Prospective Single-arm Clinical Trial Research Articles

Subcutaneous Interleukin-2 Monotherapy for Metastatic Renal Cell Carcinoma in Korean Patients

Purpose: This study was a prospective single-arm clinical trial aimed at assessing the efficacy and toxicity of subcutaneous interleukin (IL)-2 monotherapy in patients with metastatic renal cell carcinoma (RCC).Materials and Methods: We enrolled 26 patients with metastatic RCC in this multicenter controlled trial. The patients received subcutaneous injections of recombinant IL-2 (BMI-rh-IL2, an aldesleukin biosimilar, BMIKOREA Co., Ltd.) in 5-week cycles. In the first week, the patients received a subcutaneous IL-2 loading dose of 18×10<sup>6</sup> IU once on treatment days 1–5, followed by 2 days of rest. In the following 3 weeks, they received a dose of 18×10<sup>6</sup> IU via subcutaneous injection once on treatment days 1 and 2. Then, the patients received a dose of 9×10<sup>6</sup> IU via subcutaneous injection once on treatment days 3, 4, and 5, followed by 2 days of rest. The primary end point was the objective response rate; the secondary end points were progressionfree survival (PFS) and safety.Results: Overall, 22 patients were included in the final per-protocol analysis. The objective response and the disease control rates were 13.64% (3 of 22), and 90.9% (20 of 22), respectively. The mean PFS was 5.55 months (95% confidence interval, 2.71–8.4). The proportion of patients who experienced a treatment-related grade 3 or 4 adverse event was 3.85% (1 of 26). There were no treatment-related deaths.Conclusions: In this study, the subcutaneous IL-2 monotherapy regimen demonstrated efficacy and safety comparable to those reported in previous studies of subcutaneous IL-2 monotherapy and was effective in Korean patients with metastatic RCC.

Peptide GAM immunoadsorption in anti-PLA2 R positive autoimmune membranous nephropathy. The PRISM trial.

Membranous nephropathy associated with anti-PLA2 R autoantibody is a significant cause of nephrotic syndrome worldwide. Treatment remains empiric with a significant side-effect burden despite an increase in our understanding of the disease. We studied the effect of selectively removing this pathogenic autoantibody using immunoadsorption in adult patients with biopsy proven anti-PLA2 R membranous nephropathy. This was a multicenter, single-arm prospective clinical trial carried out in the United Kingdom. Twelve patients underwent five consecutive sessions of peptide GAM immunoadsorption with 12 months follow-up. Primary outcome was anti-PLA2 R titer at week 2. Secondary outcomes were safety and tolerability of therapy, antibody profile, and change in proteinuria, renal excretory function, serum albumin, total immunoglobulin, and quality of life at weeks 12, 24, and 52. Patients were also stratified by the presence or absence of the high-risk allele (heterozygous or homozygous for HLA-DQA1*05). Median pretreatment anti-PLA2 R was 702.50 U/mL, 1045.00 U/mL at week 2 (P-value .023) and 165.00 U/mL at week 52 (P-value .017). The treatment was well tolerated and safe. Two patients required rescue immunosuppression during the follow-up period. There was a significant improvement in serum albumin with a median at baseline of 20.50 g/L rising to 25.00 g/L at week 52 (P-value <.001). There was no statistical difference over the follow-up period in proteinuria or renal function. Patients in possession of a high-risk allele saw improvement in anti-PLA2 R titers, possibly representing a cohort more likely to benefit from immunoadsorption. Immunoadsorption therapy is a safe treatment and well-tolerated treatment in anti-PLA2 R positive autoimmune membranous nephropathy.

Accuracy of Endoscopic Transpapillary Gallbladder Drainage with Liquid-Based Cytology for Gallbladder Disease

Introduction: Gallbladder carcinoma is often difficult to distinguish from benign gallbladder diseases. While the diagnostic accuracy of endoscopic transpapillary gallbladder drainage (ETGD) has been reported, these results were obtained retrospectively. This prospective study aimed to evaluate the cytological diagnostic accuracy of ETGD in patients with gallbladder disease. Methods: This single-arm prospective clinical trial included a total of 35 patients scheduled to undergo ETGD between March 2017 and September 2019. A 5F pigtail nasobiliary drainage tube was inserted into the gallbladder, and bile was collected over 5 times; if ETGD failed, a drainage tube was placed into the bile duct. The endpoints were, first, the cytological diagnostic accuracy of ETGD and, second, technical success rates and adverse events. Results: Of the 35 patients, 19 were finally diagnosed with gallbladder cancer. The success rate of ETGD tube insertion was 85.7%, and the morphological pattern of the cystic duct with the angle down and located on the right side had a significantly lower success rate for ETGD than that of other cystic duct patterns (odds ratio, 13.5; 95% confidence interval, 1.7–143.7; p = 0.02). Cytological samples were collected 5 times on median. The sensitivity, specificity, and accuracy in all patients were 78.9%, 100%, and 88.6%, respectively, while those in 30 patients with successful ETGD were 87.5%, 100%, and 93.3%, respectively. Adverse events occurred in 3 patients: mild pancreatitis in 1 patient and obstructive jaundice in 2 patients; all complications were resolved with conservative therapy. Discussion/Conclusions: Cytology using an ETGD tube is useful in differentiating benign and malignant gallbladder diseases (Clinical Trial Registry No. UMIN000026929).

