Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial.

Cyclic high-dose testosterone administration, known as bipolar androgen therapy (BAT), is a treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report the results of a multicenter, single arm Phase 2 study (NCT03554317) enrolling 45 patients with heavily pretreated mCRPC who received BAT (testosterone cypionate, 400 mg intramuscularly every 28 days) with the addition of nivolumab (480 mg intravenously every 28 days) following three cycles of BAT monotherapy. The primary endpoint of a confirmed PSA50 response rate was met and estimated at 40% (N = 18/45, 95% CI: 25.7-55.7%, P = 0.02 one-sided against the 25% null hypothesis). Sixteen of the PSA50 responses were achieved before the addition of nivolumab. Secondary endpoints included objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability. The ORR was 24% (N = 10/42). Three of the objective responses occurred following the addition of nivolumab. After a median follow-up of 17.9 months, the median rPFS was 5.6 (95% CI: 5.4-6.8) months, and median OS was 24.4 (95% CI: 17.6-31.1) months. BAT/nivolumab was well tolerated, resulting in only five (11%) drug related, grade-3 adverse events. In a predefined exploratory analysis, clinical response rates correlated with increased baseline levels of intratumoral PD-1 + T cells. In paired metastatic tumor biopsies, BAT induced pro-inflammatory gene expression changes that were restricted to patients achieving a clinical response. These data suggest that BAT may augment antitumor immune responses that are further potentiated by immune checkpoint blockade.

High-Dose Intravenous Vitamin C Combined with Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer: A Randomized Placebo-Controlled Phase II Trial.

High-dose intravenous vitamin C (HDIVC) administered to produce pharmacologic concentrations shows promise in preclinical models and small clinical trials, but larger prospective randomized trials are lacking. We evaluated the clinical benefit of combining HDIVC with docetaxel in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). In this double-blind, placebo-controlled phase II trial, 47 patients were randomized 2:1 to receive docetaxel (75 mg/m2 i.v.) with either HDIVC (1 g/kg) or placebo. Coprimary endpoints were PSA50 response and adverse event rates. Secondary endpoints included overall survival, radiographic progression-free survival, and quality of life measured using the Functional Assessment of Cancer Therapy-Prostate instrument. Correlative analyses included pharmacokinetics and oxidative stress markers. Eighty-nine percent of patients previously had three or more lines of therapy. The PSA50 response rate was 41% in the HDIVC group and 33% in the placebo group (P = 0.44), with comparable adverse event rates in both groups. There were no significant differences in Functional Assessment of Cancer Therapy-Prostate scores. The median radiographic progression-free survival was not significantly different between the HDIVC and placebo groups, with durations of 10.1 and 10.0 months (HR, 1.35; 95% confidence interval, 0.66-2.75; P = 0.40), respectively. The median overall survival was 15.2 months in the HDIVC group and 29.5 months in the placebo group (HR, 1.98; 95% confidence interval, 0.85-4.58; P = 0.11). HDIVC did not decrease F2-isoprostanes, indicators of oxidative stress. The study was suspended after prespecified interim analysis indicated futility in achieving primary endpoints. In this patient population, combining HDIVC with docetaxel did not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. Findings do not support the routine use of HDIVC in mCRPC treatment outside of clinical trials. SIGNIFICANCE: This is the first randomized, placebo-controlled, double-blind trial to evaluate HDIVC in cancer treatment. The addition of HDIVC to docetaxel in patients with mCRPC does not improve PSA response, toxicity, or other clinical outcomes compared with docetaxel alone. The routine use of HDIVC in mCRPC treatment is not supported outside of clinical trials.

Creating a Program to Support Registering and Reporting Clinical Trials at Johns Hopkins University.

