outcomes; defining the stages of a clinical academic training pathway; and establishing a mentoring programme for training clinical academics.

A crab swarm at an ecological hotspot: patchiness and population density from AUV observations at a coastal, tropical seamount.

A research cruise to Hannibal Bank, a seamount and an ecological hotspot in the coastal eastern tropical Pacific Ocean off Panama, explored the zonation, biodiversity, and the ecological processes that contribute to the seamount's elevated biomass. Here we describe the spatial structure of a benthic anomuran red crab population, using submarine video and autonomous underwater vehicle (AUV) photographs. High density aggregations and a swarm of red crabs were associated with a dense turbid layer 4-10 m above the bottom. The high density aggregations were constrained to 355-385 m water depth over the Northwest flank of the seamount, although the crabs also occurred at lower densities in shallower waters (∼280 m) and in another location of the seamount. The crab aggregations occurred in hypoxic water, with oxygen levels of 0.04 ml/l. Barcoding of Hannibal red crabs, and pelagic red crabs sampled in a mass stranding event in 2015 at a beach in San Diego, California, USA, revealed that the Panamanian and the Californian crabs are likely the same species, Pleuroncodes planipes, and these findings represent an extension of the southern endrange of this species. Measurements along a 1.6 km transect revealed three high density aggregations, with the highest density up to 78 crabs/m(2), and that the crabs were patchily distributed. Crab density peaked in the middle of the patch, a density structure similar to that of swarming insects.

Is matrix metalloproteinase required in postnatal testicular tubules for germ cell maturation?

BACKGROUND/AIM: Cryptorchidism may cause infertility by failed transformation of neonatal gonocytes into adult dark spermatogonia, the putative stem cells for spermatogenesis. Gonocytes migrate centrifugally to the tubular basement membrane to become adult dark spermatogonia. Regulation of this transformation remains unknown. We aimed to investigate neonatal rodent testis matrix metalloproteinase (MMP) production to see whether MMPs loosen extracellular matrix between Sertoli cells to facilitate gonocyte movement. METHODS: Sprague-Dawley rat testes (n = 4-6 per group) were collected at embryonic day 19 (E19) and postnatal (P) days P0 to 10 for immunohistochemistry. Immunofluorescent confocal images were captured for presence of membrane type 1 MMP (MT1-MMP), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 2 (TIMP2), mouse VASA homologue, anti-Müllerian hormone, and androgen receptor in tissue sections. Testicular proteins were analyzed by immunoblotting. RESULTS: Membrane type 1 MMP was strongly present in gonocytes at E19 then decreased, whereas it increased in testicular somatic cells from P0 to P10. Testicular protein levels of MT1-MMP, MMP2, and androgen receptor were constant from E19 to P10. Anti-Müllerian hormone protein sharply decreased after P2, whereas TIMP2 gradually increased from E19 to P10. Gonocytes migrated to basement membrane at P2 to P6. CONCLUSION: Membrane type 1 MMP, MMP2, and TIMP2 were present in testis from E19 to P10 during gonocyte migration and transformation into spermatogenic stem cells. Increased knowledge about germ cell development may aid efforts to improve fertility in cryptorchidism.

Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?

PURPOSE: Cryptorchidism is the most common male congenital abnormality. The rodent gubernaculum steers the testis from abdomen to scrotum postnatally by eversion and migration through the developing inguinal fat pad (IFP). We hypothesize that extracellular matrix remodeling in/around the gubernaculum is necessary for eversion and migration and is permitted by timed IFP maturation and aimed to examine regional development and matrix metalloproteinase (MMP) content. METHODS: Embryonic day 19 (E19) and postnatal days 0 and 2 (P0, P2) wild-type Sprague-Dawley rats (n = 10) were prepared for histologic examination (trichrome) and immunohistochemistry (membrane-type MMP-1 [MT1-MMP], MMP2) and analyzed using light/confocal microscopy. RESULTS: At E19, IFP contained fibroblasts and immature cells in an extensive collagenous extracellular matrix. Cells in the gubernaculum base were cytoplasmic-MT1-MMP-positive (inactive). At P0, the gubernaculum had everted, and adjacent cells were membranous-MT1-MMP-positive (active). At P2, the gubernaculum was migrating through the IFP, and adjacent cells were membranous-MT1-MMP-positive. Adipocyte maturation began cranially in the IFP and proceeded in a craniocaudal gradient until more uniformly mature at P2. CONCLUSION: The MT1-MMP-positive cells may remodel the gubernaculum for eversion and provide the collagenolysis necessary for migration, like an icebreaking ship, through the IFP, which matures to permit migration through collagen-rich tissue. Disruption of these processes may cause cryptorchidism.

Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation.

Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple µ opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by µ opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGFß1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of µ opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.