small molecules

2026-08-07 | Intratumoral para-toluenesulfonamide as a tumor-ablative therapy for equine cutaneous tumors: a case series of three horses.

Equine neoplasia, including sarcoids, melanomas, and squamous cell carcinomas, presents therapeutic challenges due to recurrence and limitations of conventional treatments. Para-toluenesulfonamide (p-TLS) is a tumor-ablating agent that is associated with localized tumor necrosis and subsequent lesion resolution. It has been evaluated in human clinical settings as an intratumoral treatment of malignant airway obstruction caused by non-small cell lung cancer. This study aimed to describe the clinical outcomes and tolerability of intratumoral p-TLS in equine neoplasia. Three equine cases, including a fibroblastic sarcoid, perianal melanoma, and penile squamous cell carcinoma, were treated. The fibroblastic sarcoid and penile squamous cell carcinoma achieved complete response. The melanoma fulfilled the criteria for partial response at the protocol-defined clinical evaluation timepoint and subsequently demonstrated complete clinical resolution during follow-up. All cases demonstrated a consistent pattern of response characterized by tumor necrosis, sloughing, and subsequent wound healing with complete re-epithelialization. Local adverse effects were limited to transient inflammation and mild discomfort, which were effectively managed with supportive care. No severe adverse events or tumor recurrence were observed during the follow-up period ranging from 120 days to 15 months. These findings suggest that p-TLS may represent a feasible, highly minimally invasive intratumoral therapeutic approach for equine neoplasia and support further evaluation.

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2026-07-31 | [Testicular Germ Cell Tumors and Penile Cancer: Molecular-Based Diagnosis and Treatment].

Molecular diagnostics and targeted therapies are increasingly evolving towards a personalized medicine approach. This review summarizes recent advances in testicular germ cell tumors (TGCTs) and penile cancer, with a focus on emerging biomarkers and targeted therapeutic strategies. Conventional serum tumor markers such as AFP, β-HCG, and LDH remain important but are limited by suboptimal sensitivity and specificity. Novel biomarkers, particularly microRNA miR-371a-3p, have demonstrated substantially higher diagnostic accuracy and may improve risk stratification, detection of disease recurrence, and treatment decision-making in TGCTs. In addition, the analysis of circulating tumor DNA (ctDNA) has emerged as a promising liquid biopsy procedure. In penile squamous cell carcinoma, molecular classification based on human papillomavirus (HPV) status and comprehensive genomic profiling are becoming increasingly relevant for prognosis and therapeutic selection. The identification of actionable molecular alterations has facilitated the development of immunotherapy, anti-EGFR strategies, and antibody-drug conjugates. Early clinical data also suggest that ctDNA may provide valuable information for treatment monitoring and early relapse detection. Despite these promising findings, further prospective studies and standardized methodologies are required before many of these approaches can be incorporated into routine clinical practice. Overall, these developments highlight the ongoing transition towards biomarker-driven precision oncology and the potential for more individualized management of patients with TGCTs and penile cancer.

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2026-06-01 | (401) Magnetic Sentinel Node Biopsy with Sienna+®/SentiMag® in Penile Squamous Cell Carcinoma: A Feasible Radiation-Free Alternative

Abstract Introduction Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which accurate inguinal lymph node staging is essential for prognosis, management, and potential preservation of penile function. Dynamic sentinel lymph node biopsy (DSNB) using technetium-99m radiotracers and blue dye is the gold standard, but its use is limited by reliance on nuclear medicine facilities, complex logistics, and exposure to ionizing radiation. Magnetic tracers such as Sienna+® (superparamagnetic iron oxide nanoparticles), detected with the SentiMag® magnetometer, represent a radiation-free alternative that may facilitate sentinel node detection, particularly in centers without access to nuclear medicine. Objective To assess the feasibility and clinical performance of sentinel lymph node biopsy (SLNB) using Sienna+®/SentiMag® combined with methylene blue in penile SCC. Methods A 62-year-old man with a poorly differentiated (G3), HPV-negative penile SCC (cN0) underwent glansectomy with SLNB. The magnetic tracer Sienna+® was injected perilesionally 24 hours before surgery. Intraoperative sentinel node detection was performed with the SentiMag® handheld magnetometer and methylene blue dye. Surgical findings, histopathology, and short-term postoperative outcomes were evaluated. Results Two sentinel nodes were identified and excised: one in the right groin, detected by both SentiMag® (700 units) and methylene blue, and one in the left groin, detected exclusively by SentiMag® (3000 units). Histopathology confirmed pT1b disease with perineural invasion, no lymphovascular invasion, negative surgical margins, and no nodal metastases (pN0). Final staging was pT1b pN0 R0. Postoperative recovery was initially uneventful; however, the patient was readmitted with right-sided orchitis and sepsis, which resolved with antibiotics. At one-month follow-up, wound healing was satisfactory, catheter was removed, and no clinical evidence of recurrence or nodal disease was observed. Conclusions Magnetic SLNB with Sienna+®/SentiMag® is feasible and safe in penile SCC. Notably, it identified a sentinel node not detected by methylene blue, suggesting potential for improved sensitivity. This radiation-free technique offers logistical and safety advantages over conventional DSNB, particularly in centers without nuclear medicine access. By enabling more accurate nodal staging, it may reduce the need for extensive lymphadenectomy, potentially minimizing morbidity and contributing indirectly to the preservation of penile function. Limitations such as MRI artifacts and susceptibility to interference from metallic instruments remain. Larger prospective studies are needed to validate diagnostic accuracy and establish its role in routine clinical practice. Disclosure No

