Prospective Single-arm Clinical Trial Research Articles

800 - Impact of 68Ga-PSMA-11 PET on the management of biochemically recurrent prostate cancer in a prospective single-arm clinical trial

800 - Impact of 68Ga-PSMA-11 PET on the management of biochemically recurrent prostate cancer in a prospective single-arm clinical trial

Safety and efficacy of the SeparGate™ balloon-guiding catheter in neurointerventional surgery: Study protocol of a prospective multicenter single-arm clinical trial

BackgroundThe balloon-guiding catheter (BGC) reportedly reduces the number of retrievals and occurrence of distal emboli, achieving superior revascularization results and improved clinical outcomes in acute stroke. This study will aim to examine the efficacy and safety of the new SeparGate™ BGC. DesignThis prospective multicenter single-arm clinical trial will aim to include 128 patients who fulfill its inclusion and exclusion criteria. All patients will receive endovascular interventional therapy with BGC assistance. The primary endpoint will be the immediate surgical success rate, while the secondary endpoint will be product performance. The safety evaluation will include serious adverse events such as puncture site hematoma and bleeding, cerebral vasospasm, vessel dissection, vessel perforation, air embolism, thrombus (acute or subacute), vessel occlusion, distal embolization, infection, adverse reaction to antiplatelet and anticoagulant drugs, intracranial hemorrhage, stroke, death, and device defect. DiscussionThe prospective multicenter trial will provide safety and efficacy information for the SeparGate™ BGC. Its findings will provide a clinical reference for endovascular adjuvant therapy of cerebrovascular disease. Trial registrationChiCTR1800014459.

Lipiodol as an Imaging Biomarker of Tumor Response After Conventional Transarterial Chemoembolization: Prospective Clinical Validation in Patients with Primary and Secondary Liver Cancer

PURPOSE:To prospectively investigate whether Lipiodol can be used as a potential imaging biomarker of tumor response after conventional transarterial chemoembolization (cTACE) for both primary and secondary liver cancer. MATERIALS AND METHODS: This prospective single-center single-arm clinical trial enrolled a total of 39 patients with primary or secondary liver malignancy [hepatocellular carcinoma (HCC), n = 22 and non-HCC, n = 17]. Patients were treated with cTACE according to a standardized protocol and underwent multimodality imaging at baseline [magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET)]; at 24 hours post-TACE (CT); and at 30, 90, and 180 days post-TACE (MRI/CT/PET). Image data analysis included quantitative assessment of tumor characteristics, Lipiodol deposition, fluorodeoxyglucose uptake, and tumor response assessment. Statistical analysis included linear regression, Student's t tests, Wilcoxon rank sum and signed rank test, Chi-square, and Fisher's exact test. RESULTS: Image analysis demonstrated that baseline tumor diameter (R2 = 0.4, P = .0001), area (R2 = 0.45, P < .0001), volume (R2 = 0.3, P < .002), and enhancing volume (cm3, R2 = 0.23, P < .002) at baseline correlated inversely with Lipiodol tumor coverage and response rates. Baseline tumor enhancement in % of the total tumor was the only parameter to positively correlate with Lipiodol coverage (R2 = 0.189, P = .0456). Patients with high Lipiodol coverage of the tumors showed a higher tumor quantitative European Association for the Study of the Liver response rate at 30-day follow-up (P = .004). Lipiodol retention in both primary and secondary liver tumors was sustained over time, while nontarget hepatic deposits demonstrated near-complete elimination at 30-day follow-up (P < .001). CONCLUSION: Lipiodol deposition in liver tumors can be predicted using quantitative baseline imaging characteristics and correlates with tumor response. This supports another role for Lipiodol, namely, that of an imaging biomarker of tumor response after cTACE.

Impact of 68Ga-PSMA-11 PET on the management of biochemically recurrent prostate cancer in a prospective single-arm clinical trial.

