• Saphenous sparing ascending video-endoscopic inguinal lymph node dissection (VEILND-AS plus ) using a leg approach: Surgical technique, perioperative and pathological outcomes

      Fankhauser, Christian D; Lee, Esther; Issa, Allaudin; Oliveira, Pedro.; Lau, Maurice W; Sangar, Vijay K; Parnham, Arie S; The Christie NHS Foundation Trust, Dept. of Urology, Manchester (2021)
      Introduction & Objectives: Open inguinal lymph node dissection (oILND) has a high morbidity. Video-endoscopic inguinal lymph node dissection (VEILND) represents a minimally invasive alternative with potential benefits. The aim of this study was to describe our saphenous sparing ascending video-endoscopic inguinal lymph node dissection (VEILND-AS+) using a leg approach and to compare the outcomes to our oILND experience. Materials & Methods: Retrospective cohort study of penile cancer patients undergoing either oILND or VEILND comparing perioperative and pathological outcomes. Results: In 206 men we performed 40 VEILND and 251 oILND. VEILND compared to oILND had a longer operation time (185 vs 120 minutes) but shorter hospital stay (2 vs 4 days). A median of 8 resected lymph nodes with a median of 1 affected node per groin was observed in both groups with extra nodal extension in 30% after VEILND and 35% after oILND. Both groups had a median of 13 days of drainage. Wound infections were observed in 38% after VEILND and 27% after oILND. Skin necrosis or wound break down occurred in 0% and 6% after VEILND and oILND, whilst lymphoceles were drained in 18% and 7% respectively. Following VEILND and oILND 20% and 14% were referred to lymph oedema clinic. Conclusions: In this video we describe our VEILND-AS+ technique and our data suggests that VEILND-AS+ is a safe procedure. Compared to oILND, VEILND-AS+ may offer a shorter hospital stay and possibly a lower risk of skin necrosis or wound break down. Further improvement of this and other VEILND techniques are required to decrease complications associated with dead space and injury to lymphatic vessels. This study is limited by its retrospective nature.
    • Subcutaneous (SC) epcoritamab induces complete responses across R/R B-cell NHL subtypes: Updated dose-escalation data

      Hutchings, M.; Mous, R.; Clausen, M. R.; Johnson, P.; Linton, Kim M; Chamuleau, M. E. D.; Lewis, D. J.; Balari, A. S.; Cunningham, D.; Oliveri, R. S.; et al. (2021)
      Background: Epcoritamab is a CD3CD20 bispecific antibody with a favorable safety profile and encouraging preliminary antitumor activity in both aggressive and indolent B-NHL in a phase I/II trial (NCT03625037). Updated dose-escalation data are reported here. Methods: Adults with R/R CD20+ B-NHL receive a SC 1 mL injection of flat-dose epcoritamab in 28-day cycles (q1w: cycles 1-2; q2w: cycles 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Objectives include safety and antitumor activity. Results: As of 6 July 2020, 67 patients (pts) were enrolled (DLBCL, 67%; FL, 18%; MCL, 6%). Pts were heavily pretreated, with a median (range) of 3.0 (1-6) prior lines of therapy for DLBCL and 4.5 (1-18) for FL. A total of 6 pts received prior CAR-T therapy. At median follow-up of 8.3 months, treatment is ongoing in 25 pts (37%). Epcoritamab was generally well tolerated, with no discontinuations due to treatment-emergent adverse events (TEAEs). The most common TEAEs were pyrexia (70%), local injection-site reactions (48%), and fatigue (45%). Observed TEAEs of special interest were cytokine release syndrome (CRS; all events were Gr 1/2 [58%], no Gr 3/4) and limited neurotoxicities (Gr 1, 3%; Gr 3, 3%; all transient). There were no DLTs, febrile neutropenia events, or deaths due to TEAEs. In pts with DLBCL treated with epcoritamab 12 mg (n¼18), ORR was 66.7% (6 CR). For pts who received higher doses (48 mg [RP2D], n¼4; 60 mg, n¼3) ORR was 100% (2 CR, 5 PR). All 4 DLBCL pts with prior CAR-T therapy achieved a response (2 CR, 2 PR). In FL (epcoritamab 0.76 mg, n¼8), ORR was 100% (2 CR). Responses (1 CR,1 PR) were observed in 2/4 pts with blastoid variant MCL. Conclusions: Epcoritamab demonstrates a consistent, favorable safety profile, with no Gr 3 CRS events and limited neurotoxicity, in support of future outpatient administration. Emerging data are encouraging, including CR in heavily y pretreated pts with DLBCL, FL, and MCL.
    • Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