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2026-05-28 | Association of chemotherapy with survival in node-positive penile squamous cell carcinoma stratified by nodal burden: A National Cancer Database analysis.

e17033 Background: Node-positive penile squamous cell carcinoma (PSCC) carries a poor prognosis, yet the survival benefit of systemic chemotherapy remains uncertain given the lack of completed randomized trials and reliance on limited phase II and retrospective data. Although NCCN guidelines recommend chemotherapy for patients with ≥3 positive lymph nodes, whether chemotherapy benefit differs by pathologic nodal burden has not been formally evaluated using interaction analysis. We hypothesized that chemotherapy is associated with improved overall survival (OS) among patients with high nodal burden (≥3 nodes) but not among those with low nodal burden (1–2 nodes). Methods: Using the National Cancer Database (2004–2022), we identified adults with pathologically node-positive, nonmetastatic PSCC who underwent regional lymph node dissection with numeric nodal counts available. Heterogeneity of treatment effect by nodal burden was formally assessed using a chemotherapy × nodal burden interaction term. Nodal burden was classified as low (1–2 positive nodes) or high (≥3 positive nodes). OS was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable Cox proportional hazards regression adjusted for age, race, ethnicity, Charlson-Deyo comorbidity score, T stage, tumor grade, primary tumor surgery, radiotherapy, facility type, insurance status, and year of diagnosis. A 90-day landmark analysis was performed to mitigate immortal time bias. Results: Among 1,300 patients, 589 (45%) received chemotherapy. A statistically significant chemotherapy × nodal burden interaction was observed (p = 0.009), indicating differential survival associations by nodal burden. In the overall cohort, chemotherapy was not associated with OS (log-rank p = 0.47). Among patients with high nodal burden, chemotherapy was associated with improved OS (adjusted HR 0.76, 95% CI 0.59–0.98, p = 0.03; log-rank p = 0.002), with median OS of 35.9 months compared with 20.6 months for those not receiving chemotherapy. In contrast, among patients with low nodal burden, chemotherapy was not associated with improved OS (adjusted HR 1.19, 95% CI 0.95–1.49, p = 0.13; median OS 59.0 vs 65.7 months; log-rank p = 0.79). Findings were consistent in landmark analyses (interaction p = 0.008). Conclusions: In this large national cohort, the association between chemotherapy and survival in node-positive, nonmetastatic PSCC differed significantly by pathologic nodal burden. Chemotherapy was associated with improved survival among patients with ≥3 positive lymph nodes but not among those with limited nodal involvement. These findings demonstrate clinically meaningful heterogeneity in chemotherapy benefit and may inform more precise patient selection for systemic therapy in node-positive PSCC.

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2026-04-25 | Impact of Copy Number Alterations on Human Papillomavirus (HPV)-Induced and HPV-Independent Penile Cancers.

Penile squamous cell carcinomas (SCC) develop via transforming human papillomavirus (HPV) infection or independent of HPV. The association of copy number alterations (CNA) affecting chromosome arms, amplifications or deletions of tumor suppressor/oncogenes with HPV status and somatic mutations is largely unknown. CNA in 121 penile SCC (52% HPV associated, 48% HPV independent) were assessed using shallow whole-genome sequencing and correlated with hotspot mutations in 50 cancer driver genes. CNA were common with frequent complex co-occurrences in both etiologies. Arm-level changes included gains of 3q, 8q (48% each), 1q (36%), 1p (26%), 9q (36%), and 9p (31%) and losses of 19p (48%), 8p (44%), 19q (36%), and 3p (33%). Oncogene amplifications included broad 3q alterations (43%; TP63, SOX2, and PIK3CA) and 8q alterations (40%; MYC, HEY1, and RAD21). MYC amplifications coincided with an increased fraction of genome altered indicating genomic instability (P=.00001). Homozygous deletions affected 8p (29%; WRN, NRG1), and 3p (19%, BAP1, FANCD2, VHL) and 11q22/23 (19%, ARHGEF12, BCL9L, ATM) in both etiologies. CNA affecting TP53, CDKN2A/B, CDKN1A/B, and RB1 occurred in both, HPV-induced (16%) and HPV-independent SCC (24%), while tumor suppressor gene mutations were exclusive to HPV-independent SCC. Further differences included more amplifications on 1p in HPV-induced SCC (adjusted P = .003), compared to more 8q full-arm gains (adjusted P = .00003), amplifications of oncogenes on 8q including MYC (adjusted P = .006), and homozygous deletions of 8p (adjusted P = .03) in HPV-independent SCC. EGFR amplifications dominated in HPV-independent TP53/CDKN2A wild-type SCC without dermatoses. Together with mutations in PIK3CA, HRAS, and FGFR3, CNA represent an alternate RTK/Ras/PI3K-mediated carcinogenesis pathway. Therapeutically interesting targetable CNA such as EGFR, MTAP, and ATM occurred in >50% of advanced SCC irrespective of etiology. CNA are common in penile SCC, mainly independent of HPV-status and somatic mutations and may assist in personalized treatment strategies.

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cell therapies

2022-12-15 | Establishment and Characterization of Advanced Penile Cancer Patient-derived Tumor Xenografts: Paving the Way for Personalized Treatments.