292 Background: Prostate-specific membrane antigen ligand positron emission tomography (PSMA PET) induced management changes in up to every second patient in smaller clinical trials. We aim to determine the impact of 68Ga-PSMA-11 PET/CT on management of biochemically recurrent prostate cancer in a large prospective cohort. Methods: We report management changes following PSMA PET, a secondary endpoint of a prospective multicenter trial in men with prostate cancer biochemical recurrence (NCT02940262 and NCT03353740). Pre-PET, Post-PET and Post-Treatment Questionnaires were sent to referring physicians recording working clinical summaries, intended and implemented therapeutic and diagnostic management. Results: Intended management change occurred in 260/382 (68%) patients. Intended change was considered major in 176/382 (46%) patients. Management pathway aligned with PET findings, i.e. change towards local/focal therapy for locoregional disease (54/126 patients, 44%) and towards systemic therapy or combination approaches for metastatic disease (106/153 patients, 69%). Intended management was implemented in 160/206 (78%) patients. Perceived site of disease was unknown in 259/382 (68%) patients before and 111/382 (29%) patients after PSMA PET. A total of 150 intended diagnostic tests, mostly CT (n=43, 29%) and bone Scans/NaF-PET (n=52, 35%), were prevented by PSMA PET. A total of 73 tests, mostly biopsies (n=44, 60%) requested by the study protocol, were triggered. Conclusions: Disease localization by PSMA PET translated into management changes in more than half of patients with biochemical recurrence of prostate cancer. More than twice as many diagnostic tests were prevented than triggered following PET. Clinical trial information: NCT02940262 and NCT03353740.

Concurrent use of rabacfosadine and L-asparaginase for relapsed or refractory multicentric lymphoma in dogs.

BackgroundRabacfosadine (RAB), a novel antineoplastic agent conditionally licensed for the treatment of lymphoma in dogs, is efficacious in both naïve and previously treated dogs. Its use in combination with L‐asparaginase (L‐ASP) has not been studied.Hypothesis/ObjectivesTo evaluate the safety and efficacy of L‐ASP given concurrently with RAB in dogs with relapsed multicentric lymphoma.AnimalsFifty‐two dogs with relapse of lymphoma after treatment with at least 1 doxorubicin‐based chemotherapy protocol.MethodsOpen‐label, multicenter, prospective single‐arm clinical trial. Dogs were treated with RAB at 1.0 mg/kg IV every 21 days for up to a total of 5 doses. L‐asparaginase was administered at 400 IU/kg SQ concurrently with the first 2 treatments of RAB.ResultsThe overall response rate (ORR) for all dogs was 67%, with 19 dogs (41%) achieving a complete response (CR). The median progression‐free survival time (MPFS) was 63 days (range 5‐428 days). Dogs experiencing a CR as their best response had an MPFS of 144 days (range 44‐428 days). Adverse events were similar to previous studies evaluating single agent RAB. Failure to achieve a CR and having previously received L‐ASP were negative prognostic factors on multivariate analysis.Conclusions and Clinical ImportanceConcurrent RAB/L‐ASP appears to be both efficacious and safe for treating relapsed multicentric lymphoma in dogs. Adverse events were most often mild and no unexpected toxicoses were observed.

Neoadjuvant Chemotherapy With Anthracycline-Based Regimen for BRCAness Tumors in Triple-Negative Breast Cancer

BackgroundA subgroup of triple-negative breast cancer (TNBC) shows impaired BRCA1 function owing to causes other than mutation, which is called “BRCAness.” DNA-damaging agents are known to have more efficacy in BRCA1-mutant tumors than mitotic poisons. We conducted a prospective single-arm clinical trial of neoadjuvant chemotherapy (NAC) using an anthracycline-based regimen without taxanes for BRCAness TNBCs. Materials and methodsBRCAness was examined using the multiplex ligation-dependent probe amplification (MLPA) method in TNBC cases. For BRCAness cases, NAC was performed with anthracycline-based regimens without additional taxanes. ResultsA total of 30 patients with TNBC were enrolled. MLPA was successfully performed in 25 patients. Eighteen patients (72%) showed BRCAness. Twenty-three patients received NAC as per the protocol. On analysis, the clinical response rate (complete response plus partial response) was 76.4%, and the pathological complete response rate was 35.3%. ConclusionsThe interim analysis revealed that the pathological complete response rate was lower than estimated. Therefore, BRCAness by MLPA was not sufficient to predict the therapeutic response to anthracycline-based regimens in TNBC.

