Operative Management: Plantar Plate.

The plantar plate is a vital structure for maintaining lesser metatarsophalangeal joint (MPJ) stability. Its primary role is to provide static stabilization of the MPJs, working in conjunction with the long and short flexor and extensor tendons. When insufficiency or attenuation of the plantar plate occurs, a sagittal plane deformity will slowly develop, eventually leading to a "crossover toe" transverse plane deformity. Coughlin coined this descriptive term to describe the later stages of deformity, most commonly affecting the second MPJ. Shortly after, Yu and Judge elaborated on this condition describing it as "predislocation syndrome," an inflammatory condition affecting the plantar plate causing pain and instability, which could progress to subluxation at the MPJ.

Proton therapy for adult medulloblastoma: Acute toxicity and disease control outcomes.

PURPOSE: We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. METHODS: We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed. RESULTS: Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively. CONCLUSIONS: Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Biologics in the Treatment of Plantar Fasciitis.

Plantar fasciitis has been considered an acute inflammatory disorder. However, the local histologic findings represent a more chronic, degenerative state without inflammation. Patients may be stuck in a chronic state of cyclical inflammation leading to tissue degeneration, refractory symptoms, and disability. This idea process has influenced the treatment approach of some practitioners who have implemented the idea of regenerative medicine and use of biologic adjuvants in the treatment of plantar heel pain. Biologic therapies provide many different cellular components, growth factors, and proteins to restore normal tissue biology and are a useful adjunct in the treatment of recalcitrant plantar fasciitis.

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas.

BACKGROUND: Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. OBJECTIVE: This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. METHODS: Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1-4 µg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. RESULTS: A total of 10 patients have completed treatment with infusion doses of carboplatin of 1µg, 2µg, and 4µg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). CONCLUSIONS: IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4µg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.

Primary Tumoral Calcinosis in a Pediatric Patient: A Rare Presentation.

Tumoral calcinosis is a benign, progressive disorder characterized by massive periarticular deposition of calcium salts into subcutaneous and deeper tissue layers. While a majority of cases present secondary to underlying metabolic disorders, it can rarely present as a primary, idiopathic phenomenon. We present an atypical case of a pediatric patient with a large, ulcerated pedal soft tissue mass found to be consistent with primary tumoral calcinosis. This was confirmed by histopathologic analysis and comprehensive metabolic workup. The patient underwent surgical excision of the mass, with complete resolution of symptoms and no recurrence after a 1-year follow-up period.

Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone.

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.

BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.

A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study.

This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1).

Clinical practice experience with NovoTTF-100A™ system for glioblastoma: The Patient Registry Dataset (PRiDe).

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.

Radiation necrosis mimicking rapid intracranial progression of melanoma metastasis in two patients treated with vemurafenib.

Optimal treatment of metastases to the central nervous system (CNS) in patients with malignant melanoma remains a clinical challenge. In particular, for patients with BRAF-mutant melanoma and CNS metastases, much remains unknown about the safety and efficacy of the novel BRAF-targeted agents when administered in close sequence with radiation. We report two cases of rapid development of CNS radiation necrosis in patients with metastatic melanoma treated with the BRAF inhibitor, vemurafenib, closely sequenced with stereotactic radiosurgery or fractionated stereotactic radiation therapy. In the absence of prospective safety data from clinical trials, we advise vigilance in monitoring patients with BRAF-mutant melanoma whose treatment plan includes CNS radiation and vemurafenib and caution when assessing treatment response within the CNS in these patients.

Hearing Loss due to Infiltration of the Tympanic Membrane by Chronic Lymphocytic Leukemia.

Central nervous system (CNS) involvement by chronic lymphocytic leukemia (CLL) can present with dramatic neurologic findings or can be quite subtle, discovered only at the time of autopsy. We describe a case of CLL in a patient who presented initially with hearing loss and was ultimately found to have involvement of the tympanic membrane. She noted improvement of her hearing after induction therapy but was not aware at the time of the involvement of her CNS with CLL. Upon worsening of hearing at the time of relapse, she was evaluated by imaging and CSF analysis as well as biopsy of the tympanic membrane, and involvement of the CNS was confirmed. She has received CNS-directed therapy with intrathecal liposomal cytarabine and intravenous CNS-directed therapy and has noted improved hearing and resolution of her imaging and CSF findings. This is the first reported case of tympanic membrane involvement with CLL and describes potentially effective methods for managing this challenging complication.