Efficacy and Safety of Hepatitis B Virus Vaccination Following Hepatitis B Immunoglobulin Withdrawal After Liver Transplantation

Hepatitis B immunoglobulin (HBIG) and oral nucleoside/nucleotide analogs have been the mainstay of hepatitis B virus (HBV) prophylaxis after liver transplantation. However, long-term HBIG administration could have disadvantages, such as an increase in medical costs and the development of mutant HBV strains. This study aimed to investigate the safety and efficacy of HBV vaccination after the withdrawal of HBIG after liver transplantation. This prospective open-label single-arm observational clinical trial enrolled 41 patients who underwent liver transplantation between 2010 and 2016 because of a condition related to chronic HBV infection. At the time of enrollment, all patients had taken entecavir and discontinued HBIG administration. When hepatitis B surface antibody titer was undetectable after the withdrawal of HBIG, a recombinant HBV vaccine was injected intramuscularly at month 0, 1, and 6. After excluding 5 patients who dropped out and 2 patients who had a persistent hepatitis B surface antibody titer, 9 (26.5%) of 34 patients had a positive vaccination response. The median hepatitis B surface antibody titer at seroconversion was 86 (12-1000) IU/L, and those at the end of follow-up were 216 (30-1000) IU/L. No patients experienced HBV recurrence during the study period. Sex (female, odds ratio 32.91 [1.83-592.54], P=.018) and the dosing interval of HBIG before withdrawal (≥90 days, 16.21 [1.21-217.31], P=.035) were independent contributing factors for positive response to the vaccination. HBV vaccination still deserves consideration as active immunoprophylaxis after liver transplantation because it could provide added immunity to nucleoside/nucleotide analogs monotherapy with excellent cost-effectiveness.

Ethnic and Racial (E/R) Differences in Early-Stage Breast Cancer Patients (Pts) Successfully Treated With Intra-Operative Radiation Therapy (IORT) Using Electronic Brachytherapy

<h3>Purpose/Objective(s)</h3> E/R differences in early-stage breast cancer treatment outcomes are multifactorial. Women of Caucasian, Hispanic, Afro-American, Asian, Native American and other E/R who were ≥ 40 years with biopsy-proven breast cancer (invasive ductal carcinoma, ductal carcinoma in situ) ≤ 30 mm were consented in a prospective single-arm institutional review board-approved multi-institution clinical trial designed to determine the efficacy and outcome of single fraction IORT. E/R cohorts were analyzed for differences. <h3>Materials/Methods</h3> Between May 2012 and July 2018, 1200 enrolled pts were treated per protocol with lumpectomy plus a single 20 Gy fraction of IORT using disposable balloon electronic brachytherapy. Local standards of care guided adjuvant medical therapy. Follow-up was at 6, 12, and 18 months then yearly. Data collection included demographics, histopathology, prognostic factors, medical therapy, local recurrence (LR), and survival. Statistical analysis was performed using the Exact Chi-square, 2-sided test. <h3>Results</h3> 1200 pts (mean age: 66 years) had successful breast cancer treatment (mean size: 11.7 mm) using single fraction IORT per protocol. Median follow-up was 4 years. E/R was identified in 1162 pts. "Caucasian" was listed as the E/R in 950 (81.8%) pts (Body Mass Index (BMI): 29.2; Post-menopausal (PM): 92%, Grade (Gr) III/High: 15.9%, Triple Negative prognostic factors (TN): 1.6%). "Hispanic" was the E/R listing in 85 (7.3%) pts (BMI: 30.2, PM: 96%, Gr III/High: 20%, TN: 2.4%). "Afro-American" was the E/R listing in 81 (7.0%) pts (BMI: 32.8, PM: 92%, Gr III/High: 25.9%, TN:3.7%). "Asian" was the E/R listing in 40 (3.4%) pts (BMI: 26.2, PM: 90%, Gr III/High: 27.5%, TN: 0%). "Native American" was listed for 6 (0.5%) pts (BMI: 25.6, PM: 83%, Gr III/High: 16.7%, TN: 0%). Pt results by E/R, age, size, use of chemotherapy (Chemo), and LR are shown in Table 1. E/R cohort derived LR rates were not statistically different (<i>P</i> = 0.866). There was no breast cancer related death. <h3>Conclusion</h3> Utilization of single fraction IORT in this trial minimized known E/R disparities (access and delay in radiation therapy). Other E/R differences (BMI, menopausal status, tumor pathology and biologic factors, post-IORT breast cancer treatment) may have contributed to the reported E/R outcomes. Recurrence rates at median 4-year trial follow-up in Hispanics, Afro-Americans, and Asians were higher than that of Caucasian women, although the LR differences did not reach statistical significance.

18F-FLT PET/CT as a Prognostic Imaging Biomarker of Disease-Specific Survival in Patients with Primary Soft-Tissue Sarcoma.

