Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer.

T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients' prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.

Medical Student Ultrasound Education: The Radiology Chair Weighs In.

ABSTRACT: To assess the radiology department chairs' opinions concerning current status and plans for teaching ultrasound to medical students, the American College Taskforce on Radiology Ultrasound Education, commissioned by the American College of Radiology, distributed a survey to 142 radiology chairs and a medical school dean subgroup.The response rate was 30% (42/142), and 76% indicated ultrasound was currently part of the medical student curriculum. In preclinical years, radiology involvement was only 6.4%. During clinical years, radiology led ultrasound education with 51.7% in general and 82.9% in elective rotations. Regarding actual content, top 4 results were evenly distributed between learning hands-on scanning (81.1%), diagnostic use of ultrasound (75.7%), anatomy/pathology (75.7%), and ultrasound guidance for procedures (54.0%). Educational leaders in preclinical courses were emergency medicine (72.7%) followed by radiology (45.4%) physicians. During clinical years, leaders were radiology (52.6%) and emergency medicine (47.4%) physicians. Most chairs stated that knowledge of diagnostic ultrasound should be mandatory (76.2%), stressing the importance of teaching the diagnostic capabilities and uses of ultrasound as the primary goal (78.8%). Perceived barriers to implementation were evenly distributed between lack of space in the curriculum (55.6%), lack of faculty (48.2%), lack of resources (44.4%), and lack of institutional support (40.7%). The American College Taskforce on Radiology Ultrasound Education survey shows that radiology's role in ultrasound undergraduate education occurs almost exclusively during clinical years, and the chairs voice a desire to improve upon this role. Barriers include both intradepartmental (faculty and resources) and institutional (curricular) factors.

Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer.

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.

A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside.

PURPOSE: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. EXPERIMENTAL DESIGN: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. RESULTS: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC. CONCLUSIONS: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers.

Bow hunter's syndrome caused by accessory cervical ossification: posterolateral decompression and the use of intraoperative Doppler ultrasonography.

BACKGROUND: Bow hunter's syndrome refers to symptomatic vertebrobasilar insufficiency provoked by physiologic head rotation. CASE DESCRIPTION: We report a unique case of bow hunter's syndrome caused by an accessory cervical ossification and the first use of intraoperative Doppler ultrasonography directly upon the vertebral artery during the surgical repair. After a traumatic motor-vehicle collision, the patient developed recurrent syncopal episodes when he turned his head abruptly to the right. Transcranial Doppler studies and vertebral angiography with the patient's neck rotated into the symptomatic position revealed marked reduction of vertebral artery flow, and fine-cut CT of the upper cervical spine demonstrated the compressive accessory ossicle. Intraoperative Doppler ultrasound performed with the head in neutral and rotated positions, before and after surgical decompression, demonstrated restoration of blood flow in the vertebral artery. We discuss the mechanisms of bow hunter's syndrome and the advantages of intraoperative Doppler ultrasonography. CONCLUSION: This case describes the first use of intraoperative Doppler ultrasonography directly upon the vertebral artery to provide an unrestricted real-time assessment of the surgical decompression for bow hunter's syndrome.

Fetal therapy: state of the art.

OBJECTIVE: To review our experience with the use of sonography in evaluating potential candidates for in utero fetal therapy performed at The Center for Fetal Diagnosis and Treatment at The Children's Hospital of Philadelphia. METHODS: This review article was designed to discuss open hysterotomy for the 4 fetal surgical procedures that have been performed at our institution. The procedures included surgical repair of myelomeningocele, resection of sacrococcygeal teratoma in fetuses with nonimmune hydrops, resection of an enlarging congenital cystic adenomatoid malformation that is not amenable to thoracoamniotic shunting, and tracheal clip occlusion for severe left congenital diaphragmatic hernia. RESULTS: For each surgical procedure, the use of sonography in the prenatal diagnosis of the congenital anomaly was detailed, as were indications for surgery and surgical procedures, postoperative monitoring and finally delivery, postnatal treatment, and long-term follow-up. Three of the procedures have been reasonably successful with rather dramatic results in some cases such that these techniques are still being performed. The 1 exception was open hysterotomy for the tracheal clip procedure for congenital diaphragmatic hernia, which has been abandoned. CONCLUSIONS: Fetal therapy is a rapidly evolving specialty, which is being practiced at several centers in this country. Sonography is an integral part of this specialty practice and has been used extensively in the diagnosis of some congenital anomalies that have debilitating or lethal consequences for the fetus. Technologic improvements in both sonography and magnetic resonance imaging have assisted tremendously in the many advances herein reported in the diagnosis and treatment of the above-described 4 congenital anomalies.