      Eggermont, A. M. M.; Blank, C. U.; Mandala, M.; Long, G. V.; Atkinson, V. G.; Dalle, S.; Haydon, A. M.; Meshcheryakov, A.; Khattak, A.; Carlino, M. S.; et al. (2021)
      Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.
    • Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial

      Moss, J. G.; Wu, O.; Bodenham, A. R.; Agarwal, R.; Menne, T. F.; Jones, B. L.; Heggie, R.; Hill, Steve; Dixon-Hughes, J.; Soulis, E.; et al. (2021)
      Background: Hickman-type tunnelled catheters (Hickman), peripherally inserted central catheters (PICCs), and totally implanted ports (PORTs) are used to deliver systemic anticancer treatment (SACT) via a central vein. We aimed to compare complication rates and costs of the three devices to establish acceptability, clinical effectiveness, and cost-effectiveness of the devices for patients receiving SACT. Methods: We did an open-label, multicentre, randomised controlled trial (Cancer and Venous Access [CAVA]) of three central venous access devices: PICCs versus Hickman (non-inferiority; 10% margin); PORTs versus Hickman (superiority; 15% margin); and PORTs versus PICCs (superiority; 15% margin). Adults (aged ≥18 years) receiving SACT (≥12 weeks) for solid or haematological malignancy from 18 oncology units in the UK were included. Four randomisation options were available: Hickman versus PICCs versus PORTs (2:2:1), PICCs versus Hickman (1:1), PORTs versus Hickman (1:1), and PORTs versus PICCs (1:1). Randomisation was done using a minimisation algorithm stratifying by centre, body-mass index, type of cancer, device history, and treatment mode. The primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up. This study is registered with ISRCTN, ISRCTN44504648. Findings: Between Nov 8, 2013, and Feb 28, 2018, of 2714 individuals screened for eligibility, 1061 were enrolled and randomly assigned, contributing to the relevant comparison or comparisons (PICC vs Hickman n=424, 212 [50%] on PICC and 212 [50%] on Hickman; PORT vs Hickman n=556, 253 [46%] on PORT and 303 [54%] on Hickman; and PORT vs PICC n=346, 147 [42%] on PORT and 199 [58%] on PICC). Similar complication rates were observed for PICCs (110 [52%] of 212) and Hickman (103 [49%] of 212). Although the observed difference was less than 10%, non-inferiority of PICCs was not confirmed (odds ratio [OR] 1·15 [95% CI 0·78-1·71]) potentially due to inadequate power. PORTs were superior to Hickman with a complication rate of 29% (73 of 253) versus 43% (131 of 303; OR 0·54 [95% CI 0·37-0·77]). PORTs were superior to PICCs with a complication rate of 32% (47 of 147) versus 47% (93 of 199; OR 0·52 [0·33-0·83]). Interpretation: For most patients receiving SACT, PORTs are more effective and safer than both Hickman and PICCs. Our findings suggest that most patients receiving SACT for solid tumours should receive a PORT within the UK National Health Service.
    • Sequencing therapies in Hodgkin lymphoma

      Phillips, Elizabeth H; Collins, G. P; Cwynarski, K.; University of Manchester, The Christie Hospital and National Institutes of Health Research Manchester Biomedical Research Centre, Manchester M20 4BX, (2021)
      None
    • Radical hemiscrotectomy and en-bloc orchidectomy: Surgical technique, perioperative and oncologic outcomes of a supra-regional UK referral centre