The purpose of this study was to evaluate 18F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival and disease-specific survival (DSS) in soft-tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This was a 10-y follow-up of a previous single-center, single-arm prospective clinical trial. Patients underwent 18F-FLT PET/CT before treatment (PET1) and after NAT (PET2). Posttreatment pathology specimens were assessed for tumor necrosis or fibrosis and for Ki-67 and thymidine kinase 1 expression. Maximally selected cutoffs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1; 16 of the 26 with primary STS underwent PET2. Thirteen deaths occurred during a median follow-up of 104 mo. In the overall cohort, overall survival was longer in patients with a low than a high PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8.5 vs. <8.5: not yet reached vs. 49.7 mo; P = 0.0064). DSS showed a trend toward significance (P = 0.096). In a subanalysis of primary STS, DSS was significantly longer in patients with a low PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8 vs. <8; P = 0.034). There were no significant 18F-FLT PET response thresholds corresponding to DSS or overall survival after NAT at PET2. Conclusion:18F-FLT PET may serve as a prognostic baseline imaging biomarker for DSS in patients with primary STS.

Magnetic-Guided Axillary UltraSound (MagUS) Sentinel Lymph Node Biopsy and Mapping in Patients with Early Breast Cancer. A Phase 2, Single-Arm Prospective Clinical Trial.

Simple SummarySuperparamagnetic iron oxide nanoparticles (SPIO) have been shown to identify sentinel lymph nodes (SLNs) in patients with breast cancer. This study investigated whether a minimally invasive approach with MRI-LG after SPIO injection in the breast followed by a magnetic guided axillary ultrasound and core biopsy of the SLN (MagUS) could accurately stage the axilla. The study included not only patients planned for primary surgery but also patients with recurrent cancer after previous surgery, but also patients scheduled for neoadjuvant treatment (NAT). The latter underwent minimally invasive SLNB prior to treatment and had their SLN clipped; surgery in the axilla was performed after NAT. In 79 included patients, MagUS detected all patients with macrometastasis and performed comparably with surgical sentinel lymph node dissection (SLND). It also allowed for marking of the SLN in patients planned for PST and enabled tailored decision making in breast cancer recurrence.Lymph Node Dissection (SLND) is standard of care for diagnosing sentinel lymph node (SLN) status in patients with early breast cancer. Study aim was to determine whether the combination of Superparamagnetic iron oxide nanoparticles (SPIO) MRI-lymphography (MRI-LG) and a Magnetic-guided Axillary UltraSound (MagUS) with biopsy can allow for minimally invasive, axillary evaluation to de-escalate surgery. Patients were injected with 2 mL of SPIO and underwent MRI-LG for SN mapping. Thereafter MagUS and core needle biopsy (CNB) were performed. Patients planned for neoadjuvant treatment, the SLN was clipped and SLND was performed after neoadjuvant with the addition of isotope. During surgery, SLNs were controlled for signs of previous biopsy or clip. The primary endpoint was MagUS SLN detection rate, defined as successful SLN detection of at least one SLN of those retrieved in SLND. In 79 patients, 48 underwent upfront surgery, 12 received neoadjuvant and 19 had recurrent cancer. MagUS traced the SLN in all upfront and neoadjuvant cases, detecting all patients with macrometastases (n = 10). MagUS missed only one micrometastasis, outperforming baseline axillary ultrasound AUS (AUC: 0.950 vs. 0.508, p < 0.001) and showing no discordance to SLND (p = 1.000). MagUS provides the niche for minimally invasive axillary mapping that can reduce diagnostic surgery.

First-in-Human Clinical Application of the Medyria TrackCath System in Endovascular Repair of Complex Aortic Aneurysms (ACCESS Trial): A Prospective Multicenter Single-Arm Clinical Trial

Purpose: The Medyria TrackCath Catheter (MedTCC) is an innovative, thermal convection–based blood flow velocity (BFV) tracking catheter that may be used during complex aortic endovascular procedures for identification and catheterization of target orifices. The ACCESS Trial analyzes the safety and performance of the MedTCC for targeted vessel catheterization to generally evaluate the feasibility of thermal convection–based BFV. Materials and Methods: We performed a first-in-human, proof-of-concept, prospective single-arm multicenter clinical trial between March 2018 and February 2019 in patients who underwent endovascular aortic procedures at 4 high-volume centers. During these procedures, the MedTCC was advanced over a guidewire through the femoral access. The D-shape was enfolded in the reno-visceral part of the aorta and target orifices were identified and catheterized with a guidewire via the side port of the MedTCC through BFV tracking. BFV measurements were performed at baseline (Baseline-BFV), alignment to the orifice (Orifice-BFV), and following catheterization (Confirmation-BFV) to prove correct identification and catheterization of target orifices. The procedural success rate, the catheterization success rate, procedure-related parameters, and (serious) adverse events ((S)AE) during the follow-up were analyzed. Results: A total of 38 patients were included in the safety group (SG) and 26 in the performance group (PG). The procedural success rate was 89% (PG), the MedTCC catheterization success rate was 98% (PG). The MedTCC reliably measured BFV changes indicated by significant differences in BFV between Baseline-BFV and Orifice-BFV (p<0.05). Median (interquartile range; IQR) fluoroscopy time per orifice was 5.0 (1.5–8.5) minutes [total surgery 49 (26–74) minutes], median (IQR) contrast agent used per orifice was 1.0 (0–5.0) mL [total surgery 80 (40–100) mL], and median (IQR) MedTCC-based procedural time was 3.0 (2.0–6.0) minutes. There was no device-related SAE. Conclusions: The ACCESS Trial suggests that BFV measurement allows for reliable target orifice identification and catheterization. The use of MedTCC is safe and generates short fluoroscopy time and low contrast agent use, which in turn might facilitate complex endovascular procedures.