Intraoperative evaluation of hepatic artery blood flow during pancreatoduodenectomy (HEPARFLOW): Protocol of an exploratory study

IntroductionPancreatoduodenectomy is the treatment of choice for a range of benign and malignant diseases. The pancreatic head must be separated from its supplying vessels, especially the gastroduodenal artery, during this operation. However, dissection of the gastroduodenal artery can disturb blood supply to the liver and result in liver ischemia. There is currently no well-established algorithm to evaluate and ensure sufficient blood flow in patients with altered hepatic artery blood flow. To address this important issue, this study aims to establish a basis for assessing liver blood supply during pancreatoduodenectomy. Furthermore, factors influencing arterial blood flow and related postoperative complications will be evaluated. Methods and analysisThe HEPARFLOW study is a single institutional single-arm prospective exploratory observational clinical trial. All consecutive patients undergoing elective partial or total pancreatoduodenectomy will be screened for inclusion until 100 patients are enrolled. Blood flow in the proper hepatic artery, gastroduodenal artery, portal vein, and additional vessels supplying the liver will be measured during pancreatoduodenectomy using Doppler flowmetry. All patients will be followed up for 90 days after surgery. At each visit, standard clinical data, postoperative complications and mortality will be recorded. DiscussionThis will be the first study to prospectively assess intraoperative flow rates of the hepatic artery and portal vein to evaluate liver blood supply during pancreatoduodenectomy. The preoperative and intraoperative factors influencing blood flow in the hepatic arteries will be identified. This study may also reveal the hemodynamic and clinical relevance of a compression of the celiac axis during pancreatoduodenectomy. Ethics and disseminationThis study was approved by the Ethics Committee of the University of Heidelberg (S-073/2018). The results will be published in a peer-reviewed journal and will be presented at medical meetings.

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

Preoperative hypofractionated radiotherapy 5x5 Gy for five consecutive days, and then immediate surgery in patients with locally advanced soft tissue sarcomas (STS) showed a good local control rate and treatment tolerance. Myxoid liposarcoma (MLPS) is highly radiosensitive as compared with other STS, thus a longer gap between the end of RT and surgery may increase the local efficacy and allow to obtain better pathological response rate. The main objective of the study was to assess the safety of 5x5 Gy hypofractionated preoperative RT with prolonged gap (6-8 weeks) to surgery in patients with locally advanced primary MLPS. In this single-arm prospective clinical trial. Patients with locally advanced MLPS underwent preoperative 5x5 Gy RT with 6-8 weeks gap between RT end and surgery from April 2015 to January 2019. The primary endpoint of the study was the rate of perioperative wound healing complications. The secondary endpoints were the pathological response according to the European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group recommendations (EORTC-STSBG) and local control rate at 5 years. From April 2015 until February 2019 29 patients with primary MLPS finished the whole planned protocol treatment. All of the patients had the tumors located in the lower limb. The median tumor size was 16 cm. The median follow-up time was 13 months. Perioperative wound complications occurred in 9 patients (31%). 6 patients (21%) required medical intervention (antibiotics or wound revision, grade 2 or higher according to Common Terminology Criteria for Adverse Events version 4.03). These results are similar (32.4%) to our historical controls of 272 patients with advanced STS who were treated with 5x5 Gy RT and immediate surgery. R0 margins were achieved in all but two patients (7%) who had R1 resection margin. None of the patients had local recurrence and four patients (14%) developed distant metastases at the moment of analysis (February 2019). The pathological response category according to the EORTC-STSBG recommendations were B (3.5%), C (20.7%), D (34.5%) and E (41.38%). Preoperative hypofractionated RT with the prolonged gap between the RT and surgery is a reasonable approach to MLPS treatment providing a low rate of perioperative complications and good local control.

Abstract CT147: Celiac plexus radiosurgery a new palliative modality for upper gastrointestinal malignancies - final quality of life results from a proof-of-concept clinical trial