Development and validation of sensitive liquid chromatography/tandem mass spectrometry method for quantification of bendamustine in mouse brain tissue.

A liquid chromatography-tandem mass spectrometry method for quantification of bendamustine in mouse brain tissue was developed and fully validated. Methanol was used to precipitate proteins in brain tissue. Bendamustine and internal standard (chlorambucil) were separated with reverse-phase chromatography on a C-18 column with a gradient of water and 95% methanol in 0.1% formic acid. Positive mode electrospray ionization was applied with selected reaction monitoring to achieve 5 ng/ml lower limits of quantitation in mouse brain tissue. The calibration curve for bendamustine in mouse brain was linear between 5 and 2000 ng/ml. The within- and between-batch accuracy and precision of the assay were within 15% at 10, 100 and 1000 ng/ml. The recovery and matrix effect of bendamustine in mouse brain tissue ranged from 41.1% to 51.6% and 107.4% to 110.3%, respectively. The validated method was then applied to quantitate bendamustine in an animal study. Results indicate the assay can be applied to evaluate bendamustine disposition in mouse brain tissue. This assay will be applied in the future to detect and quantify bendamustine in human brain tissue samples.

Recent innovations in the management of low-grade gliomas.

OPINION STATEMENT: Advancement in the understanding of biologic mechanisms of low-grade glioma pathophysiology has allowed the modern era of patient-specific genetic profiling, molecular biology, and neuroimaging to design new methods of surgery, radiation, and chemotherapy in hopes of preventing malignant transformation and improving outcomes. Recent innovations in the understanding of MGMT promoter methylation, IDH1 and IDH2 mutations, temozolomide chemotherapy, vascular monoclonal antibody treatment, use of radiation therapy, choice of antiepileptic drugs, surgical resection, and neuroimaging of low-grade gliomas are reviewed.

Bevacizumab for glioblastoma refractory to vascular endothelial growth factor receptor inhibitors.

Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.

Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma.

PURPOSE: Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. PATIENTS AND METHODS: Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. RESULTS: Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. CONCLUSION: AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Stereotactic radiosurgery alone for patients with 1-4 radioresistant brain metastases.

Brain metastases from radioresistant histologies are perceived to be less responsive to WBRT compared to other histologies, and stereotactic radiosurgery (SRS) may provide better local control. The aim of this study was to examine the outcomes of patients with 1-4 brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with SRS alone. Thirty-eight patients with 1-4 radioresistant brain metastases (66 lesions) were treated with SRS alone. The median age was 55 years. Fourteen and 24 patients had renal cell carcinoma (RCC) and melanoma brain metastases, respectively. Distribution of number of lesions was as follows: one lesion, 22 patients; 2 lesions, 8 patients; 3 lesions, 5 patients; and 4 lesions, 3 patients. Distribution of RTOG recursive partitioning analysis (RPA) classes was as follows: II, 37 patients and III, 1 patient. The median marginal dose was 20 Gy. The median follow-up was 6.1 months. The 3-, 6-, 9-, 12-, and 18-month local control (LC) rates were 87.9, 81.4, 67.9, 67.9, and 60.3%, respectively. The corresponding free-from-distant-brain failure (FFDBF) rates were 71.3, 58.1, 49.8, 40.2, and 27.6%. The corresponding progression-free survival (PFS) rates were 55.3, 41.9, 33, 23.3, and 13.3%. RCC histology was associated with better LC (P = 0.0055). Although SRS alone could yield reasonable LC in patients with 1-4 radioresistant brain metastases, the risk of distant brain failure was substantial. The approach of routine omission of WBRT outside of a trial setting should be used judiciously.