Systemic treatments for penile squamous cell carcinoma (pSCC) are toxic and inefficient. Patient-based preclinical models are essential to study novel treatments. To establish a library of patient-derived tumor xenograft (PDX) models of human papillomavirus-positive (HPV+) and -negative (HPV-) pSCC and characterize these at the genomic and histological levels. Eighteen tumor samples from 14 patients with recurrent or metastatic pSCC were implanted in nude mice. A biobank of PDX tumors was established after passaging of patient samples (F0) for three generations (F1, F2, F3) and was characterized using histopathology and targeted next-generation sequencing (tNGS). Single-nucleotide polymorphism fingerprinting was used to confirm PDX genealogy. The engraftment rate, overall growth rate, and pSCC histomorphology were checked for each PDX generation. Staining for p40 (a pSCC marker) and p16 (a surrogate for HPV infection) was performed for F0 samples. The mutational profile according to a validated panel of 96 cancer genes was determined for F0 and F3 samples and compared to a larger tNGS database. Including a previously established pilot model, 11 out of 18 tumor samples (61%) successfully engrafted in F1. The mean time from implantation in F1 to completion of F3 was 36 wk (standard deviation 18). Histological fidelity was demonstrated across generations. The patient mutational profiles were preserved in F3 and were representative of 277 pSCC samples in the Foundation Medicine database. The rapid progression of pSCC in patients from our selected high-risk cohort impeded the use of PDXs as avatars. We successfully established the first library of 11 PDX models of HPV- and HPV+ pSCC. Our PDX models showed high engraftment rates and histological and genomic fidelity to the tumor tissue of origin. These models may help in paving the way towards the development of novel treatments. We established 11 animal models based on tumor tissue from patients with penile cancer. These models could play a vital role in selection of novel treatments according to genetic mutations. In the future, therapies with confirmed preclinical effects may have a profound impact on the development of personalized treatments in penile cancer.

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2021-06-09 | Expansion of tumor-infiltrating lymphocytes (TIL) from penile cancer patients.

Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3+ (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8+ T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer.

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2019-09-01 | Surgical and Oncological Outcomes in Patients After Vascularised Flap Reconstruction for Locoregionally Advanced Penile Cancer

Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue.To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps.From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions.Local surgical resection with RAM or abdominal advancement flap reconstruction.Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications.Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence-free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size.The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category.Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery.

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2018-06-07 | Molecular characterization and integrative genomic analysis of a panel of newly established penile cancer cell lines

Abstract Cell line models are essential tools to study the molecular mechanisms underlying tumor initiation and progression. There are limited treatment options for penile squamous cell carcinoma (PSCC), accounting for 1–2% of male tumors in developing countries, and limited progress in preclinical research in PSCC due to lacking available models with identified genomic characteristics. Here, biological and molecular characteristics and whole-genomic alterations were analyzed in a panel of PSCC cell lines newly established in our laboratory. These cell lines were all human papillomavirus (HPV)-negative, epithelial-like, immortalized, and tumorigenic in nude mice, whereas they displayed different proliferation, migration and invasion capacities in vitro, and tumorigenic ability in nude mice. They were all cisplatin sensitive, anti-EGFR therapy resistant, and androgen irresponsive. Whole-genomic sequecing analysis revealed that transition mutations (C:G>T:A and T:A>C:G) were the most common substitution types in these cell lines, whereas ERCC5 , TP53 , PTH1 , CLTCL1 , NOTCH2 , MAP2K3 , CDK11A/B , USP6 , ADCH5 , BCLAF1 , CDKN2A , FANCD2 , HRAS , and NOTCH1 were the most frequently altered genes. Amplifications of MYC , PLAG1 , NCOA2 , RUNX1T1 , COX6C , and EGFR and losses of FBXW7 , TET2 , XPC , and FANCE were frequently observed in cell lines. The exomic variations between cell lines and their corresponding cancer tissues were highly consistent. Genetic variations were mainly involved in the MAPK, Jak-STAT, TGF-beta, Notch, and apoptosis signaling pathways. Conclusively, these panel of PSCC cell lines established in our laboratory harbor some common or specific biological characteristics and genomic variations, and they may serve as optimal models to investigate the molecular mechanisms underlying the progression, metastasis, relapses, and treatment resistance of PSCC and to develop effective treatment strategy.

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2018-03-21 | Neo-glans reconstruction for penile cancer: Description of the primary technique using autologous testicular tunica vaginalis graft

Partial penectomy (glansectomy with/or without distal corporectomy) is an acceptable alternative for smaller distal pT3 penile carcinoma lesions in highly motivated and compliant patients. The authors describe a novel technique of neo-glans reconstruction using a tunica vaginalis (TV) testis allograft. However, due to an unclear resection margin on final histology, the patient underwent re-do surgery with a neo-glans revision using the well-established mesh split-thickness skin graft (STSG) technique. The penile length was preserved and the penile and bulbar part of the urethra was additionally mobilised in order to obtain a natural and aesthetic result for the meatus.Neo-glans reconstruction with TV coverage may be another promising alternative, which certainly requires further evaluation. We believe that the donor-site associated morbidity is minimal when compared to other harvesting sites. However, this is just an assumption, because direct comparison data on grafting techniques and neo-glans reconstruction are not available. Nevertheless, we think that for re-do procedures a standardised approach using a STSG technique should be the treatment method of choice.