Abstract Background: Many patients with upper-abdominal malignancies suffer from severe low back / epigastric pain caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. The celiac plexus has not previously been targeted using radiation. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain and improve quality of life (QOL). Methods: We conducted a single arm prospective clinical trial. Eligible patients had celiac-pain &amp;gt; 4/10 on Numerical Rating Scale (NRS) and completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as either five fractions of 9 Gy or a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by ‘Brief pain assessment short-form’. Analgesic use was not restricted. Here we report results from those who received single fraction treatment. Results: 19 patients were evaluable. The median age of the study population was 67 yr with a median ECOG of 2, 89% had pancreatic cancer. Patients were a median 8 months from diagnosis, and had received a median of one systemic treatment. Toxicity was limited to grade 1-2. Average pain decreased from 5.9/10 at baseline, to 3.1/10 at 3w, and to 1.8/10 (both p &amp;lt; 0.0001) at 6w post-treatment. Number of rescue analgesic doses decreased from 3.6 (baseline) to 1.9 at 3w and 1.7 at 6w (both p&amp;lt;0.001). Improvement was seen in all domains of pain-interference (table). Conclusions: Single fraction celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with advanced upper-GI cancer. An international phase II trial is accruing. Pain interference measuresdomainweek 0 (baseline)week 3p (w0 vs v3)week 6p (w0 vs v6)General Activity7.93.4&amp;lt;0.00012.0&amp;lt;0.0001Mood6.93.6&amp;lt;0.0051.80.0001Walking ability4.21.80.051.00.01Normal Work7.43.4&amp;lt;0.0051.30.0001Relations with other people62.40.0031.70.003Sleep6.93.2&amp;lt;0.0051.80.0001Enjoyment of life8.32.4&amp;lt;0.00011.8&amp;lt;0.0001 Citation Format: Yaacov R. Lawrence, Liat Hammer, Ofir Morag, Maoz Ben-Ailan, Dror Alezra, Ofer Margalit, Naama Halpern, Ben Boursi, Einat Shacham Shmueli, Galia Jacobson, Uri Amit, Tamar Katzman, Kinneret Shefer, Ilana Weiss, Inessa Yanovsky, Adam P. Dicker, Talia Golan, Zvi Symon, David Hausner. Celiac plexus radiosurgery a new palliative modality for upper gastrointestinal malignancies - final quality of life results from a proof-of-concept clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT147.

Re: Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial

Re: Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial

Single-shot celiac plexus radiosurgery in pancreatic cancer: Palliative and functional outcomes—Final results of a prospective clinical trial.

309 Background: Pancreatic cancer is characterized by severe epigastric/lower back pain caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the abdominal aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain. Here we report results for pancreatic cancer patients treated with a single fraction of radiation. Methods: We conducted a single-institution single-arm prospective clinical trial. Eligible cancer patients had celiac-pain &gt; 4/10 on Numerical Rating Scale (NRS) and completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by the ‘The Brief Pain Inventory’. Analgesia was not restricted. Total daily dose of opioids was measured in morphine milligram equivalents (MME). Results: Seventeen patients were evaluable, 65% female, median age 68 yr (range 51-79), three had undergone pancreatic resection, nine had liver metastases, median ECOG = 1. Sixteen patients reported 3-week outcomes, and 10 reported 6-week outcomes. At time of treatment subjects were a median of 8.2 months from diagnosis, and had received a median of one systemic treatment (range 0-3). Toxicity was limited to grade 1. Median baseline pain was 6/10 (IQR 5-7), was reduced to 2.3/10 (IQR 0.9-3.6) (p &lt; 0.0005) at 3 w, and to 2.5/10 (IQR 0-3.1) at 6 w post-treatment, for both p &lt; 0.001. Median opioid consumption numerically decreased (baseline 52.9 MME, 3 w 43.9 MME, 6 w 37.5 MME, NS). ‘BPI pain interference’ improved significantly: median baseline score 7.1 dropped to 1.1 at 3 weeks and 0 at 6 weeks (p &lt; 0.01 for both time points). Conclusions: Celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with pancreatic cancer. A follow-up international trial is accruing. Clinical trial information: NCT02356406.

Using Functional Performance Measures to Assess Clinical Response in Patients with Sclerotic Chronic Graft Versus Host Disease: An Exploratory Study

