Phase 1 Trial of Vaccination with Autologous Tumor Cells and Antisense Directed Against the Insulin Growth Factor Type 1 Receptor (IGF-1R AS ODN) in Patients with Recurrent Glioblastoma

Background: Extending a previous Phase I study, we report the results of a second Phase I autologous tumor cell vaccination trial for patients with recurrent glioblastomas (IND 14379-101, NCT01550523). Methods: Following surgery, subjects were treated by 24 hour implantation in the rectus sheath of ten biodiffusion chambers containing irradiated autologous tumor cells and IGF-1R AS ODN with the objective of stimulating tumor immunity. Patients were monitored for safety, clinical and radiographic as well as immune responses. Results: There were no Grade 3 toxicities related to protocol treatment and overall median survival from initial diagnosis was 91.4 weeks. Two protocol survival cohorts with median survivals of 48.2 and 10 weeks were identified and predicted by our pre-treatment assessments of immune function, corroborated by post-vaccination pro-inflammatory cytokine profiles. Longer survival subjects had imaging findings including transient elevations in cerebral blood volume (rCBV) and sustained elevations of apparent diffusion coefficient (ADC) interpreted as transient hyperemia and cell loss. Conclusions: The vaccine paradigm was well-tolerated with a favorable median survival. Our data support this as a novel treatment paradigm that promotes anti-tumor immunity

Review of Concussion and Return-to-Play Guidelines in Sport

Concussion is a form of mild traumatic head injury (TBI) associated with a variety of neurologic signs and symptoms. While historically trivialized in its significance, significant progress has been made in the medical literature and lay understanding of concussion. Severe TBI, long the subject of extensive research, has come under increased scrutiny following experience with blast injuries during the wars in Afghanistan and Iraq. Such experience, grievously earned, has brought significant public attention and funding to the study of head injury. However, for the civilian population, concussion continues to be the most common form of traumatic brain injury, and athletics continues to be the single largest cause of concussion. Concussion in sports has come under substantial scrutiny as a result of widely publicized injuries in major American sports, particularly football and hockey. Media coverage has increased further as understanding of the related yet distinct syndrome of chronic traumatic encephalopathy (CTE), formerly known as dementia pugilistica or punch-drunk syndrome , and its proposed mechanism of repeated sub-concussive trauma has increased. While media attention has focused primarily on concussion in professional athletes, the majority of sports-related concussions occur in youth participants.1 With relative unavailability of physicians trained in on-field assessment of concussed athletes relative to professional sports teams, youth athletes are at significant risk for short- and long-term neurologic injury from concussion. This manuscript aims to outline the natural history of sports concussion and review recent updates in on-field assessment and return-to-play guidelines

Salvage Fractionated Stereotactic Re-irradiation (FSRT) for Patients with Recurrent High Grade Gliomas Progressed after Bevacizumab Treatment

Purpose/Objectives: Bevacizumab failure is a major clinical problem in the manage- ment of high grade gliomas (HGG), with a median overall survival of less than 4 months (m). This study evaluated the efficacy of fractionated stereotactic re-irradiation (FSRT) for patients with HGG after progression on Bevacizumab. Materials/Methods: Retrospective review was conducted of patients treated with FSRT after progression on bevacizumab. A total of 36 patients were identified. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. Results: Among the 36 patients, 31 patients had recurrent glioblastoma, and 5 patients had recurrent anaplastic astrocytoma. The median time from initial bevacizumab treatment to FSRT was 8.5 m (range 2.3 – 32.0 m). The median plan target volume for FSRT was 27.5 cc (range 1.95 – 165 cc). With a median follow up of 20.4 m, the overall survival of the patients since initial diagnosis was also 24.9 m. The median overall survival after initiation of bevacizumab was 13.4 months. The median overall survival from FSRT was 4.8 m. FSRT treatment was well tolerated with no Grade \u3e3 toxicity. Conclusions: Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment