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proteins

2026-05-28 | Granulomatous posthitis caused by <i>Halicephalobus gingivalis</i> in association with penile squamous cell carcinoma in an equine: clinical and anatomopathological aspects

Penile and preputial squamous cell carcinomas are among the most common tumors in horses, and inflammation of the external genitalia caused by Halicephalobus gingivalis is an important differential diagnosis. H. gingivalis is a free-living nematode that causes fatal parasitic encephalitis in horses and humans and can eventually be diagnosed in the kidneys, lymph nodes, lungs, genital and ocular mucosa. The objective was to characterize clinical and pathological lesions caused by H. gingivalis infection in the prepuce with concomitant involvement of penile squamous cell carcinoma in an equine. A 15-year-old male Pampa horse with prepuce and penis ulcerated lesions had these surgically excised. Histopathological analysis revealed granulomatous posthitis with H. gingivalis intralesional and ulcerated penile squamous cell carcinoma. The animal had a satisfactory clinical and surgical evolution, and there was no recurrence of the lesions after a six-month follow-up period. Considerations regarding the route of infection, treatment, and zoonotic potential were highlighted, showing the importance of including this pathogen in the differential diagnosis of nodular lesions affecting the preputial and penile areas in horses.

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2026-04-06 | Clinical, epidemiological, and diagnostic aspects of erythroplasia of queyrat

BACKGROUND: Erythroplasia of Queyrat (ICD-10 code: D07.4) is an intraepithelial neoplasia affecting the glans penis and inner preputial leaf. It is classified as a squamous cell carcinoma in situ. However, available publications lack data on its prevalence across age groups. AIM: The work aimed to examine the clinical and epidemiological aspects of erythroplasia of Queyrat and assess the efficacy of various diagnostic approaches. METHODS: A retrospective, cross-sectional case history study in patients who sought medical advice for penile lesions of various origins (n = 327) and a prospective observational study in patients with erythroplasia of Queyrat (n = 49) were conducted. Toluidine blue staining, dermatoscopy, and cytological and histological examinations were used in the diagnosis of erythroplasia of Queyrat. Additionally, an ultrasound of the penis and inguinal lymph nodes, tests for sexually transmitted infections, and a transrectal prostate ultrasound were performed. RESULTS: The observational study in patients with erythroplasia of Queyrat revealed a trend towards younger onset. The majority of patients (30.61%) were aged 50–59 years, with the disease detected before the age of 29 in 12.24% of cases and at the age of 30–39 in 20.4% of cases. A total of 89.8% of patients saw physicians of various specialties (urologists, dermatovenerologists, oncologists, etc.), whereas 10.2% self-medicated. The time between the onset of penile rashes and seeking medical advice is particularly concerning, ranging from 1 week (4.0%) to more than 5 years (2.0%). Thus, patients with a disease duration of ≥ 1 year (12.1%) are at the highest risk of penile squamous cell carcinoma. The majority of patients with erythroplasia of Queyrat consult with a dermatovenerologist, with the final diagnosis made on the initial or follow-up visit in 93.87% of cases, indicating that dermatovenerologists are familiar with clinical signs and diagnostic approaches in this condition. CONCLUSION: This work addresses the gaps in the modern assessment of clinical and epidemiological aspects and diagnostic efficacy in patients with erythroplasia of Queyrat, facilitating the selection of effective therapeutic options.

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2026-03-25 | Locally Advanced Squamous Cell Carcinoma of the Penis- Case Report and Literature Review

Squamous cell carcinoma of the penis is a rare but aggressive tumor, the prognosis of which depends closely on the stage at diagnosis. Locally advanced forms pose a major therapeutic challenge, requiring multidisciplinary management. We report the case of a patient with advanced squamous cell carcinoma of the penis, detailing the diagnostic approach, treatment strategy, and outcome, while also discussing current data from the literature.

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2026-03-17 | Association of CCL21+ CAFs with B-cell recruitment and TLS maturation in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. Tertiary lymphoid structures (TLSs) can support antitumour immunity, yet TLS maturation and maturation-associated stromal determinants in PSCC remain unclear. Here, we integrated hematoxylin and eosin (H&E) staining, multiplex immunohistochemical (mIHC) colocalization, spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), and bulk RNA sequencing (bulk RNA-seq) to profile TLS maturity and TLS-associated stromal-immune features in PSCC. TLS maturity was quantified using an AUCell germinal centre-like signature, and the presence of mature TLSs (mTLSs) coincided with improved survival. We identified a CCL21+ CAF subset that was preferentially enriched in mTLSs, spatially concentrated in the mTLS-core and adjacent to B-cell-rich areas; mIHC further confirmed dense CCL21+ACTA2+ CAFs near CD20+ aggregates. Along an inferred iTLS-to-mTLS continuum, the abundance of CCL21+ CAFs increased, and the expression of chemokines increased. Spatial and transcriptomic analyses further linked B-cell chemotaxis- and activation-related signatures to the CCL21-CCR7 axis, accompanied by germinal centre-like B-cell features. Clinically, higher CCL21 expression, elevated CCL21+ CAF signature scores, and stronger CCL21-CCR7 signatures in B cells were associated with favourable outcomes. Together, these data suggest that CCL21+ CAFs or CCL21 are potential prognostic biomarkers for risk stratification and immune microenvironment profiling and highlight the CCL21-CCR7 axis as a candidate pathway for therapeutic modulation of TLS maturity in PSCC.

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2026-03-13 | Tertiary lymphoid structures in genitourinary cancers: a comprehensive review.