Graft Failure in Patients With Hematological Malignancies: A Successful Salvage With a Second Transplantation From a Different Haploidentical Donor.

Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days−6 to−2) and cyclophosphamide (1,000 mg/m2/day) (days−5 to−4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8–55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35–120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95–12.51) × 108/kg and CD34 + cells 2.28 (0.75–5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10–20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.

Abstract No. 4 Accuracy of scout dose Y90 liver biodistribution for personalized treatment planning of Y90 radioembolization of hepatocellular carcinoma: interim analysis of a prospective clinical trial

To evaluate the accuracy of scout dose Yttrium-90 (Y90) resin microspheres versus technetium-99m MAA (Tc99m-MAA) in predicting the therapeutic dose Y90 liver biodistribution for radioembolization (RE) planning in hepatocellular carcinoma (HCC) patients In a prospective single-arm clinical trial patients with HCC undergoing Y90 RE were recruited. Inclusion criteria included unilobar disease with ≤3 lesions with the largest lesion ≤ 7cm. Each patient underwent mapping angiography study with Tc99m-MAA and MAA SPECT/CT followed by second mapping study using 15 mCi Y90 resin microspheres and Y90 SPECT/CT and PET/CT. Prospective treatment planning with MAA data was performed using partition model with the goal of >200 Gy to the targeted tumor. Prescribed Y90 activity minus previously administered scout activity was administered 3 days after the mapping studies. Same microcatheter type and position were used for all stages of the study in each patient. Sureplan (MIM Software, Cleveland, OH) was used for all dosimetry analyses. Using paired t-test, the tumor:normal (TNR) calculated by MAA SPECT and scout dose Y90 SPECT and PET were compared to that of therapeutic dose Y90 SPECT and PET. First N = 15 patients treated in the clinical trial are included in this interim analysis. Mean TNR by MAA SPECT was 2.33. Mean TNR by scout dose Y90 SPECT and PET were 1.79 and 2.59, respectively. Mean TNR by therapeutic dose Y90 SPECT and PET were 1.75 and 2.65, respectively. MAA TNR was greater than both Y90 scout and therapeutic dose TNRs calculated by SPECT (Ps< 0.001). MAA TNR was statistically similar to both scout dose and therapeutic dose Y90 TNRs calculated by PET (P = 0.33 and P = 0.55, respectively). Y90 Scout and therapeutic dose TNRs calculated by SPECT were similar (P = 0.59) and the same finding was observed for Y90 TNRs calculated by Y90 scout and therapeutic dose PET (P = 0.74). Y90 scout dose is an accurate predictor of therapeutic Y90 dose biodistribution in the liver on both SPECT and PET, respectively. On the other hand, Tc99-MAA TNR was significantly greater than both Y90 scout and therapeutic dose TNRs on SPECT, whereas it was statistically similar to that of PET.

Abstract PS1-21: Molecular fluorescence-guided surgery using Beva800 for the assessment of tumor margins during breast conserving surgery of patients with primary breast cancer (MARGIN-II)

Abstract Introduction:The goal of breast conserving surgery (BCS) for early breast cancer (EBC) is to remove the tumor and a surrounding rim of normal tissue, while preserving as much of the normal breast tissue as possible. Incomplete resections are associated with higher rates of surgical re-excision. Repeat surgeries are not only a burden to patients physically but also psychologically and can delay recommended adjuvant therapies. Accurate determination of tumor margins during surgery is therefore critical for successful outcome. Breast cancer tissue produces significantly higher amounts of VEGF-A than healthy tissue. VEGF-A stimulates tumor angiogenesis and is therefore an excellent target for molecular imaging techniques. The fluorescence imaging agent bevacizumab-IRDye800CW (Beva800) is a conjugate of bevacizumab (a humanized antibody targeting human VEGF) and IRDye800CW (a near-infrared fluorescence dye) which binds specifically to VEGF-A. Beva800 provides a potentially highly efficacious approach to imaging specimen and cavity margins during BCS. Herein we present a phase II study that combined Beva800 with the SurgVision Explorer Air camera for intraoperative margin assessment during BCS for EBC.Methods:MARGIN II is a multicenter open-label single arm prospective clinical trial aimed at evaluating Beva800 for assessment of tumor margins in women with EBC scheduled for BCS. The study was a within-patient comparison of positive tumor margin rates using BCS standard of care compared to intraoperative assessment with 4.5 mg Beva800 and fluorescence imaging with the SurgVision Explorer Air camera. Patients undergoing neoadjuvant chemotherapy were excluded. All patients received a single intra-venous bolus injection of 4.5 mg of Beva800 three days before surgery. The fluorescent signal was visualized during surgery using NIR fluorescence imaging (700-1000 nm). This wavelength window typically has very low tissue auto-fluorescence (filtering out background noise) and greater tissue penetration depth due to reduced haemoglobin absorption. Standard of care assessment was defined as visual inspection, palpation and, in cases of pre-operative wire marking, specimen sonography or mammography. Beva800 efficacy was determined as the number of patients in which a pathology-confirmed positive margin was identified by fluorescence guided surgery using Beva800 but not by standard of care BCS. The results per patient were divided into two clusters: results after standard of care BCS and results after fluorescence guided surgery, according to their margin status at pathology. The need for re-operation because of involved margins within 30 days after the first BCS and the safety of 4.5 mg Beva800 was assessed.Results:The recruitment goal of 40 patients in 5 centers has almost been reached and results of the final analysis will be presented at the meeting.Conclusion:Molecular fluorescence-guided surgery using Beva800 has the potential to change the practice of breast conserving surgery by avoiding unnecessary re-operations. This would lead to fewer interventions, a reduced burden on patients through repeat surgery and reduced delay of adjuvant therapies. Citation Format: Hans-Christian Kolberg, Carmen Röhm, Angrit Stachs, Florian Schütz, Jens-Uwe Blohmer, Sarah Wetzig, Steffi Hartmann, Jörg Heil, Markus Hahn. Molecular fluorescence-guided surgery using Beva800 for the assessment of tumor margins during breast conserving surgery of patients with primary breast cancer (MARGIN-II) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-21.