Determining the Role of Surgery in Diagnosis and Treatment of Primary CNS Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare entity typically treated with a combination of chemotherapy and radiation. The role of surgery is controversial, and biopsy may be non-definitive or injurious. We review our series of stereotactic and excisional biopsy as well as surgical debulking of PCNSL to quantify overall risk and benefits. Methods: Patients with biopsy-confirmed intracranial PCNSL were identified from a large singlecenter academic institution between 2012-2018. Preoperative factors and perioperative outcomes were retrospectively reviewed. Results: A total of 61 cases of PCNSL were identified. Most patients presented with confusion (23.0%), weakness/paralysis (19.7%), and gait disturbance (18.0%). 1.6% were incidentally identified. HIV status was positive in 8.2% of cases. CSF cytology was positive for malignancy in 33.3% of applicable cases. Of all procedures, 44.3% were needle biopsy, 27.9% were open excisional biopsies, and 27.9% were surgical debulking procedures. Prior biopsy had been performed in 9.8%, of which 83.3% (5/6) were positive for PCNSL. Intraoperative frozen pathology failed to illicit a definitive diagnosis in 39.3% of cases despite adequate sampling. Stereotactic biopsies did not demonstrate an increased risk of non-diagnostic frozen pathology compared to open excisional biopsy. Intraoperative complications, 30-day mortality, and long-term survival was not associated with open vs. stereotactic biopsy. Discussion: Biopsy of PCNSL carries a moderate surgical risk that should not be discounted, particularly in the setting of previously diagnosed PCNSL or with evidence of malignancy in CSF cytology. Early initiation of chemotherapy continues to be the mainstay of long-term response and control

Middle Fossa Extension of Posterior Fossa Meningiomas is Associated with Poorer Clinical Outcomes

Introduction: Progression of posterior fossa meningiomas (PFMs) can lead to extension into the middle cranial fossa. Pre-operative imaging allows for quantification of middle fossa extension (MFE). We aimed to determine the clinical impact of MFE on surgical and clinical outcomes during resection of PFMs. Methods: Craniotomies for meningiomas performed at a large single center academic institution from January 2012 to December 2018 were identified. Preoperative MRI and CT imaging was reviewed to determine the presence of MFE of posterior fossa meningiomas and correlated to post-operative outcomes. Results: 65 PFMs were identified and mean follow-up was 28.8 ± 20.1 months. 13/65 PFMs showed MFE preoperatively. Average size of PFMs with MFE (36.1 cm ± 12.1 cm) was similar to PFMs without MFE (33.5 cm ± 9.2 cm, p \u3e 0.05). 9/13 PFMs with MFE were petrous or petroclival, and 4/13 involved the cavernous sinus. Retrosigmoid craniotomy was the most utilized approach for both isolated PFMs (51.9%) and PFMs with MFE (76.9%). Anterior approaches were used in 2/13 PFMs with MFE. Presence of MFE was strongly associated with decreased rates of GTR (RR= 0.1; p \u3c 0.05). MFE wasn’t associated with longer LOS or rates of readmission within 30 days of discharge, but was associated with a significantly higher rate of overall mortality at last follow-up (RR=5.3; 95%; p \u3c 0.05). Conclusion: PFMs with MFE are easily identifiable and are associated with decreased rates of GTR and overall prognosis and may suggest the need for anterior or combined approaches

Phase I Study of Ipilimumab Combined with Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients with Brain Metastases

Purpose: We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) in patients with brain metastases (BM) from melanoma. Methods: Based on intracranial (IC) disease burden, patients were treated with WBRT (Arm A) or SRS (Arm B). Ipilimumab starting dose was 3 mg/kg (every 3 weeks, starting on day 3 of WBRT or 2 days after SRS). Ipilimumab was escalated to 10 mg/kg using a two-stage, 3+3 design. The primary endpoint was to determine the MTD of ipilimumab combined with radiotherapy. Secondary endpoints were overall survival (OS), IC and extracranial (EC) control, progression free survival (PFS), and toxicity. This trial is regis- tered with ClinicalTrials.gov, number NCT01703507. Results: Characteristics of the 16 patients enrolled between 2011 and 2014 were: mean age, 60; median BM, 2 (1 to \u3e10); number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), ipilimumab 3mg/kg (n=7), 10 mg/kg (n=9). Median follow-up was 8 months (Arm A) and 10.5 months (Arm B). There were 21 grade 1-2 neuro- toxic effects with no dose-limiting toxicities (DLTs). One patient experienced grade 3 neurotoxicity prior to ipilimumab administration. Ten additional grade 3 toxicities were reported with gastrointestinal (n=5, 31%) as the most common. There were no grade 4/5 toxicities. Median PFS and OS, respectively, in Arm A were 2.5 months and 8 months, and in Arm B were 2.1 months and not reached. Conclusion: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early due to slow accrual, but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced DLT. Larger studies with ipilimumab 10 mg/kg and SRS are warranted