      Fankhauser, Christian D; Issa, Allaudin; Lee, Esther; Oing, Christoph; Oliveira, Pedro; Parnham, Arie S; Oates, Jeremy E; Sangar, Vijay K; Gulamhusein, Aziz; Clarke, Noel W; et al. (2021)
      Introduction & Objectives: Several rare urogenital cancers arising from tissues of the spermatic cord, epididymis, testis or scrotal skin have a high risk of local recurrence. A radical resection by a hemiscrotectomy with or without en-bloc orchidectomy is therefore recommended to try to reduce this complication. Given the limited literature describing this surgery, we summarized our surgical technique, perioperative and oncological outcomes. Materials & Methods: Retrospective cohort study of 16 men treated at a supra-regional referral centre between 2010 and 2020. Results: Radical hemiscrotectomy and en-bloc orchidectomy was performed in 16 patients with a mean age of 56 years (range 20 to 80). Four men had a primary resection, 9 underwent completion surgery with the remaining 3 undergoing salvage surgery. In men with primary surgery 2 patients had well differentiated liposarcoma (WDLS), 1 rhabdomyosarcoma and 1 mammary type myofibroblastoma. Completion surgery was performed within a mean of 3 months (range 1-4 months) after initial diagnosis of dedifferentiated liposarcoma (DLS) in 4, WDLS in 2, leiomyosarcoma in 2 and mesothelioma in 1 patient. In the subsequent hemiscrotectomy specimens, 6 out of 9 (67%) showed no evidence of tumour whereas 3 patients had residual disease including LDS, WDLS and mesothelioma (Figure 3). Salvage surgery was performed in two patients 31 and 50 months after inguinal excision of a lipomatous mass which was incorrectly diagnosed as lipoma and reclassified on review as WDLS. The third patient with salvage surgery was operated 72 months after orchiectomy as the patient initially refused completion orchiectomy and failed to re-attend thereafter. The median hospital stay was 2 days (IQR 2–4). Four patients (25%) had 90-day postoperative complications. Two (12%) had wound infections requiring oral antibiotics (Clavien-Dindo II), with the remaining 2 (12%) developing a haematoma (Clavien-Dindo I) which was managed conservatively. During a median follow-up of 18 months (IQR 2-66), one patient (6%) initially presenting with locally advanced dedifferentiated liposarcoma measuring 130x50x48mm had recurrence. Metastatic disease in the pelvic and retroperitoneal lymph nodes was diagnosed 2 months after hemiscrotectomy with rapid clinical deterioration. He died 4 months after initial diagnosis despite palliative chemotherapy with Doxorubicin and Olaratumab. Conclusions: If careful dissection is performed, radical hemiscrotectomy and en-bloc orchidectomy is a radical but safe procedure with a short hospital stay. Haematoma and infection represent the main complications and within limited follow-up most men appear to be cured
    • Magnetic resonance guided adaptive Radiotherapy (MRgRT) for localised prostate cancer: The first result from a prospective international registry for the evidence-based Introduction of MRgRT

      Teunissen, F. R.; Willigenburg, T.; Tree, A. C.; Hall, W. A.; Choi, S. L.; Choudhury, Ananya; Christodouleas, J. P.; De Boer, J. C. J.; De Groot-Van Breugel, E. N.; Kerkmeijer, L. G. W.; et al. (2021)
      Introduction & Objectives: Magnetic Resonance (MR) guided adaptive radiotherapy (MRgRT) is a new technique for treatment of localised Prostate Cancer (PCa). MR-guided linear accelerator (MR-Linac) systems have been implemented in radiotherapy departments around the world. However, the theoretical benefits of MRgRT still need to be confirmed in clinical practice. We report the short-term outcomes for the first PCa patients treated within an international consortium on a 1.5T MR-Linac system with ultrahypofractionated radiotherapy. Materials & Methods: Patients treated with 5x7.25 Gray were identified within the registry. Prostate Specific Antigen (PSA), Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcome (PRO) using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-PR25, EORTC QLQ-C30 and the EuroQol EQ5D-5L were prospectively recorded at baseline and at 3 and 6 months follow-up (FU). Descriptive and pairwise comparative statistics were conducted. Results: One-hundred-and-fifty-six consecutive patients with localised PCa (13.2% low-, 77.2% intermediate-, and 9.6% high-risk [National Comprehensive Cancer Network risk groups]) were included. Thirty-one patients (19.9%) received neoadjuvant Androgen Deprivation Therapy (ADT). A significant decline of PSA in non-ADT patients was observed between baseline (median: 7.8 ng/mL), 3 months FU (median: 2.7 ng/ mL) and 6 months FU (median: 1.7 ng/mL) (p<0.001). No grade ≥3 Genitourinary (GU) and Gastrointestinal (GI) toxicity was reported (table). No significant deterioration of PRO scores were observed. The percentage of men reporting no difficulty getting or maintaining an erection remained constant throughout FU (44.4% at baseline, 40.0% at 3 months FU, and 42.9% at 6 months FU). Conclusions: Ultrahypofractionated 1.5T MR-Linac treatment of localised PCa is effective and safe (no grade ≥3 GU and GI toxicity). In the first 6 months following treatment, patients reported stable erectile function. No significant deterioration of PROs at 3- and 6-months FU was observed.
    • Is robotic surgery safe and feasible for horseshoe kidneys? A multicentre case series