Application of micronised acellular dermal matrix for primary premature ejaculation: A preliminary study.

This study aimed to explore the efficacy of injection of micronised acellular dermal matrix (MADM) particles for treating primary premature ejaculation. This study was a prospective single-arm clinical trial. Thirty patients who met the surgical indications were enrolled. MADM particles, mixed in platelet-rich plasma, were injected into Buck's fascia to spread over the dorsal penile nerve, suppress the influx of nerve impulses and, thus, reduce penis sensitivity. We evaluated the changes according to intravaginal ejaculation latency time using a stopwatch and a premature ejaculation diagnostic tool. Meanwhile, we also recorded sexual partner satisfaction and adverse events. All patients recovered well after surgery with no complications such as infections or allergies. The mean intravaginal ejaculation latency time before surgery was 0.72±0.28min, compared with 2.41±0.54min, 2.64±0.41min, 2.79±0.25min and 2.89±0.35min at, respectively, 4, 8, 16 and 20weeks after surgery. The premature ejaculation diagnostic values and sexual partner satisfaction had significantly improved after treatment. Injection of MADM particles is an effective, safe and simple method for treating premature ejaculation.

Clinical trial outcomes and thoracic aortic morphometry after one year with the Valiant Navion stent graft system

Authors' NoteOn February 17, 2021, Medtronic Incorporated issued a global voluntary recall of the Valiant Navion Thoracic Stent Graft System (the device under study in the Valiant Evo Global Clinical Program that is the subject of this publication), and instructed physicians to immediately cease use of the Valiant Navion system and return any unused product. Medtronic initiated the recall in response to three clinical trial subjects recently observed with stent fractures, two of whom have confirmed type IIIb endoleaks. The data collection, analysis, and manuscript submission occurred before the notice of this recall, and, specifically, the 100 procedures reviewed for this series were free of events at 1 year related to the reason for this device recall. The authors of this article and the manufacturer were unaware of the recently detected adverse events at the time of the preparation of the manuscript, and the 1-year trial results, and imaging-based analyses described are unchanged.Management of thoracic aortic aneurysms continues to be a challenging problem and outcomes are dependent on patient anatomy. The present publication focuses on the importance of achieving proximal and distal seals and the consideration of the temporal changes of the aortic morphology as a part of the TEVAR planning process. The authors believe there is still scientific merit in disclosing this information, despite the current nonavailability of the Valiant Navion system. ObjectiveThe Valiant Navion stent graft system (Medtronic Inc, Santa Rosa, Calif) is a third-generation device with improved conformability. We have reported the 1-year clinical trial outcomes, with a focus on an imaging-based analysis of the aortic morphology. We assessed the effects of graft implantation on the native anatomy and the effects of the 1-year changes in thoracic aorta morphology on the original seal zones of the stent graft. MethodsA total of 100 subjects were enrolled in a prospective single-arm clinical trial investigating the Valiant Navion stent graft system. An independent core laboratory (Syntactx, New York, NY) assessed the anatomic characteristics and performance outcomes. ResultsThrough 1 year of follow-up, the freedom from all-cause mortality, aneurysm-related mortality, and secondary procedures was 89.8%, 97.0%, and 94.8% respectively. Of the 100 patients, 5 had undergone a total of six secondary procedures, and 9 patients had developed an endoleak (type Ia and Ib in 1, type Ia in 1, type Ib in 3, and type II in 4 patients) within the first year. After 1 year, 2 of 76 patients (2.6%) had had an increase in their maximum aneurysm diameter of ≥5 mm, 62 (81.6%) had had stable sacs, and 12 (15.8%) had experienced sac shrinkage. Although no deployment failures had occurred, 36 of the 100 proximal (36%) and 31 of the 100 distal (31%) attachment zones were considered short according to our definitions. The stent graft had conformed to the native anatomy at implantation, because the preprocedural thoracic aorta tortuosity (1.45 ± 0.02) had not significantly changed at 1 month after implantation (1.46 ± 0.02). Despite a natural increase in thoracic tortuosity after 1 year (1.49 ± 0.02), wall apposition had been maintained over time, as evidenced by the low endoleak rates. Aortic elongation and dilation had occurred at the proximal end of the graft by an average of 1.2 mm and 1.6 mm, respectively. Aortic remodeling was more pronounced at the distal end, with an average increase of 4.2 mm in length and 2.8 mm in diameter. ConclusionsThe included patients had had positive 1-year outcomes with high freedom from mortality, endoleak development, and secondary procedures. Aortic elongation and dilation were more prevalent at the distal end, emphasizing the importance of distal attachment zone consideration as part of preoperative planning. Because aortic remodeling can be expected to continue over time, additional follow-up and imaging analysis in the trial will be necessary to assess the aortic morphology and its effects on stent graft performance.