Tertiary lymphoid structures (TLSs) are lymphoid cell clusters that form in non-lymphoid tissues in response to chronic inflammation and function as sites for localized, antigen-specific immune responses, potentially enhancing anti-tumor immunity. This review examines TLS presence, composition, and clinical significance across genitourinary (GU) cancers to evaluate their potential as prognostic and therapeutic targets. In prostate cancer, TLSs are infrequently found due to a typically immunologically inactive tumor microenvironment (TME), but when present, they correlate with improved outcomes and reduced recurrence, especially when structurally mature with active germinal centers (GCs). Bladder cancer, in contrast, demonstrates increased TLS activity, particularly in high-grade disease, with high TLS density associated with superior responses to Bacillus Calmette-Guérin (BCG) therapy and anti-PD-L1 treatment. In testicular seminomas, TLSs have been associated with a more favorable prognosis, whereas non-seminomatous germ cell tumors demonstrate TLS suppression driven by SERPINB9-mediated downregulation of chemokines that promote their development. In clear cell renal cell carcinoma (ccRCC), TLSs correlate with improved survival and enhanced immunotherapy responses, although elevated CXCL13 expression may paradoxically signal more aggressive disease. Unlike ccRCC, TLSs are infrequent in papillary and chromophobe RCC, reflecting a less-inflamed TME that likely contributes to reduced immunotherapy responsiveness and prognostic value. TLSs in penile squamous cell carcinomas show enhanced immune infiltration and improved overall survival (OS) independent of stage. Notably, mature TLSs are key for effective anti-tumor immunity, whereas immature TLSs may fail to generate an adequate response. Collectively, these findings highlight TLSs as prognostic biomarkers with prognostic value and therapeutic potential in GU malignancies.

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antibodies

2026-06-23 | Long-term survival analysis of TNT: A phase II study of neoadjuvant toripalimab plus nimotuzumab combined with taxol-based chemotherapy in locally advanced penile squamous cell carcinoma.

177 Background: Locally advanced penile squamous cell carcinoma (La-PSCC) is an aggressive malignancy, and the previous standard neoadjuvant TIP regimen has shown moderate efficacy and unfavorable survival outcomes, with an objective response rate (ORR) of 50%, a pathological complete response (pCR) rate of 10%, and median progression-free survival (PFS) and overall survival (OS) of 8.1 months and 17.1 months, respectively. Our preliminary results of the TNT regimen showed promising efficacy, with an ORR of 82.8% and a pCR rate of 48.3%. Here, we present the long-term survival results of this trial with a long time follow-up. Methods: In this multi-center study, single-arm, phase II study, eligible patients with histologically confirmed La-PSCC (cT4/cN3) received TNT regimen (comprising toripalimab, nimotuzumab, and TIP chemotherapy [nab-paclitaxel, cisplatin, and ifosfamide]) every 3 weeks for up to 4 cycles, followed by consolidative surgery. While the primary endpoint was pCR (previously reported), this updated analysis focuses on secondary endpoints, including PFS and OS. The data cutoff date for this analysis was February 10, 2026. Results: With a median follow-up of 59.3 months (range, 2.33-66.93), median PFS and mOS were not reached for the cohort (n=29). The estimated 5-year PFS and OS were 65.5% (95%CI: 50.3%–85.3%) and 69.0% (95%CI: 54.1%–88.2%), respectively. Survival outcomes were significantly stratified by treatment response. In patients achieving a pCR (n=14), the median PFS and OS were not reached. Whereas the non-pCR group (n=15) showed mPFS of 9.7 months (95%CI: 5.63–not reached[NR]) (HR=0.08; 95%CI: 0.009–0.616; p=0.002) and mOS of 33.4 months (95%CI: 12–NR) (HR=0.10; 95%CI: 0.012–0.771; p=0.006). Responders (those achieving a complete response [CR] or partial response [PR], n=24) exhibited significantly better outcomes than non-responders (n=5, all experienced disease progression and death), with median PFS not reached vs 2.47 months (95% CI: 1.7–NR) (HR=0.031, 95%CI: 0.006–0.169, p<0.001) and median OS not reached vs 10.5 months (95% CI, 6.93–NR) (HR=0.033, 95%CI: 0.006–0.181, p<0.001). No new safety signals emerged during the near 5-year follow-up. Conclusions: With a median follow-up of 59.3 months, the TNT regimen continued to provide clinically superior survival outcomes in patients with locally advanced PSCC, maintained by a favorable safety profile. Our findings confirm the long-term durability of TNT regimen, reinforcing its role as a highly effective neoadjuvant strategy for these patients. Clinical trial information: NCT04475016 .

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2026-06-23 | Neoadjuvant toripalimab combined with TIP chemotherapy for locally advanced penile squamous cell carcinoma: A multicenter prospective, single-arm, phase II clinical trial.