PROBLEM: The Food and Drug Administration Amendments Act of 2007 (FDAAA) and the National Institutes of Health (NIH) require that many clinical trials register and report results on ClinicalTrials.gov. Noncompliance with these policies denies research participants and scientists access to potentially relevant findings and could lead to monetary penalties or loss of funding. After discovering hundreds of potentially noncompliant trials affiliated with the institution, the Johns Hopkins University School of Medicine (JHUSOM) sought to develop a program to support research teams with registration and reporting requirements. APPROACH: JHUSOM conducted a baseline assessment of institutional compliance in 2015, launched the ClinicalTrials.gov Program in June 2016, and expanded the program to the Sidney Kimmel Comprehensive Cancer Center in April 2018. The program is innovative in its comprehensive approach, and it was among the first to bring a large number of trials into compliance. OUTCOMES: From September 2015 to September 2020, JHUSOM brought completed and ongoing trials into compliance with FDAAA and NIH policies and maintained almost perfect compliance for new trials. During this period, the proportion of trials potentially noncompliant with the FDAAA decreased from 44% (339/774) to 2% (32/1,304). NEXT STEPS: JHUSOM continues to develop and evaluate tools and procedures that facilitate trial registration and results reporting. In collaboration with other academic medical centers, JHUSOM plans to share resources and to identify and disseminate best practices. This report identifies practical lessons for institutions that might develop similar programs.

Biopsy-Proven Small-Fiber Neuropathy in Primary Sjögren's Syndrome: Neuropathic Pain Characteristics, Autoantibody Findings, and Histopathologic Features.

OBJECTIVE: Painful small-fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large-fiber involvement. SFN can be diagnosed by punch skin biopsy results that identify decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves. METHODS: We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh). RESULTS: There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti-Ro 52 (P = 0.01) and anti-Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking-and-glove pain, and 12 patients had nonstocking-and-glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients). CONCLUSION: SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking-and-glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies.

Brief Report: Anti-Calponin 3 Autoantibodies: A Newly Identified Specificity in Patients With Sjögren's Syndrome.

OBJECTIVE: Autoantibodies are clinically useful for phenotyping patients across the spectrum of autoimmune rheumatic diseases. Using serum from a patient with Sjögren's syndrome (SS), we detected a new specificity by immunoblotting. This study was undertaken to identify this autoantibody and to evaluate its disease specificity. METHODS: A prominent 40-kd band was detected when immunoblotting was performed using SS patient serum and lysate from rat dorsal root ganglia (DRGs). Using 2-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing, the autoantigen was identified as calponin 3. Anti-calponin 3 antibodies were evaluated in sera from patients with primary SS (n = 209), patients with systemic lupus erythematosus (SLE; n = 138), patients with myositis (n = 138), patients with multiple sclerosis (MS; n = 44), and healthy controls (n = 46) by enzyme-linked immunosorbent assay. Expression of calponin 3 was assessed by immunohistochemistry. RESULTS: Calponin 3 was identified as a new autoantigen. Anti-calponin 3 antibodies were detected in 23 (11.0%) of the 209 SS patients, 12 (8.7%) of the 138 SLE patients, 7 (5.1%) of the 138 myositis patients, 3 (6.8%) of the 44 MS patients, and 1 (2.2%) of the 46 healthy controls. Among SS patients, the frequency of anti-calponin 3 antibodies was highest in those with neuropathies (7 [17.9%] of 39). In this subset, the frequency of anti-calponin 3 antibodies differed significantly from that in the control group (P = 0.02). Calponin 3 was expressed primarily in rat DRG perineuronal satellite cells but not neurons. CONCLUSION: Calponin 3 is a novel autoantigen. Antibodies against this protein are found in SS and associate with the subset of patients experiencing neuropathies. Intriguingly, we found that calponin 3 is expressed in DRG perineuronal satellite cells, suggesting that these may be a target in SS.

Cortical blindness and not optic neuritis as a cause of vision loss in a Sjögren's syndrome (SS) patient with the neuromyelitis optica spectrum disorder (NMOSD): Challenges of ascribing demyelinating syndromes to SS: a case report.