      Ng, A.; Nathan, A.; Campain, N.; Fortune-Ely, M.; Patki, S.; Yuminaga, Y.; Mumtaz, F.; Gulamhusein, Aziz; Tran, M.; Barod, R.; et al. (2021)
      Introduction & Objectives: Horseshoe kidneys (HSK) are the most common renal fusion abnormality. However, they are only present in 0.2% of the population. Due to anatomical variation in vasculature, ectopia and malrotation, surgery has traditionally been performed via an open approach. Robotic surgery has been widely adopted for other urological procedures due to the superior ergonomics; high definition, 3D stereoscopic vision; and 7 degrees of freedom, providing a viable, less invasive surgical option. We aimed to assess the safety and feasibility of robot-assisted surgery for HSK. Materials & Methods: Retrospective data were collected for consecutive patients with HSK undergoing robotic surgery between 2016 and 2020 across two high-volume centres by experienced robotic surgeons. 3D reconstruction using CT renal angiograms were used to help identify vasculature and tumour location, where appropriate. Results: Seven patients underwent robotic surgery for HSK including three partial nephrectomies and one nephroureterectomy for renal masses and three benign nephrectomies for non-functioning kidneys. The median age was 53 years (IQR 44-57) and median BMI was 25 (IQR 25-26.5). Median tumour size in four patients with renal masses was 36 mm (IQR 25-45). Median console time was 120 minutes (IQR 118-215), median operating time was 170 minutes (IQR 155-247) and median estimated blood loss was 150 mL (IQR 125-250). The median pre-operative eGFR was 76 (IQR 72-90) and median post-operative eGFR was 71 (IQR 60-81). There was no grade III or higher Clavien-Dindo complication. There was one Clavien-Dindo II, wound infection complication, requiring a five-day length of stay. All other operations were uneventful and median length of stay was two days. Negative margins were achieved in 75% of tumour resections, and final histology demonstrated clear cell renal cell carcinoma (RCC), RCC, urothelial sarcomatoid and angiomyolipoma. Conclusions: We report one of the largest series of robotic-assisted surgery on HSK. Robotic surgery is safe and feasible for HSK in centralised high centres with acceptable perioperative outcomes, early oncological outcomes and morbidity comparable to standard renal surgery. A further prospective, multi-centre study is required to evaluate the role of robotic surgery in renal fusion anomalies.
    • Treatment-related toxicity using prostate bed versus prostate bed and pelvic lymph node radiation therapy following radical prostatectomy: A national population-based study

      Parry, M. G.; Sujenthiran, A.; Nossiter, J.; Morris, M.; Berry, B.; Cathcart, P.; Clarke, Noel W; Payne, H.; Van der Meulen, J; Aggawal, A.; et al. (2021)
      Introduction & Objectives: There is debate about the effectiveness and toxicity of pelvic lymph node (PLN) irradiation when used for disease recurrence following radical prostatectomy. This study compared the toxicity of radiation therapy (RT) to the prostate bed and pelvic lymph nodes (PBPLN-RT) with prostate-bed only radiation therapy (PBO-RT). Materials & Methods: Patients with prostate cancer who underwent post-prostatectomy RT in the English National Health Service between 2010-2016 were identified by using data from the Cancer Registry, the National Radiotherapy Dataset, and Hospital Episode Statistics, an administrative database of all hospital admissions. Follow-up was available up to December 31, 2018. Validated indicators were used to identify patients with ≥ Grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity according to the presence of both a procedure code and diagnostic code in patient Hospital Episode Statistics records. A competing risks regression analysis, with adjustment for patient and tumour characteristics, estimated subdistribution hazard ratios by comparing GI and GU toxicity for PBPLN-RT vs. PBO-RT. Results: 5-year cumulative incidences in the PBO-RT (n=5,087) and PBPLN-RT (n=593) groups was 18.2% and 15.9% for GI toxicity, respectively. For GU toxicity it was and 19.1% and 20.7%, respectively. There was no difference in GI or GU toxicity between PBO-RT and PBPLN-RT (GI: adjusted sHR, 0.90, 95% CI, 0.67 to 1.19; P=0.45); (GU: adjusted sHR, 1.18, 95% CI, 0.98 to 1.44; P=0.09). Conclusions: Including PLNs in the radiation field following radical prostatectomy is not associated with a significant increase in rates of ≥ Grade 2 GI or GU toxicity at 5 years.
    • Treatment options and outcomes of men with Penile Intraepithelial Neoplasia (PeIN): A systematic review