Introduction In allogeneic hematopoietic stem cell transplant survivors, sclerotic chronic graft-versus-host disease (ScGVHD) is associated with poor quality of life (QOL) and range of motion restrictions. The latter can limit patients' ability to perform important activities of daily living (ADLs). The NIH Consensus Development Project established a standard set of measures to monitor chronic GVHD (cGVHD) progression. This includes indicators of patient-reported QOL and symptom burden, which is defined as the subjective severity and impact of physiological symptoms. Adding measures of functional performance may allow clinicians to more fully characterize the impact of ScGVHD on daily life. Objective To determine whether change in functional capacity and QOL relate to changes in symptom burden and clinician-rated cGVHD severity. Methods Between December 2008 and February 2011, patients with ScGVHD enrolled in a single-arm prospective clinical trial assessing the efficacy of imatinib mesylate. At baseline and 6 months, patients completed measures of functioning [Disabilities of the Arm, Shoulder, and Hand (DASH); Human Activity Profile (HAP); Manual Ability Measure (MAM-36)] and QOL [Short Form 36 version 2 (SF 36); Lee Symptom Scale (Lee)]. Clinicians rated patients' ADL ability [Assessment of Motor and Process Skills version 7 (AMPS)] and cGVHD symptom severity [Provider Global Score (PGS)]. Spearman's rank correlation tests evaluated the association among measures. The alpha level was set to 0.01. Results Twenty patients with ScGVHD enrolled in the trial; 13 patients were assessable for primary endpoint analysis. At study entry, patients were a median of 53 years old, a median of 53 months post-transplant, and had a median of 5 cGVHD-affected organs. Change in PGS was not correlated with change of any measures. Reduced symptom burden (Lee) correlated with improved SF 36 physical component scores (r = -0.72, p = 0.008), AMPS ADL motor skill scores (r = -0.84, p Conclusion Our results suggest the value of supplementing the Lee scale and the SF 36 with functional measures to assess clinical response to ScGVHD treatment. The association between changes in symptom burden and changes in ADL ability (AMPS and DASH scores) indicate the potential utility of these measures in this clinical population. Such scales may allow for a better understanding of patients' functional limitations, thereby promoting individualized clinical care and rehabilitative efforts. Clinician-reported cGVHD severity may not have been related to functional changes due to insufficient sensitivity of the measure or the small size of this sample. Our findings highlight the potential relevance of the AMPS and DASH in patients with cGVHD, though further exploration in larger and more diverse samples is necessary.

Modulatory effect of International Standard Scalp Acupuncture on brain activation in the elderly as revealed by resting-state fMRI.

The specific mechanisms by which acupuncture affects the central nervous system are unclear. In the International Standard Scalp Acupuncture system, acupuncture needles are applied at the middle line of the vertex, anterior parietal-temporal oblique line, and the posterior parietal-temporal oblique line. We conducted a single-arm prospective clinical trial in which seven healthy elderly volunteers (three men and four women; 50-70 years old) received International Standard Scalp Acupuncture at MS5 (the mid-sagittal line between Baihui (DU20) and Qianding (DU21)), the left MS6 (line joining Sishencong (EX-HN1) and Xuanli (GB6)), and the left MS7 (line joining DU20 and Qubin (GB7)). After acupuncture, resting-state functional magnetic resonance imaging demonstrated changes in the fractional amplitude of low frequency fluctuations and regional homogeneity in various areas, showing remarkable enhancement of regional homogeneity in the bilateral anterior cingulate, left medial frontal gyrus, supramarginal gyrus, right middle frontal gyrus, and inferior frontal gyrus. Functional connectivity based on a seed region at the right middle frontal gyrus (42, 51, 9) decreased at the bilateral medial superior frontal gyrus. Our data preliminarily indicates that the international standard scalp acupuncture in healthy elderly participants specifcally enhances the correlation between the brain regions involved in cognition and implementation of the brain network regulation system and the surrounding adjacent brain regions. The study was approved by the Ethics Committee of the China-Japan Union Hospital at Jilin University, China, on July 18, 2016 (approval No. 2016ks043).

Phase I Study of the Combination of Bendamustine, Rituximab, and Pixantrone in Patients With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

BackgroundFor patients with aggressive lymphomas who relapse after initial therapy, a durable response is rarely achieved with standard salvage therapies. Significant efforts have focused on the development of novel treatments with reduced toxicity. We conducted a phase I prospective single arm clinical trial of the novel combination of BuRP (bendamustine, rituximab, and pixantrone) in patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). Patients and MethodsEligible patients included adults with biopsy-proven R/R B-cell NHL who met the criteria for treatment. Patients received bendamustine 120 mg/m2, rituximab 375 mg/m2, and pixantrone, per cohort dose, on day 1 for up to 6 cycles. Dose escalation used a 3 + 3 design, from a starting dose level of pixantrone 55 mg/m2 to 115 mg/m at dose level 3. ResultsTwenty-two patients were enrolled onto the study with a median follow-up of 7.9 months. The maximum tolerated dose was not reached, but the highest dose level of pixantrone of 115 mg/m2 was well-tolerated. The most common grade 3/4 adverse events were neutropenia (27%) and thrombocytopenia (23%). The mean change in left ventricular ejection fraction was 2.5% (standard deviation, 5.51%; 95% confidence interval, 0.0%-4.9%). The overall response rate for the entire cohort was 37.5% (95% confidence interval, 15%-65%), but at the highest pixantrone dose, the overall response rate was 63%, with a complete response rate of 25%. ConclusionThe BuRP regimen was found to be safe in patients with R/R B-cell NHL. The favorable toxicity profile plus the encouraging response rates seen suggest that continued investigation of the highest dose level is warranted.