RATIONALE: The conception that multiple sclerosis may be challenging to distinguish from demyelinating manifestations of Sjögren's syndrome (SS) was introduced more than 30 years ago. However, it is now recognized that the neuromyelitis optica spectrum disorder (NMOSD) may occur more frequently in SS as opposed to multiple sclerosis. Characteristic NMOSD features can include severe attacks of optic neuritis, myelitis which is frequently longitudinally-extensive (spanning at least three vertebral segments on magnetic resonance imaging [MRI]), and an association with anti-aquaporin-4 antibodies. In addition, whereas NMOSD was initially thought to spare the brain, it is now recognized that brain lesions occur in a majority of NMOSD patients. Therefore, it is important for the multi-disciplinary team of physicians who care for SS patients to understand this widening spectrum of NMOSD as encompassing brain lesions. In this case-report we describe clinical features, radiographic findings, and treatment of a SS NMOSD patient presenting with severely decreased visual acuity, visual hallucinations, and encephalopathy. PATIENT CONCERNS: The SS NMOSD patient presented with rapid, bilateral onset of severely decreased visual acuity and was therefore suspected as having bilateral optic neuritis. DIAGNOSIS: However, the patient lacked stigmata of optic neuritis, instead had visual hallucinations and encephalopathy suggestive of cortical blindness, and was noted to have occipital lobe lesions on brain MRI. Other radiographic findings included simultaneous enhancement of brainstem and periventricular lesions. INTERVENTIONS: The patient was initially treated with methylprednisolone with no change in her neurological deficits. She was then treated with plasma exchange therapy. OUTCOMES: The patient had resolution of decreased visual acuity, visual hallucinations, encephalopathy, and contrast-enhancing brain lesions in response to plasma exchange therapy. LESSON: We provide the first example of severely decreased visual acuity in a NMOSD patient due to cortical blindness and not bilateral optic neuritis. This finding expands the spectrum of central nervous system syndromes and brain lesions which may occur in NMOSD. The synchronous enhancement of a brainstem lesion (known to occur in NMOSD) with occipital lobe lesions also suggests that our patient's occipital lobe findings were due to NMOSD. All of our patient's findings had an excellent clinical and radiographic response to plasma exchange therapy.

Magnetic resonance imaging of the spinal cord in the evaluation of 3 patients with sensory neuronopathies: Diagnostic assessment, indications of treatment response, and impact of autoimmunity: A case report.

RATIONALE: Sensory neuronopathy can be a devastating peripheral nervous system disorder. Profound loss in joint position is associated with sensory ataxia, and reflects degeneration of large-sized dorsal root ganglia. Prompt recognition of sensory neuronopathies may constitute a therapeutic window to intervene before there are irreversible deficits. However, nerve-conduction studies may be unrevealing early in the disease course. In such cases, the appearance of dorsal column lesions on spinal-cord MRI can help in the diagnosis. However, most studies have not defined whether such dorsal column lesions may occur within earlier as well as chronic stages of sensory neuronopathies, and whether serial MRI studies can be used to help assess treatment efficacy. In this case-series of three sensory neuronopathy patients, we report clinical characteristics, immunological markers, nerve-conduction and skin-biopsy studies, and neuroimaging features. PATIENT CONCERNS: All three patients presented with characteristic features of sensory neuronopathy with abnormal spinal-cord MRI studies. Radiographic findings included non-enhancing lesions in the dorsal columns that were longitudinally extensive (spanning ≥ 3 vertebral segments). DIAGNOSES: All patients had anti-Ro/SS-A and/or anti-La/SS-B antibodies, with patients one and two having Sjögren's syndrome. MRI findings were similar when performed in the earlier stages of a sensory neuronopathy (patient one, after four months) and chronic stages (patients two and three, after five and three years, respectively). INTERVENTIONS: Patient one was treated with rituximab combined with intravenous immunoglobulin therapy. OUTCOMES: Patient one was initially wheelchair-bound and had improved ambulation after treatment. In this patient, serial MRI studies revealed partial resolution of dorsal column lesions, associated with decreased sensory ataxia and improved nerve-conduction studies. LESSONS: In addition to vitamin B12 and copper deficiency, it is important to include sensory neuronopathies in the differential diagnosis of dorsal column lesions. MRI spinal-cord lesions have similar appearances in the earlier as well as chronic phases of a sensory neuronopathy, and therefore suggest that such dorsal column lesions may reflect inflammatory as well as a gliotic burden of injury. MRI may also be a useful longitudinal indicator of treatment response.