      Issa, Allaudin; Lee, Esther; Oliveira, Pedro; Lau, Maurice W; Parnham, Arie S; Sangar, Vijay K; Lucky, M.; Grossmann, N.; Fronzaroli, J.; Janisch, F.; et al. (2021)
      Introduction & Objectives: Penile intraepithelial neoplasia (PeIN) is a rare skin condition characterised by dysplastic changes of the epidermal squamous cells which does not extend beyond the basement membrane. Successful treatment options for PeIN with minimal side effects are essential as progression into invasive cancer may require more extensive surgery in a cosmetically sensitive anatomical location. Our aim was to systematically review the published literature for treatment options and outcomes of men with PeIN. Materials & Methods: We performed a systematic review to summarise treatment options and outcomes in the published literature using the electronic databases MEDLINE, EMBASE and Cochrane Database of Systematic Reviews. Results: Of 1594 publications 94 full-text manuscripts of publications were screened and finally 19 studies contributing 691 patients with PeIN were included. Topical therapies included imiquimod and Fluorouracil (5-FU) with complete response rates in 40-100% and 48-74% respectively. Progression after Imiquimod and 5-FU was observed in 20% and 11% respectively. Adverse events were observed in 10% during imiquimod and in 5-12% during 5-FU with the most common being local inflammation causing pain and severe irritation. Phimosis was observed in 5% treated with imiquimod. Discontinuation of treatment in men treated with imiquimod and 5-FU was described in 10% and 11% and one study reported that 11% of men treated with 5-FU were admitted to hospital because of severe inflammation and pain. There were several energy-based therapies discussed in the literature including Yag laser, CO2 laser and phototherapy. Laser treatment demonstrated higher rates of total response (52%-100%). Recurrence was reported in 7%-48%. A significant side effect following laser treatment was a change in penile sensitivity including increased sensitivity in 50% and decrease sensitivity in 15%. Phototherapy led to complete response in 40%-70% but recurrence was observed in 30% and progression in 36%. Surgical treatment of PeIN was associated with recurrence in 4%-30%. Circumcision cleared all preputial PeIN whereas recurrence after surgical treatment of PeIN of the glans was observed in 25% after wide local excision, 4% after Mohs surgery, 5% after total glans resurfacing and 10% after Glansectomy. Conclusions: In summary the data on treatment options and outcomes of men with PeIN is limited and based on small retrospective cohort studies. Our conclusion from the published literature is that circumcision represents the most effective treatment for preputial PeIN whereas several treatment options should be discussed in men with PeIN of the glans and ideally assessed in prospective studies.
    • Perioperative safety and short-term oncological outcomes of minimally invasive retroperitoneal lymph node dissection

      Fankhauser, C D; Afferi, L.; Stroup, S. P.; Rocco, N. R.; Olson, K.; Bagrodia, A.; Cazzaniga, W.; Mayer, E.; Nicol, D.; Islamoglu, E.; et al. (2021)
      Introduction & Objectives: Open Retroperitoneal Lymph Node Dissection (RPLND) is a treatment option in men with stage 1/2 testis cancer and the standard of care in men with post-chemotherapy retroperitoneal residuals. Minimally invasive RPLND (miRPLND) has been introduced but only limited data regarding safety and oncological outcomes are available. Materials & Methods: International, multicentre, retrospective cohort study describing patient characteristics, perioperative safety and oncological outcomes of men scheduled for miRPLND. Results: 406 men (14 sites, 8 countries) were studied. Laparoscopic RPLND was performed in 57 and robotic RPLND in 349 men. Indications included pre-chemotherapy RPLND in 261 including 8 with recurrence after one cycle of adjuvant chemotherapy for stage 1 disease and post-chemotherapy RPLND in 145. The median retroperitoneal mass size was 15mm (IQR 10-19, range 0-31) in pre-chemotherapy RPLND and 20 mm (IQR 15-30, range 0-104) in post-chemotherapy RPLND. Median operative time was 265 minutes (IQR 201-334). Median intraoperative blood loss was 75mL (IQR 50-200) with RBC transfusions in 11 men. Conversion to open surgery was performed in 13 (3%; access problems (6), bleeding complications (4) with blood loss of 1000-6000mL and extent of disease (3)). Intraoperative complications occurred in 15 (4%) men (bleeding (9), ureteric injury (4), bowel injury (1) and thoracic duct injury (1). Postoperative complications in 28 (7%) men included ascites and/or pleural effusion (11), deep vein thrombosis (6), wound infection (3), rhabdomyolysis (2), incisional hernia (2), post-operative bleeding requiring transfusion (1), clostridia difficile infection (1), limb compartment syndrome (1) and pneumonia (1). Median length of stay overall was 3 days (IQR 2-4) and in men with complications 4 days (IQR 2-6). Within the first 30 days after operation 20 men (5%) were readmitted. During a median follow-up of 13 months (IQR 4-28), relapse was observed in 25 men (6%). Unusual sites of recurrence included the peritoneum around the sigmoid and port site in 1 patient each. At the latest follow-up 401 (98%) men were disease free, 3 alive under treatment and 2 had died from progression. Conclusions: In an international cohort, low blood loss and short hospital stay was reported for selected men with small volume retroperitoneal disease undergoing pre- and post-chemotherapy miRPLND. Although complications were rare, miRPLND should only be performed in experienced high-volume centres and surgical teams should be prepared for emergency conversion to open surgery because massive bleeding can occur. Based on encouraging intraoperative safety data together with no concerning signal of peritoneal seeding during the short follow-up period, prospective studies of miRPLND in high volume centres are justified to further evaluate miRPLND technique, complications, functional and oncological outcomes.
    • Localised activation of the EMT switch by peri-neural invading epithelial cells in prostate cancer