Endovascular Repair of Aortic Dissection Involving the Left Subclavian Artery by Castor Stent Graft: A Multicentre Prospective Trial

The left subclavian artery (LSA) origin can be intentionally covered by stent grafts, to provide adequate proximal landing zones during thoracic endovascular repair for Stanford type B aortic dissections (TBADs). To preserve the LSA, a novel single branched stent graft, named “Castor” was designed and a clinical trial conducted to investigate its suitability. From April 2013 to March 2015, 73 patients with TBAD were treated by Castor stent grafts at 11 Chinese tertiary hospitals as part of a single arm prospective clinical trial. There were 50 acute (<2 weeks [68.5%]) and 23 chronic aortic dissections (>2 weeks [31.5%]). The technical success rate was 97% (n = 71/73). The two failures were caused by occlusion of the branch section of the stent graft. There were four intra-operative endoleaks (two type Ia, two type B from the LSA). The endoleak rate was 5% (n = 4/73). There was one in hospital death and no major complications. The median follow up time was 61 months (range 48–72 months). The mortality was 5% (n = 4/73) within one year and 7% within six years (n = 5/73). Two deaths were of unknown cause and three were not related to the aorta. Two new entry tears were found on the proximal or distal edge of the stent graft and were retreated endovascularly. Six occlusions of the branch section of the Castor stent graft were found, and the follow up patency rate of the branch section was 93% (n = 63/68). Two intra-operative endoleaks were left during follow up and eventually disappeared according to the latest computed tomography angiograms. For patients with TBADs needing anchoring proximal to the origin of LSA, the Castor single branched stent graft may provide an easily manipulated, safe, and effective endovascular treatment.

Endovascular Repair of Aortic Dissection Involving the Left Subclavian Artery by Castor Stent Graft: A Multicentre Prospective Trial

The left subclavian artery (LSA) origin can be intentionally covered by stent grafts, to provide adequate proximal landing zones during thoracic endovascular repair for Stanford type B aortic dissections (TBADs). To preserve the LSA, a novel single branched stent graft, named "Castor" was designed and a clinical trial conducted to investigate its suitability. From April 2013 to March 2015, 73 patients with TBAD were treated by Castor stent grafts at 11 Chinese tertiary hospitals as part of a single arm prospective clinical trial. There were 50 acute (<2 weeks [68.5%]) and 23 chronic aortic dissections (>2 weeks [31.5%]). The technical success rate was 97% (n=71/73). The two failures were caused by occlusion of the branch section of the stent graft. There were four intra-operative endoleaks (two type Ia, two type B from the LSA). The endoleak rate was 5% (n=4/73). There was one in hospital death and no major complications. The median follow up time was 61 months (range 48-72 months). The mortality was 5% (n=4/73) within one year and 7% within six years (n=5/73). Two deaths were of unknown cause and three were not related to the aorta. Two new entry tears were found on the proximal or distal edge of the stent graft and were retreated endovascularly. Six occlusions of the branch section of the Castor stent graft were found, and the follow up patency rate of the branch section was 93% (n=63/68). Two intra-operative endoleaks were left during follow up and eventually disappeared according to the latest computed tomography angiograms. For patients with TBADs needing anchoring proximal to the origin of LSA, the Castor single branched stent graft may provide an easily manipulated, safe, and effective endovascular treatment.

A Novel Therapy-Resistance Transcriptional Signature Based on Single Cell Analysis in Kydar Clinical Trial