Priming with percutaneous bacillus Calmette-Guerin (BCG) prior to intravesical BCG treatment safely improves BCG-specific response in patients with bladder cancer

Abstract Bacillus Calmette-Guérin (BCG) is the gold standard immunologic agent for patients with high-grade non-muscle invasive bladder cancer (NMIBC). Nevertheless, responses to BCG are heterogeneous and limited options exist when BCG therapy fails. Preclinical data in animal models of bladder cancer (BC) suggests that priming with percutaneous BCG vaccine prior to intravesical BCG instillation can enhance BCG-specific immunity and improve outcome. To study the safety, immunogenicity and preliminary efficacy of this approach, we administered percutaneous BCG 21 days prior to intravesical BCG instillation in “prime patients” with NMIBC (n=13) in a prospective single-arm clinical trial. Immune responses and clinical outcomes were monitored and compared to a contemporaneous cohort of “control patients” (n=9) receiving intravesical BCG without prior percutaneous BCG. Priming was well tolerated and no grade ≥3 adverse events were observed. Compared to control, prime patients had improvement in both local and systemic measures of BCG-specific immunity, scored by increased post-BCG urinary IL-8 and IL-17A and increased circulating CD4, CD8, and γδ T cell proliferation and effector function in response to BCG. Furthermore, ex vivo cytotoxicity of circulating NK and γδ T cells against RT4 BC was significantly increased in prime patient after BCG treatment and was mediated in part by NKG2D, suggesting an important role of innate effector immune mechanisms underlying BCG’s antitumor activity. Remarkably, no prime patients progressed whereas 3 out of 9 control patients progressed to muscle-invasive disease and underwent cystectomy. Thus, BCG priming safely enhances BCG-specific immunity and could improve outcome for patients with NMIBC.

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study.

Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single‐arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC‐P) were similar to the MMAC group in the retrospective study (MMAC‐R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.

New Therapy for Refractory Chronic Mechanical Low Back Pain—Restorative Neurostimulation to Activate the Lumbar Multifidus: One Year Results of a Prospective Multicenter Clinical Trial

ObjectivesThe purpose of the international multicenter prospective single arm clinical trial was to evaluate restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical low back pain (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or spinal cord stimulation (SCS).Materials and MethodsFifty‐three subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was low back pain evaluated on a 10‐Point Numerical Rating Scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of ≥2‐point in low back pain NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and Quality of Life (QoL; EQ‐5D).ResultsFor 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58%. The percentage of subjects at 90 days, six months, and one year with ≥MCID improvement in single day NRS was 63%, 61%, and 57%, respectively. Percentage of subjects with ≥MCID improvement in ODI was 52%, 57%, and 60% while those with ≥MCID improvement in EQ‐5D was 88%, 82%, and 81%. There were no unanticipated adverse events (AEs) or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach.ConclusionsElectrical stimulation to elicit episodic lumbar multifidus contraction is a new treatment option for CMLBP. Results demonstrate clinically important, statistically significant, and lasting improvement in pain, disability, and QoL.

Long-term cosmesis following a novel schedule of accelerated partial breast radiation in selected early stage breast cancer: result of a prospective clinical trial.

PurposeThere is controversy regarding the cosmetic outcome after accelerated partial breast radiation (APBR). We report the cosmetic outcome from a single-arm prospective clinical trial of APBR delivered using intensity-modulated radiation therapy (IMRT) in elderly patients with stage I breast cancer (BC), using a novel fractionation schedule.Materials and MethodsForty-two patients aged ≥65, with Stage I BC who underwent breast-conserving surgery were enrolled in a phase I/II study evaluating a 2-week course of APBR. Thirty eligible patients received 40 Gy in 4 Gy daily fractions. Cosmetic outcome was assessed subjectively by physician/patient and objectively by using a computer program (BCCT.core) before APBR, during, and after completion of the treatment.ResultsThe median age was 72 years, the median tumor size was 0.8 cm, and the median follow-up was 50.5 months. The 5-year locoregional control in this cohort was 97% and overall survival 87%. At the last follow-up, patients and physicians rated cosmesis as ‘excellent’ or ‘good’ in 100% and 91 %, respectively. The BCCT.core program scored the cosmesis as ‘excellent’ or ‘good’ in 87% of the patients at baseline and 81% at the last follow-up. The median V50 (20 Gy) of the whole breast volume (WBV) was 37.2%, with the median WBV V100 (40 Gy) of 10.9%.ConclusionAn excellent rate of tumor control was observed in this prospective trial. By using multiple assessment techniques, we are showing acceptable cosmesis, supporting the use of IMRT planned APBR with daily schedule in elderly patients with early stage BC.