178 Background: The neoadjuvant regimen of paclitaxel, ifosfamide, and platinum (TIP) regimen is recommended for local advanced penile squamous cell carcinoma (La-PSCC) by NCCN guideline; however, its objective response rate (ORR) is only 50%, with limited long-term survival benefits. This phase II study was designed to evaluate the efficacy and safety of toripalimab (anti-PD-1 monoclonal antibody) combined with TIP chemotherapy as neoadjuvant therapy in chemotherapy-naïve patients with La-PSCC. Methods: This was a prospective, multicenter, single-arm phase II study utilizing a Simon’s two-stage design. Patients with T4 or N2-3 M0 PSCC received up to four cycles of neoadjuvant toripalimab combined with TIP chemotherapy, followed by consolidative surgery. Postoperatively, toripalimab maintenance therapy was administered every three weeks for up to 17 cycles. The primary endpoint was the ORR assessed according to RECIST v1.1. Secondary endpoints include pathological complete response (pCR), event-free survival (EFS), overall survival (OS), and the incidence of treatment-related adverse events (TRAEs). This trial is registered on ClinicalTrials.gov (Identifier: NCT06415318). Results: From May 30, 2024, to Jun 1, 2025, a total of 25 patients with La-PSCC were enrolled (median age 60 years, range 31-71). All received ≥2 cycles of toripalimab combined with TIP chemotherapy. The ORR was 84.0% (21/25), with 2 patients (8.0%) achieving CR and 19 (76.0%) achieving PR. Twenty-one patients received following consolidative surgery, with a pCR rate of 48.0% (12/25). All patients (100%) experienced TRAE of any grade; grade 3-4 TRAEs occurred in 84.0% (21/25). The most common grade 1-2 TRAEs were alopecia (100%), peripheral neuropathy (96.0%), and fatigue (84.0%). The predominant grade 3–4 TRAEs were neutropenia (72.0%, 18/25) and leukopenia (60.0%, 15/25). Hypothyroidism (grade 1–2) was the main immune-related adverse event (irAE), affecting 2/25 patients (8%). No grade 5 TRAEs or treatment-related deaths occurred. At a median follow-up of 14.8 months, the 12-month EFS and OS rates were 71.6% (95% CI: 55.8–91.9) and 87.8% (95% CI: 75.8–100), respectively. Median EFS and OS were not reached. Mature survival data are awaited with longer follow-up. Conclusions: Neoadjuvant toripalimab combined with TIP chemotherapy exhibits significant efficacy in chemotherapy-naïve patients with La-PSCC, with acceptable treatment-related toxicity. This combination holds great promise as a new standard neoadjuvant treatment for La-PSCC. Clinical trial information: NCT06415318 .

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2026-05-28 | Eiu-104101: A first-in-human phase 1a/1b study of EVOLVE104, a trispecific CD3×CD2×ULBP2/5/6 T-cell engager, in advanced urothelial and squamous cell carcinomas.

TPS2682 Background: EVOLVE T cell engagers (TCEs) bind to a tumor antigen and to both CD3 and CD2 on T cells, thereby providing integrated costimulation via CD2 binding. EVOLVE TCEs demonstrate superior T cell activation and tumor cell killing compared to first generation TCEs, without excess cytokine release or tonic T cell activation, and may offer clinical benefits such as enhanced potency and duration of activity. UL16 binding proteins 2, 5 and 6 (ULBP2/5/6) belong to a family of cell surface proteins that are ligands for the NKG2D receptor. We have previously reported that cell-surface ULBP2/5/6 is not present in vital organs and found in some mucosal epithelia. Cell surface ULBP2/5/6 is found in urothelial carcinomas and squamous cell carcinomas (SCCs). With high expression on malignant cells and limited normal tissue expression, ULBP2/5/6 are intriguing targets for cancer immunotherapy. EVOLVE104 is a trispecific TCE that binds ULBP2/5/6 and both CD3 and CD2 on T cells. Preclinical studies with EVOLVE104 demonstrated enhanced T cell activation and killing of ULBP2/5/6-positive tumor cells compared to bispecific TCEs, and no safety concerns were identified in preclinical toxicity studies. With this encouraging preclinical profile, EVOLVE104 represents a novel approach to redirected T cell therapy in solid tumors. Methods: EIU-104101 is a first-in-human phase 1a/1b study evaluating EVOLVE104 monotherapy in adults with advanced solid tumors. Eligible tumor types include urothelial carcinoma of the bladder and SCCs of the bladder, lung, esophagus, tongue, skin, and anogenital region (penis, anus, vagina, vulva, cervix, and urethra). Subjects must have locally advanced or metastatic disease that has relapsed from, or is refractory to, standard-of-care therapies. Study objectives include assessing the safety, efficacy, pharmacokinetics and pharmacodynamics of EVOLVE104 and identifying the recommended phase 2 dose (RP2D). The phase 1a portion of the study will enroll up to 80 subjects using a Bayesian optimal interval (BOIN) dose-escalation scheme including backfill at dose levels deemed safe, with a key objective to identify one or more recommended doses for expansion (RDEs). Phase 1b includes two expansion cohorts: Cohort A, which will be a dose optimization cohort in a single indication (to be determined based on the phase 1a observations) in which 40 subjects will be randomized 1:1 to two RDEs to determine the RP2D; and Cohort B, which will enroll up to 40 subjects in other relevant indications. The study opened in October 2025 and is actively enrolling at US sites. ClinicalTrials.gov Identifier: NCT07217171. Clinical trial information: NCT07217171 .

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2026-05-27 | Neoadjuvant Treatment for Penile Cancer: A Systematic Review of Contemporary Evidence.