Substantial progress in the treatment of Multiple Myeloma (MM) extends survival for many patients (Pts), though most Pts eventually relapse and become therapy refractory. Patients with induction resistant multiple myeloma (IRMM), either primary refractory or early (≤18 months) relapse, have a particularly compromised survival. New treatment strategies and molecular biomarkers for patient stratification and effective clinical care are needed. We previously reported outcomes of KYDAR (NCT04065789) single-arm prospective clinical trial, in which pts primary resistant to a bortezomib-based induction achieved high rates of durable responses when treated with carfilzomib/daratumumab/lenalidomide/dexamethasone (Cohen YC et al. Blood (2019) 134 (Suppl 1): 982). We applied comprehensive single cell RNA-seq analysis of plasma cells (PCs) obtained from longitudinal bone marrow aspirate samples, taken from KYDAR participants (n=34), compared to newly diagnosed MM Pts (n=15) and to healthy controls (n=11). We discovered a novel MM resistance signature differentially expressed between IRMM and newly diagnosed MM groups. This "gene module is enriched for several pathways that were perturbed in the IRMM Pts, including mitochondrial stress genes, the ER and UPR pathway, and the proteasome machinery. Furthermore, differential gene expression analysis between KYDAR responders and non-responders unveil potentially druggable escape mechanisms. These include upregulation of genes associated with immune regulation, proteasome, apoptotic and ER-stress pathways, e.g. Cyclophilin A (PPIA) creating an elaborated signature and potential target list of pathways and escape mechanisms from a highly potent quadruple therapy. This signature includes many novel genes which were not previously described in the context of MM (Fig 1A). Here we report external validation of this novel resistance signature among 908 MM Pts in the MMRF CoMMpass dataset. We found that our genes signature expression follows a normal distribution with no apparent sub-populations in naïve patients, but when examining Pts after multiple relapses, we detected gradient increase in our signature with a clear bi-model distribution (Fig. 1B). The prevalence of high module-1 expression was 5% in newly diagnosed Pts vs 14% in Pts in 3rd or subsequent relapse (p&amp;lt;0.001). Survival analysis on MMRF "module 1 high" (module 1 score &amp;gt; 200) Pts (n = 68) compared with the rest of the population (n = 711) revealed a striking hazard-ratio of 3.9 (2.22 - 6.87) with p-value = 4.57x10-17 (Fig 1C). Module-1 was highly predictive of treatment outcome in KYDAR trials, beyond FISH cytogenetics (Fig 1D). We hypothesized that PPIA may function as a protective resistance gene in MM malignant cells, by accelerating protein folding pathways and reducing stress associated to proteasome inhibitors. In order to test whether PPIA is merely a marker for highly resistant patients or has a causal role in MM resistance to proteasome inhibitors, we used Cyclosporine A (CsA), a known inhibitor of PPIA, in a series of in vitro experiments, to explore it's potential synergy with carfilzomib, a proteasome inhibitor, on RPMI-8226 and U266B MM cell lines, expressing high levels of PPIA. Using MTS proliferation assay, we found that the combined CsA and carfilzomib therapy was significantly more effective than carfilzomib alone. Apoptosis as measured by Propidium Iodide, DAPI and Annexin V FITC staining, was dramatically increased in the combination therapy setting compared to carfilzomib or CsA monotherapy (Fig 1E). In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials. We reveal and externally-validate a novel transcriptional signature for therapy resistance. We show inhibition of PPIA, a potential target identified, by CsA, overcomes relative resistance of MM cell lines to carfilzomib. We anticipate that such studies will significantly improve the ability to define mechanism of action of treatment, molecularly characterize the Pts that may benefit from the treatment, and reveal potential novel targets. Disclosures Tadmor: AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau.

CT Ventilation Image-Guided Lung Functional Avoidance Radiotherapy: A Single-Arm Prospective Pilot Clinical Trial

Lung functional avoidance radiotherapy (RT) that preferentially avoids irradiating functionally normal lung regions has the potential to reduce pulmonary toxicity after RT. The primary objective of this single-arm prospective pilot clinical trial (NCT02308709) was to assess the safety and feasibility of computed tomography (CT) ventilation image-guided functional avoidance RT. We herein report on the feasibility and dosimetric results. Patients with primary lung cancer or metastatic disease to the lungs to be treated with either conventionally fractionated RT (CFRT) or stereotactic body RT (SBRT) were eligible for this trial. All patients underwent 4-dimensional (4D) CT ventilation imaging during RT simulation based on a 4D CT scan, deformable image registration, and image analysis to quantify regional volume changes as surrogates for ventilation. Each patient required clinically-approved intensity-modulated RT plans for both standard anatomic RT and CT ventilation image-guided functional avoidance RT without compromising target coverage or adherence to constraints of organs at risk (OARs). The lung dose-function metrics were compared between the two plans using the paired two-tailed t test. The primary endpoint was the rate of grade ≥3 toxicities that occurred within 12 months after treatment, to be compared with predefined acceptable rates determined based on published toxicity data. Between May 2015 and November 2019, 34 patients were enrolled (25 patients with stage II-III NSCLC to be treated with CFRT with concurrent chemotherapy and 9 patients with stage I-II NSCLC to be treated with SBRT). One patient died before initiating RT. Of 33 evaluable patients, 32 patients received full dose (CFRT 60 Gy in 2 Gy daily fractions; SBRT 54 Gy in 3 fractions or 55 Gy in 5 fractions) and 1 patient chose to discontinue concurrent chemoradiotherapy due to grade 4 esophagitis. Compared with standard RT planning, functional avoidance RT planning significantly reduced the functional mean lung dose by 0.9 Gy (95% confidence interval [CI] 0.6-1.2 Gy; P < 0.01) (relative reduction 5.2%; 95% CI 3.5-6.8%) and the percentage of total lung function receiving ≥20 Gy by 4.2% (95% CI 3.0-5.4%; P < 0.01) (relative reduction 13.2%; 95% CI 10.5-15.9%) without compromising target coverage or adherence to constraints of OARs in patients treated with CFRT. In patients treated with SBRT, functional avoidance RT planning also significantly reduced the functional mean lung dose by 0.9 Gy (95% confidence interval [CI] 0.7-1.1 Gy; P < 0.01) (relative reduction 9.6%; 95% CI 6.6-12.7%). This pilot study demonstrates the feasibility of CT ventilation image-guided functional avoidance RT that significantly reduces the dose to functionally normal lung regions. Final toxicity results will be reported upon completion of the follow-up phase.