      Brown, M.; Hart, C.; Sachdeva, A.; Oliveira, Pedro; Fankhauser, Christian D; Wedge, D; Clarke, Noel W; University of Manchester, Dept. of Genito Urinary Cancer Research, Manchester (2021)
      Introduction & Objectives: Invasion of the peri-neural space by malignant epithelial cell, known as Peri-neural Invasion (PNI), is an acknowledged prostate cancer (PCa) pathological feature associated with recurrence, increased risk of bone metastasis and poor survival. However the molecular mechanism underlying this pathology is relatively unknown. Here we assess the presentation of a metastatic phenotype by the peri-neural invading prostate epithelial cells, their spatial relationship to the tumour lesion and clinical outcome. Materials & Methods: FFPE blocks from an archival cohort (n=54) of radical prostatectomy patients, with associated full clinical history was retrieved under research ethics REC07/H1003/161+5 10_NOCL_02. Serial 4µm sections were stained using an automated multiplex TSA protocol on a Ventana Discovery platform for a panel of metastatic biomarkers (EphA2, pEphA2s897 , pMLC2, E-Cadherin, Vimentin, TOMM20, MTC01, NDUFB8, PTEN) along with the housekeeping landmark markers S100 (neural), pan-cytokeratin and DAPI. Slides were scanned on a Versa 3 platform with Halo image analysis. Prostate spatial zones were defined at 500µm intervals either side of the prostate capsule and pathological features were characterised. Univariate and multivariate (hierarchical clustering, UMap clustering) expression analysis and correlation with clinicopathological features was conducted within GraphPad Prism and R. Results: Marker expression analysis of the pooled (patient independent) PNI showed that all markers have significantly different expression levels dependent on their spatial location in relation to the prostate organ and tumour lesion (Kruskal Wallis p-value <2.2x10-16 except MCT01 (p=5.3x10-10)). Marker expression of amoeboid signalling (EphA2, pEphA2s897 , pMLC2) and mitochondrial defects (loss of Complex I/IV and gain of mitochondrial mass (TOMM20)), associated with a migrational switch to an activated metastatic phenotype in peri-neural invading epithelial cells in PNI close to the prostate edge but outside the tumour lesion correlates with a reduction in overall survival of 28 months (119 months 95%CI 0.3572-1.835 vs 147 months 95% CI 0.5451-2.8; p=0.0249). Conclusions: Peri-neural invading epithelial cells close to the edge of the prostate have features consistent with a switch metastatic behaviour in contrast to the tumour embedded peri-neural invading epithelial cells. This switch was associated with a significant reduction in overall survival.
    • Long term outcomes of Dynamic Sentinel Lymph Node Biopsy (DSNB) for clinically impalpable (cN0) penile cancer patients- an eUROGEN study