Background/Objectives: Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which survival declines sharply once regional lymph nodes are involved. Neoadjuvant therapy is recommended for clinically node-positive disease to improve resectability and address micro-metastatic spread; however, the supporting evidence remains limited. We systematically reviewed contemporary data on neoadjuvant strategies for penile SCC, including cytotoxic chemotherapy, radiotherapy, immunotherapy, and molecularly targeted agents. Methods: A systematic search of MEDLINE, EMBASE, ClinicalTrials.gov, and CENTRAL was conducted from inception to January 2026 in accordance with MECIR guidance. Eligible studies included patients with histologically confirmed penile cancer treated with neoadjuvant intent prior to curative surgery. Primary outcomes were objective response rate (ORR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Data were synthesised narratively by treatment modality. Results: Forty-two studies met the inclusion criteria (32 chemotherapy, five radiotherapy, five immunotherapy, three targeted therapy). The evidence base was dominated by retrospective cohorts with limited prospective phase II data and no completed randomised trials. Across chemotherapy studies, the median reported ORR was 50% (range 29-90%), with pCR/ypN0 rates ranging 10-25%. Median reported PFS and OS were approximately 11 and 18 months, respectively, with durable survival concentrated among responders undergoing complete surgical consolidation. Radiotherapy data were sparse and heterogeneous. Early-phase immunotherapy combinations reported higher short-term response and pCR signals than historical chemotherapy, though the results were based on small single-arm cohorts. Molecularly targeted systemic monotherapy demonstrated modest activity. Conclusions: Neoadjuvant taxane-platinum-based chemotherapy remains the guideline-supported standard for cN2-3 penile SCC, supported by phase II and retrospective data but limited by methodological heterogeneity and absence of randomised evidence. Emerging combination immunotherapy strategies show promising efficacy signals and warrant prospective validation within biomarker-informed trial frameworks.

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2026-04-15 | The Immune Microenvironment in Penile Squamous Cell Carcinoma: Distinctions Between HPV-Driven and HPV-Independent Pathways

Background: Penile squamous cell carcinoma (pSCC) is a global health burden with poor systemic treatment efficacy for advanced disease, relying on pathway-agnostic regimens despite two distinct carcinogenic pathways (HPV-driven vs. HPV-independent). We conducted an integrative review to systematically compare the tumor immune microenvironment (TIME) of HPV-driven and HPV-independent pSCC to guide immunotherapy stratification. Methods: An integrative review of 21 studies, including single-cell/spatial transcriptomics and a Phase II clinical trial, synthesized evidence from over 4,500 pSCC patients published between January 2020 and April 2026. Results: HPV-positive pSCC presents an immunologically active but partially suppressed TIME, defined by significantly higher CD8+ T-cell infiltration and lower immune checkpoint co-expression and exhaustion (e.g., TIGIT). HPV-negative tumors exhibit a broadly immunosuppressive niche marked by elevated PD-L1 prevalence (51.4% pooled), increased regulatory T-cell and M2-macrophage polarization, and multi-checkpoint co-exhaustion (PD-1, TIM-3, LAG-3). PD-L1 overexpression is associated with shorter cancer-specific survival. Clinically, HPV positivity and CD8+ T-cell density independently predicted progression-free survival benefit from atezolizumab. Conclusion: These findings establish HPV status and TIME composition as actionable determinants of immunotherapy benefit. We recommend prospective integration of HPV testing and tumor-infiltrating lymphocyte quantification into future randomized trials to guide patient selection and explore combinatorial checkpoint blockade, particularly for the multi-exhausted HPV-negative disease subset.

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2026-07-27 | Vaccine Therapy for the Management of Penile Cancer: Evidence, Opportunities and Challenges.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies.

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2025-12-18 | Prevalence and time trends of human papillomavirus in penile cancer over 26 years-A comprehensive study of 1040 penile cancer cases from Denmark.

Penile cancer is rare. It has been suggested that approximately half are human papillomavirus (HPV) associated, but large-scale studies on HPV prevalence and time trends are limited. We aimed to examine the high-risk HPV (hrHPV) prevalence in a large single-country study of penile squamous cell carcinomas (SCC) during a 26-year period. From the nationwide Danish Pathology Register, we identified all penile SCCs diagnosed during the period 1995-2020 at hospitals covering most regions in Denmark. Histologic slides were evaluated by expert pathologists, and archived tumor tissue was tested for the presence of HPV DNA using the INNO-LiPA assay. We assessed the overall and type-specific HPV prevalence according to calendar period, age, and histology, and estimated the annual percentage change (EAPC) of hrHPV positivity over the entire study period. We included 1040 penile SCCs. The overall HPV prevalence was 54.5% and the hrHPV prevalence was 50.4%. We observed no change in the prevalence of hrHPV over time (EAPC = -0.03% [95% confidence interval: -0.91; 0.85]). HPV16 was the most prevalent genotype (41.1%), and 50.0% of the penile SCCs had an HPV type that would be covered by the nine-valent HPV vaccine (HPV6/11/16/18/31/33/45/52/58). Penile SCCs with HPV-associated histological features had the highest hrHPV prevalence, particularly tumors exhibiting basaloid features (81.8%-87.7%). In this large population-based study, covering most regions in Denmark, we found no substantial change in hrHPV prevalence during 1995-2020. Our findings suggest that prophylactic vaccination with the nine-valent HPV vaccine could prevent a considerable part of penile SCCs in Denmark.

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2025-09-27 | Evaluating the Evolving Treatment Landscape of Systemic Therapies in Penile Cancer.

Penile squamous cell carcinoma (PSCC) represents a malignancy with low incidence. Despite advances in chemotherapy-based management, outcomes for patients with locally advanced and metastatic disease remain poor, with 5-year survival rates of 51% and 9%, respectively. Early diagnosis is crucial, yet psychosocial/structural barriers often delay it. Treatment strategies are stage-dependent, ranging from organ-sparing surgery and targeted radiotherapy for early-stage disease to cisplatin-based chemotherapy for locally advanced and metastatic cases. However, systemic therapies provide modest survival benefits and can expose the patient to unnecessary toxicities. Immunotherapy has emerged as a promising area, given the high expression of PD-L1 in PSCC and the significant proportion of HPV-driven tumors. Although initial results from immunotherapy-based trials are limited, preliminary trials such as HERCULES, ALPACA, PULSE, and PERICLES aim to define their role better. Similarly, combination regimens utilizing toripalimab in combination with nimotuzumab and taxane-based chemotherapy (TNT) followed by consolidative surgery are currently underway. Furthermore, the development of therapeutic HPV vaccines offers a novel strategy to enhance local antitumor immunity. Antibody-drug conjugates (ADCs) targeting HER-2, Trop-2, and Nectin-4 antigens represent another evolving therapeutic avenue that has shown preliminary promising results. As the landscape of penile cancer treatment continues to grow, incorporating these novel strategies could further improve survival outcomes and/or offer improved quality of life. This review provides a comprehensive overview of emerging systemic therapies in PSCC, underscoring ongoing research efforts to address unmet needs.