Enhanced recovery after surgery in laparoscopic distal gastrectomy: Protocol for a prospective single-arm clinical trial.

Background:The enhanced recovery after surgery (ERAS) programme is feasible and effective in reducing the length of hospital stay, overall complication rates and medical costs when applied to cases involving colonic and rectal resections. However, a recent prospective, randomised, open, parallel-controlled trial (Chinese Laparoscopic Gastrointestinal Surgery Study-01 trial), initiated by our team, indicated that under conventional peri-operative management, the reduction of the post-operative hospital stay of laparoscopic distal gastrectomy (LDG) is quite limited compared with open gastrectomy. Thus, if we could provide valuable clinical evidence for demonstrating the efficacy of the ERAS programme for gastric cancer patients undergoing LDG, it would significantly enhance the peri-operative management of gastrectomy and benefit the patients.Methods:In this prospective single-arm trial, patients who are 18–75 years of age with gastric adenocarcinoma diagnosed with cT1-4aN0-3M0 and expected to undergo curative resection through LDG, are considered eligible for this study. All participants underwent LDG with peri-operative management under the ERAS programme. The primary outcome measures included the post-operative hospital stays and rehabilitative rate of the post-operative day 4. The secondary outcome measures are morbidity and mortality (time frame: 30 days), post-operative recovery index (time frame: 30 days), post-operative pain intensity (time frame: 3 days) and the medical costs from surgery to discharge.Conclusion:With reasonable and scientific designing, the trial may be a great help to further discuss the benefit of ERAS programme and thus improving the peri-operative management of patients with gastrectomy.

Prospective Interventional Cohort Study of Ocular Surface Disease Changes in Eyes After Trabecular Micro-Bypass Stent(s) Implantation (iStent or iStent inject) with Phacoemulsification.

IntroductionThis study sought to assess ocular surface disease changes following cataract surgery combined with trabecular micro-bypass stent(s) implantation (iStent or iStent inject).MethodsThis prospective interventional single-arm clinical trial enrolled 47 eyes with mild-to-moderate open-angle glaucoma (OAG) on 1–4 glaucoma medications who underwent phacoemulsification and trabecular micro-bypass stent(s) implantation. Key glaucoma and ocular surface data through 3 months postoperatively included the Ocular Surface Disease Index score (OSDI), corneal/conjunctival staining (Oxford Schema), fluorescein tear break-up time (FTBUT), conjunctival hyperemia (Efron Scale), glaucoma medications, and intraocular pressure (IOP).ResultsMean OSDI scores improved from 40.1 ± 21.6 (severe) preoperatively to 17.5 ± 15.3 (mild) at 3 months (p < 0.0001). While 73% of eyes had moderate or severe OSDI scores preoperatively, 29% had such scores at 3 months, and the OSDI score was normal in 57% of eyes versus 9% preoperatively. Mean FTBUT increased from 4.3 ± 2.4 s preoperatively to 6.4 ± 2.5 s at 3 months (p < 0.0001); mean Oxford corneal/conjunctival staining reduced from 1.4 ± 1.0 preoperatively to 0.4 ± 0.6 at 3 months (p < 0.0001); mean Efron conjunctival hyperemia score reduced from 1.4 ± 0.7 preoperatively to 1.2 ± 0.6 at 3 months (p = 0.118). The number of glaucoma medications decreased from 1.5 ± 0.9 to 0.6 ± 0.8 mean medications (60% reduction, p < 0.0001), with all eyes maintaining or reducing medications versus preoperatively and 55% of eyes becoming medication-free (versus 0% preoperatively). Mean IOP reduced from 17.4 ± 4.2 mmHg to 14.5 ± 3.2 mmHg (p < 0.0001). The safety profile was excellent.ConclusionImplantation of trabecular micro-bypass stent(s) (iStent or iStent inject) with cataract surgery produced significant improvements in ocular surface health, alongside significant reductions in IOP and medications.Trial registrationClinicalTrials.gov identifier, NCT04452279.

Hypofractionated Radiotherapy in Locally Advanced Myxoid Liposarcomas of Extremities or Trunk Wall: Results of a Single-Arm Prospective Clinical Trial.

Introduction: Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas. The main objective of the study was to assess the efficacy of hypofractionated radiotherapy (RT) in the preoperative setting in patients with locally advanced primary MLPS. Methods: Single-arm prospective exploratory clinical trial enrolled MLPS patients for preoperative 5 × 5 Gy RT with delayed surgery. The endpoints of the study were the rate of early wound healing complications and 5-year local control rate. Results: 29 patients (pts) were included, all had tumors located on the lower limb. The median maximum size of the tumor was 13 cm (IQR 10–15 cm). Early RT tolerance was good. Postoperative wound complications occurred in 11 pts (37.9%), late complications concerned 13.8% of patients. A total of 27 patients were included for the efficacy analyses. The pathological features of response to RT were detected in all analyzed surgical specimens. In 25 patients R0 margins were achieved, two patients had an R1 resection. None of the patients had local recurrence. Conclusion: Preoperative hypofractionated RT with a prolonged gap between RT and surgery is a feasible method of the management of MLPS, providing a good local control and low rates of treatment toxicity.