      Pozzi, E.; Cakir, O. O.; Castiglione, F.; Schifano, N.; Hadway, P.; Nigam, R.; Rees, R.; Albersen, M.; Parnham, Arie S; Lau, Maurice W; et al. (2021)
      Introduction & Objectives: Dynamic Sentinel Lymph Node Biopsy (DSNB) is routinely offered to patients presenting with penile cancer ³T1G2 and clinically impalpable inguinal lymph nodes (cN0). We aimed to assess the diagnostic accuracy of DSNB, Cancer Specific Survival (CSS) in patients with positive DSNB and positive LN at further Radical Lymph Node groin Dissection (RLND). Materials & Methods: An eUROGEN retrospective study of 509 penile cancer patients undergoing DSNB. Age, type of primary surgery, complications after DSNB, tumour stage, tumour grade were all reported. Number of true positives, true negatives, false negatives and false positives were recorded. False negative was defined as inguinal lymph node recurrence within 12 months from a previous negative DSNB. Sensitivity and specificity of DSNB were calculated. Kaplan-Meier analysis was used to estimate the 5-years CSS and recurrence free-survival rates among patients with positive DNSB and RLND. Results: Overall, 509 patients with cN0 penile cancer were identified. The median follow-up for local recurrence and CSS were 62.5 months (IQR 28.5-91) and 63.5 months (IQR 26.5-90) respectively. All patients underwent DSNB at the time of primary surgery or as a delayed procedure. A total of 993 groins were studied. 37 patients had positive histology at DSNB. 37 patients underwent further RLND with 34 of them having positive histology at RLND. At DSNB true positives were 37 (7.27%), false negatives 3 (0.59). Sensitivity and specificity were 92.5% and 100% respectively. Multivariable Cox regression analysis identified positive LN histology both at DSNB and at RLND as predictors for reduced CSS (HR 4.59, CI: 2.35-8.95, p<0.0001) and (HR 5.64, p=0.0004). Likewise, positive LN histology at DSNB and RLND was a predictor for reduced recurrence free survival HR 4.04 and HR 6.98 all p<0.0001. At Kaplan-Meier analysis, the 5-years CSS for positive LN histology at DSNB/RLND were 69.7% and 69.6% respectively.
    • Outcomes in men undergoing complex circumcision: An aid to consent and litigation

      Issa, Allaudin; Syed, K. B.; Fankhauser, Christian D; Oliveira, Pedro; Parnham, Arie S; Lau, Maurice W; Sangar, Vijay K; The Christie NHS Foundation Trust, Dept. of Urology, Manchester (2021)
      Introduction & Objectives: Circumcision is a common procedure and in complex pathology can be difficult even in expert hands. Litigation for unexpected or poor outcomes is also not uncommon. There is limited data on clinical outcomes in complex circumcision. Here we report initial data from a tertiary referral centre, to highlight complications which may help in consenting of patients. Materials & Methods: A retrospective cohort review of men undergoing a circumcision between 2015 and 2020 was performed. Review of operation notes, pre- & postoperative clinical notes and histology were utilized to record relevant parameters. We included men undergoing complex circumcision which included Redo-circumcision, circumcision for glans adherence (>50%), circumcision with the addition of: wide local excision glans lesion, excision of primary cancer of foreskin, urethral meatal dilatation. Those undergoing circumcision in the setting of a Glansectomy were excluded. Results: Records identified 197 cases of circumcision. Mean age 63.1 yrs, (21 – 92yrs). Of 97 complex circumcisions 24 were performed for pre-operative diagnosis of severe phimosis, 48 for suspected cancer, 13 for lichen sclerosis, 3 were redo circumcisions for residual penile cancer, 7 for PeIN and 2 for severe condylomata. 39 were confirmed cancer cases of which 19 were T1a and 17 T1b. 3 cases revealed T2. Grading of the malignant cases was 7 of grade 1, 15 of grade 2 and 17 grade 3. Complications occurred in 7%: 2 (2%) infections requiring antibiotics, 1 (1%) change in sensation and 1 (1%) patient unhappy with cosmesis. 3 (3%) patients complained of skin tightness. Bleeding, return to theatre within 30 days, erectile dysfunction, wound breakdown and glans dryness occurred at a rate of 0%. Circumcision alongside a further procedure in the same sitting was performed in 29 of the cases including 11 biopsies and 17 wide local excisions of lesions on the glans and 1 urethral dilatation. Positive margins reported in 3 cases they did not experience any post-operative complications. Conclusions: Complex Circumcision can be a difficult procedure. Our data show that when performed at a tertiary centre complications are lower than expected and cosmetic complaints are minimal. When complete this data will be beneficial in consenting and litigation
    • Post traumatic growth during COVID-19: unity in diversity