Prevalence of USA300 colonization or infection and associated variables during an outbreak of community-associated methicillin-resistant Staphylococcus aureus in a marginalized urban population

et al. Prevalence of USA300 colonization or infection and associated variables during an outbreak of community-associated methicillin-resistant Staphylococcus aureus in a marginalized urban population. Can J Infect Dis Med Microbiol 2007;18(6):357-362. BACKGROUND: In 2004, an outbreak of the USA300 strain of methicillin-resistant Staphylococcus aureus (MRSA) was identified in persons with histories of homelessness, illicit drug use or incarceration in the Calgary Health Region (Calgary, Alberta). A prevalence study was conducted to test the hypotheses for factors associated with USA300 colonization or infection. METHODS: Participants were recruited at sites accessed by this marginalized population. Health care staff administered a questionnaire and collected crack pipes and nasal, axillary and skin infection swabs. Pipes and swabs were cultured according to standard techniques. MRSA isolates were further characterized by polymerase chain reaction (mecA, Panton-Valentine leukocidin and Staphylococcal cassette chromosome mec) and typing methods (pulsed-field gel electrophoresis, staphylococcal protein A typing and multilocus sequence typing). Colonization or infection was determined by having any one of nasal, axillary, skin infection or pipe swabs positive for USA300. Colonized participants had one or more nasal, axillary or pipe swab positive for USA300; infected participants had one or more skin infection swab positive for USA300. RESULTS: The prevalence of USA300 colonization or infection among 271 participants was 5.5% (range 3.1% to 9.0%). USA300 cases were more likely to report manipulation of skin infections (OR 9.55; 95% CI 2.74 to 33.26); use of crack pipes was not significant despite identification of the USA300 strain on two of four crack pipes tested. USA300 cases were more likely to report drug use between sex trade workers and clients (OR 5.86; 95% CI 1.63 to 21.00), and with casual sex partners (OR 5.40; 95% CI 1.64 to 17.78). CONCLUSION: Ongoing efforts to promote the appropriate treatment of skin infections in this population are warranted. The association of USA300 colonization or infection and drug use with sexual partners suggest a role for sexual transmission of the USA300 strain of MRSA

Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis

Background: Global and regional prevalence estimates for blindness and vision impairment are important for the development of public health policies. We aimed to provide global estimates, trends, and projections of global blindness and vision impairment. Methods: We did a systematic review and meta-analysis of population-based datasets relevant to global vision impairment and blindness that were published between 1980 and 2015. We fitted hierarchical models to estimate the prevalence (by age, country, and sex), in 2015, of mild visual impairment (presenting visual acuity worse than 6/12 to 6/18 inclusive), moderate to severe visual impairment (presenting visual acuity worse than 6/18 to 3/60 inclusive), blindness (presenting visual acuity worse than 3/60), and functional presbyopia (defined as presenting near vision worse than N6 or N8 at 40 cm when best-corrected distance visual acuity was better than 6/12). Findings: Globally, of the 7·33 billion people alive in 2015, an estimated 36·0 million (80% uncertainty interval [UI] 12·9–65·4) were blind (crude prevalence 0·48%; 80% UI 0·17–0·87; 56% female), 216·6 million (80% UI 98·5–359·1) people had moderate to severe visual impairment (2·95%, 80% UI 1·34–4·89; 55% female), and 188·5 million (80% UI 64·5–350·2) had mild visual impairment (2·57%, 80% UI 0·88–4·77; 54% female). Functional presbyopia affected an estimated 1094·7 million (80% UI 581·1–1686·5) people aged 35 years and older, with 666·7 million (80% UI 364·9–997·6) being aged 50 years or older. The estimated number of blind people increased by 17·6%, from 30·6 million (80% UI 9·9–57·3) in 1990 to 36·0 million (80% UI 12·9–65·4) in 2015. This change was attributable to three factors, namely an increase because of population growth (38·4%), population ageing after accounting for population growth (34·6%), and reduction in age-specific prevalence (–36·7%). The number of people with moderate and severe visual impairment also increased, from 159·9 million (80% UI 68·3–270·0) in 1990 to 216·6 million (80% UI 98·5–359·1) in 2015. Interpretation: There is an ongoing reduction in the age-standardised prevalence of blindness and visual impairment, yet the growth and ageing of the world’s population is causing a substantial increase in number of people affected. These observations, plus a very large contribution from uncorrected presbyopia, highlight the need to scale up vision impairment alleviation efforts at all levels

Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis

Background: Contemporary data on causes of vision impairment and blindness form an important basis for recommendations in public health policies. Refreshment of the Global Vision Database with recently published data sources permitted modeling of cause of vision loss data from 1990 to 2015, further disaggregation by cause, and forecasts to 2020. Methods: Published and unpublished population-based data on the causes of vision impairment and blindness from 1980 to 2015 were systematically analysed. A series of regression models were fit to estimate the proportion of moderate and severe vision impairment (MSVI; defined as presenting visual acuity <6/18 but ≥3/60 in the better eye) and blindness (presenting visual acuity <3/60 in the better eye) by cause by age, region, and year. Findings: Among the projected global population with MSVI (216.6 million; 80% uncertainty intervals [UI] 98.5-359.1), in 2015 the leading causes thereof are uncorrected refractive error (116.3 million; UI 49.4-202.1), cataract (52.6 million; UI 18.2-109.6), age-related macular degeneration (AMD; 8.4 million; UI 0.9-29.5), glaucoma (4.0 million; UI 0.6-13.3) and diabetic retinopathy (2.6 million; UI 0.2-9.9). In 2015, the leading global causes of blindness were cataract (12.6 million; UI 3.4-28.7) followed by uncorrected refractive error (7.4 million; UI 2.4-14.8) and glaucoma (2.9 million; UI 0.4-9.9), while by 2020, these numbers affected are anticipated to rise to 13.4 million, 8.0 million and 3.2 million, respectively. Cataract and uncorrected refractive error combined contributed to 55% of blindness and 77% of MSVI in adults aged 50 years and older in 2015. World regions varied markedly in the causes of blindness, with a relatively low prevalence of cataract and a relatively high prevalence of AMD as causes for vision loss in the High-income subregions. Blindness due to cataract and diabetic retinopathy was more common among women, while blindness due to glaucoma and corneal opacity was more common among men, with no gender difference related to AMD. Conclusions: The numbers of people affected by the common causes of vision loss have increased substantially as the population increases and ages. Preventable vision loss due to cataract and refractive error (reversible with surgery and spectacle correction respectively), continue to cause the majority of blindness and MSVI in adults aged 50+ years. A massive scale up of eye care provision to cope with the increasing numbers is needed if one is to address avoidable vision loss

Buildout and integration of an automated high-throughput CLIA laboratory for SARS-CoV-2 testing on a large urban campus

In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the first cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for COVID-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University (BU), created an on-campus COVID-19 screening protocol as part of a plan for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we put together an automated high-throughput clinical testing laboratory with the capacity to run 45,000 individual tests weekly by Fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed reverse transcription PCR (RT-qPCR) test, robotic instrumentation, and trained staff. There were many challenges including supply chain issues for personal protective equipment and testing materials in addition to equipment that were in high demand. The BU Clinical Testing Laboratory (CTL) was operational at the start of Fall 2020 and performed over 1 million SARS-CoV-2 PCR tests during the 2020-2021 academic year.Boston UniversityPublished versio