Adapted Surgical Procedure for Argus II Retinal Implantation: Feasibility, Safety, Efficiency, and Postoperative Anatomic Findings

To evaluate the feasibility, safety, and efficiency of an adapted surgical procedure used for postmarket Argus II implantations, so as to lower risks of postoperative hypotony or conjunctivoscleral erosion, and to describe the observed anatomic characteristics of the positioning of the implanted array. Single-arm prospective multicenter clinical trial. Eighteen consecutive patients with end-stage retinitis pigmentosa. To protect the site of insertion of the cable of the device, a scleral flap was systematically added to the standardized implantation procedure. It was associated with temporalis fascia autograft, so as to cover the episcleral-fixed electronics case. Intraoperative and postoperative data at day 1, weeks 1 and 2, and months 1, 3, and 6 were collected. Postoperative distance between electrode-array and retina was measured on spectral-domain optical coherence tomography images. Position of the array was evaluated on fundus images between months 1 and6. Feasibility of the modified surgical technique (time constraints, intraoperative complications), variations of intraocular pressure over time, postoperative ocular findings and adverse events, postoperative distance between the array and the retina, and rotation of the array between months 1 and 6 after implantation. The adapted surgical technique was performed easily without associated specific complications. No cases of chronic hypotony or conjunctivoscleral erosion were reported. One serious device/procedure-related adverse event was recorded (sterile posterior uveitis), which resolved after vitrectomy. Postoperative distance between array and retina was variable: full apposition was achieved in 4 patients (22.22%), partial apposition observed in 9 patients (50.00%), and absence of strict apposition noted in 5 patients (27.78%, 4 of whom had posterior staphyloma). A statistically significant slight rotation of the array was observed between months 1 and 6 (P < 0.0001), occurring downwardly in 68.75% of cases. The combined use of scleral flap and temporalis fascia autograft was easily achieved and effective in preventing hypotony and conjunctival erosion in our study. Postoperative distance between semirigid array and retinal surface was variable, and increased in the case of preoperative staphyloma. A slight rotation of the device occurred over time. Further studies based on larger samples are needed to confirm our findings and determine their functional consequences.

Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial.

The rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma is high. Seeding upper urinary tract urothelial carcinoma cells onto the damaged bladder wall is considered to be one of the causes of intravesical recurrence after radical nephroureterectomy. We evaluated the utility of early ureteral ligation in preventing the intravesical recurrence. This prospective single-arm clinical trial included patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma in the Tohoku Urological Evidence-Based Medicine Study Group between 2012 and 2013. Early ureteral ligation was defined as ligation of the ureter as quickly as possible after expanding the retroperitoneal space. A historical control was extracted from 454 patients who underwent radical nephroureterectomy in the same group, using propensity score-matched analysis. Intravesical recurrence-free survival rates were analyzed using Kaplan-Meier curves. Factors predicting intravesical recurrence were assessed using multivariate analyses. Seventy-four patients underwent early ureteral ligation. Seventeen (23%) patients had intravesical recurrence with a median follow-up period of 24 months. The 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 81% and 76%, and in the control group 75% and 63%, respectively (P = 0.160). In patients with renal pelvic cancer, the 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 89% and 86%, but in the control group 74% and 64%, respectively (P = 0.025). However, intravesical recurrence-free survival rates were similar in patients with ureteral cancer. Multivariate analyses of a subset of patients with renal pelvic cancer identified early ureteral ligation as an independent predictor of intravesical recurrence. Early ureteral ligation decreases the rate of intravesical recurrence after radical nephroureterectomy in patients with renal pelvic cancer. Thus, early ureteral ligation might help in prevention of intravesical recurrence for renal pelvic cancer.