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2025-09-05 | Etiologic fraction of HPV-attributed anal and penile squamous cell carcinoma: study in specialized hospitals, Sri Lanka

Introduction The Human Papilloma Virus (HPV) infection is known to cause anogenital cancers. Male HPV prevalence and population-attributable risk (PAR)are important to plan future HPV preventive strategies for HPV-driven anogenital cancers in males. Methods A hospital-based case-control study was carried out to determine the etiologic fraction attributed to HPV-driven anal and penile(anogenital) cancers among male patients presenting to tertiary care hospitals in Gampaha district and Apeksha Hospital (cancer specialized), Sri Lanka and to calculate PAR percentage on anogenital SCC among the study population where HPV prevalence was 5.7%. New or already diagnosed patients for anal and penile SCC who reported to selected hospitals from August 2022 to June 2023 were recruited for data and specimen collection. A sample size of 20 cases and 80 controls were selected, with four controls chosen per case from sexually active, clinically normal men aged 20-70 years residing in the Gampaha district. Additional etiological factors that were checked included the presence of sexually transmitted infections, phimosis, anogenital injury, and the use of tobacco, alcohol or illegal drugs. The chi-square test was used at the level p<0.05 significance. Bivariable and logistic regression analyses were used to calculate odds ratios (ORs). Results A significantly associated factor for getting anal and penile SCC was HPV infection (p<0.001; adjusted OR: 27.7; 95% CI: 4.3,177.8).For any HPV genotype & high-risk HPV genotype, prevalence was 55% & 50% among cases and 5% & 2.5% among controls respectively. Assuming prevalence among controls as the population prevalence, the calculated PAR% was 62.2% for any HPV genotype and 33% for the HPV 16 HR genotype. Conclusions Sixty-two per cent of the anal and penile SCCs were attributed to any HPV genotype and one-third of anal and penile SCCs can be prevented by introducing HPV 16 genotype-containing vaccine to male.

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2025-05-28 | Effect of exosome-derived lncRNA on MAL + CTL apoptosis in remodeling of the immune microenvironment in HPV + penile squamous cell carcinoma.

e17022 Background: Patients with HPV + PSCC have a poor prognosis, and the immune escape mechanisms remain a major challenge in improving clinical outcomes. This study aims to investigate the role of exosome-derived long non-coding RNAs (lncRNAs) in modulating the immune microenvironment, particularly through their interaction with MAL + CTLs in HPV + PSCC. Methods: We collected tumor samples from HPV + PSCC patients and performed scRNA-seq to analyze the distribution and functional state of immune cells within the tumor microenvironment. Spatial transcriptomics were employed to explore the spatial localization of Tregs and CTLs within the tumor. Exosomes were isolated from the culture media of Treg cells and analyzed for the presence of lncRNAs. Additionally, the interaction between exosome-derived lncRNAs and miRNAs, particularly hsa-miR-619-3p, was examined in vitro. The impact of exosome-derived lncRNAs on MAL + CTL apoptosis was assessed using flow cytometry and apoptosis assays. Results: Our clinical data and scRNA-seq analysis revealed that HPV + PSCC tumors are characterized by an increased proportion of Treg cells and a decreased presence of CD8 + CTLs compared to HPV- PSCC or normal tissues. Importantly, we observed a significant correlation between the number of Tregs and the severity of immune suppression in HPV + PSCC. Spatial transcriptomics further revealed that Tregs were predominantly located in close proximity to CD8 + CTLs within the tumor microenvironment, suggesting potential interactions between these cell populations. Interestingly, exosome isolation from Tregs confirmed the presence of exosome-derived lncRNAs, which were shown to significantly alter the miRNA profile in surrounding immune cells. Specifically, we identified that exosome-derived lncRNAs from Tregs bound to hsa-miR-619-3p, a miRNA previously linked to T-cell dysfunction and immune evasion. We further demonstrated that this interaction led to an increase in MAL expression in CTLs, which in turn triggered their apoptosis. Flow cytometry analysis revealed that exposure to exosome-derived lncRNAs from Tregs resulted in a significant increase in MAL + CTLs and a concomitant increase in CTL apoptosis. Besides, the in vivo experiments using HPV + PSCC xenografts in mice showed that Treg-derived exosomes significantly impaired anti-tumor immunity, leading to increased tumor growth and reduced CTL infiltration in the tumor. Importantly, inhibition of MAL expression in CTLs by RNA interference rescued CTL function and partially restored anti-tumor immunity, confirming the pivotal role of MAL + CTLs in immune suppression. Conclusions: Our findings reveal a novel mechanism of immune evasion in HPV + PSCC, where Tregs secrete exosome-derived lncRNAs that interact with miR-619-3p to upregulate MAL expression in CTLs, leading to their apoptosis.

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