      Lakha, M. A.; Bhowmik, A.; Bisht, S.; Shrestha, S.; Gajanan, Kantappa; Shah, S.; Wrightington Wigan & Leigh NHS Foundation Trust (2021)
      Aims This poster reflects how the experience of staying with people of diverse nations and cultural background helped the stranded IMGs cope with this agony in a foreign land during an unprecedented tumultuous situation. The aim is to show that despite diversity among people, the hard times made them unite and overcome countless difficulties. Background The COVID 19 pandemic has been a period of global health crisis and has exponentially affected mental health issues in the world population. In these difficult times, several International Medical Graduates (IMGs), who had come to the UK to attend their PLAB exams, were left stranded as the exams were postponed, flights cancelled and borders sealed. Faced with huge uncertainty their mental health was of great concern. At this time the British Association of Physicians of Indian Origin (BAPIO) came forward to help this cohort of stranded doctors in terms of accommodation, finances, mental health support, preparation for exams to the extent of liaising with General Medical Council (GMC) and Home Office. The virtual support group provided a platform for IMGs from different nations and cultures to get in touch with each other helping overcome mental burden and stress. The stories presented in the poster show how unity in diversity helped these young doctors deal with mental trauma amidst the Pandemic. Method 276 doctors from 27 countries were looked after by BAPIO. From those excerpts taken from 26 IMGs, personal narratives was used as a method for qualitative assessment. The percentage of IMGs clearing their exams and getting jobs in the NHS has been used for quantitative assessment. Result Qualitative: The personal narratives of the IMGs show how they were positively impacted by staying together albeit different nationalities and cultural background. Quantitative: A total of 21 IMGs out of the 26 cleared their PLAB 2 exams and got registration under General Medical Council giving a percentage of 81.7%. 20 IMGs have successfully joined the NHS in various posts giving a job success rate of 95.2%. Conclusion The experience of living and sharing housings with people from different nationalities, has increased appreciation and also prepared them to work in the NHS which has a diverse work force. This learning experience has been integral for all of us in shaping our life in the UK making everyone more compassionate.
    • Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials

      Bourien, H.; Lamarca, Angela; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; Edeline, J; Department Of Medical Oncology, Centre Eugène Marquis, Rennes, France, France (2021)
      Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.
    • Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

      Koessler, T.; Alsina, M.; Arnold, D.; Ben-Aharon, I.; Lutz, M. P.; Obermannova, R.; Peeters, M.; Sclafani, F.; Smyth, E.; Valle, Juan W; et al. (2021)
      Last year the field of immunotherapy was finally introduced to GI oncology, with several changes in clinical practice such as advanced hepatocellular carcinoma or metastatic colorectal MSI-H. At the virtual ASCO-GI symposium 2021, several large trial results have been reported, some leading to a change of practice. Furthermore, during ASCO-GI 2021, results from early phase trials have been presented, some with potential important implications for future treatments. We provide here an overview of these important results and their integration into routine clinical practice
    • A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future

      Ren, S.; Xu, A.; Lin, Y.; Camidge, D. R.; Di Maio, M.; Califano, Raffaele; Hida, T.; Rossi, A.; Guibert, N.; Zhu, C; et al. (2021)
      Objective: This review summarizes the current status of neoadjuvant therapy and discusses the choice of new clinical research endpoints for non-small cell lung cancer. Background: Neoadjuvant chemotherapy is a recognized practice in patients with resectable and locally advanced lung cancer. With the introduction of molecular targeted drugs and immune checkpoint inhibitors (ICIs), the overall survival (OS) of patients with lung cancer has been significantly improved, and the original traditional clinical research endpoints are no longer suitable for existing clinical research. In order to accelerate the process of clinical trials and the development and approval of drugs, it is necessary to find suitable alternative indicators as the main indicators of clinical research. Methods: Therefore, this article focuses on clinical trials using disease-free survival (DFS), progression free survival, and pathological evaluation indicators, pathologic complete response and major pathologic response, as surrogate endpoints. We search related literature through PubMed database and clinical trials through clinicaltrials.gov. Conclusions: Pathologic complete response and major pathologic response are recommended as surrogate endpoints in the era of neoadjuvant immunotherapy, and secondary endpoints are listed for the prediction of pathological results. In addition, the definitions of major pathological response (MPR) and PCR should be standardized, and a new pathological evaluation standard should be developed, which is applicable to all current treatment methods.
    • Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data in ROS1+ NSCLC

      Doebele, R. C.; Perez, L.; Trinh, H.; Martinec, M.; Martina, R.; Riehl, T.; Krebs, Matthew G; Meropol, N. J.; Wong, W B; Crane, G.; et al. (2021)
      Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n = 94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n = 65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9-17.4) months for entrectinib; 8.8 (6.2-9.9) months for crizotinib (weighted hazard ratio, 0.72 [0.51-1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1-19.9) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.