Exceptional synergistic response of PARP inhibitor and immune checkpoint inhibitor in esophageal adenocarcinoma with a germline BRCA2 mutation: a case report.

Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in various tumors. A significant therapeutic challenge with either ICIs or PARP inhibitors as monotherapy is treatment failure from intrinsic primary resistance or the development of secondarily acquired resistance after a period of responsiveness. The combination of PARP inhibitors and ICIs could mitigate this by potentiating treatment response. We describe an 83-year-old male patient who initially presented with abdominal pain, and weight loss along with alternating constipation and diarrhea. Imaging and biopsy revealed metastatic esophageal adenocarcinoma. Genomic testing revealed germline BRCA2 mutation. The patient initially underwent a few cycles of chemoimmunotherapy. However, due to intolerance to chemotherapy, the patient's case was discussed at a multidisciplinary molecular tumor board. He was switched to PARP inhibitor olaparib and ICI nivolumab. This combination led to a durable complete response. A combination of poly-ADP ribose polymerase inhibitor (PARPi) plus ICI may work in synergy through various mechanisms including enhanced neoantigen expression, release of immune-activating cytokines, and increased programmed death-ligand 1 expression. This may culminate in accentuated efficacy outcomes with a manageable safety profile. This exceptional response with ICI and PARPi in our case is consistent with the synergistic value of this combination, and prospective studies are warranted to definitively characterize clinical utility.

Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report.

BACKGROUND: Although common in lung cancer, somatic epidermal growth factor receptor (EGFR) mutations are rarely found in colorectal cancer, occurring in approximately 3% of cases. Treatment with anti-EGFR antibodies is commonplace, but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer. Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis. CASE SUMMARY: A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair, scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases. Next generation sequencing revealed a RAS/RAF wild-type, microsatellite stable, PD-L1 negative malignancy. Mutations in TP3 and APC were also identified, as well as EGFR amplification. Cell-free DNA analysis revealed an EGFR T790M mutation. She was unable to tolerate first-line treatment with panitumumab, 5-fluorouracil and leucovorin, progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab, and was unable to tolerate third-line treatment with regorafenib. She was started on fourth-line treatment with off-label osimertinib, with clinical response - decrease in size of hepatic metastases and a pericardial effusion. She remained on treatment with osimertinib for seven months. CONCLUSION: This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

Effectiveness of Thermal Ablation for Renal Cell Carcinoma after Prior Partial Nephrectomy.

Background: Repeat partial nephrectomy (PN) for tumors recurring in the ipsilateral kidney is associated with surgical complexity and a higher rate of complications. Objective: To evaluate the local oncologic efficacy of thermal ablation (TA) for renal cell carcinoma (RCC) in the ipsilateral kidney following PN. Design setting participation: We included patients who underwent ablation for renal tumors in the ipsilateral kidney after PN between January 2005 and December 2019. Demographics, tumor size, procedural details, complications, pathology, local oncologic outcomes, and survival outcomes are described. Outcome measurements and statistical analysis: The procedural, pathologic, and oncologic outcomes are described. Survival rates were estimated using the Kaplan-Meier method. Results and limitations: A total of 66 patients (46 male and 20 female) with a median age of 62 yr (interquartile range [IQR] 52-69) met our inclusion criteria. In these patients, 74 TA procedures were performed for 86 lesions (median tumor size 1.9 cm, IQR 1.6-2.5). Radiofrequency ablation and cryoablation accounted for 60 (81%) and 14 (19%) procedures, respectively. Three patients (3.7%) had Clavien-Dindo grade III complications. Of 65 lesion biopsies, 62 (95.5%) were diagnostic. The most common subtype was clear cell RCC (n = 37). The median imaging follow-up duration was 60 mo (IQR 43-88). Recurrence in the ablation zone occurred for four lesions (4.6%) at a median of 6.9 mo (IQR 6.4-10.7). The rates of overall, recurrence-free, and disease-free survival were 93.1%, 94.4%, and 65.6% at 5 yr, and 71.6%, 94.4%, and 60.1% at 10 yr, respectively. Limitations include the retrospective design and the lack of a control group. Conclusions: TA is effective for the treatment of RCC in the ipsilateral kidney following PN. Patient summary: Heat treatment to remove tumor tissue is an effective option for small kidney masses recurring after partial kidney removal for cancer. Long-term follow-up data revealed that this treatment resulted in low recurrence and complication rates.

Utility of RNA Expression to Determine the Tissue of Origin of Malignancies with an Inconclusive Histopathology.

We present 2 cases of cancer of unknown origin in which RNA-based cancer classification testing provided vital insight and directed treatment management. The tissue of origin could not be determined in both of these patients utilizing morphology and immunohistochemical analysis of the tissue samples. Next-generation sequencing and tumor-of-origin testing using an RNA-based molecular cancer classifier were performed to elucidate the possible tissue of origin. A 61-year-old male with a history of localized basal cell carcinoma presented with a 4.4-cm axillary lymph node in addition to upper extremity edema and supraclavicular lymphadenopathy. RNA-based tumor origin testing revealed skin basal or squamous cell carcinoma as the likely tissue of origin, with a probability of 97%. He received vismodegib, a hedgehog inhibitor, after progression on cemiplimab and experienced a partial response by RECIST criteria, which is currently ongoing for over a year. A 74-year-old female patient with a remote history of ovarian cancer for which she underwent resection and adjuvant chemotherapy presented 15 years later with abdominal pain. The diagnostic workup revealed a 2-cm pancreatic mass and enlarged peritoneal lymph nodes. RNA sequencing revealed a 99% likelihood of the tissue of origin being serous ovarian carcinoma. Subsequently, she underwent surgery and adjuvant chemotherapy and is currently in remission with letrozole maintenance. Genomic data already plays a crucial role in therapeutic decision-making for individuals with cancer. These cases highlight the complementary role of genomic data in the diagnostic workup of cancer, leading to favorable patient outcomes.

Transmission of Lung Adenocarcinoma From a Single Donor in 2 Transplant Recipients: A Case Report With Literature Review.

Malignancies transmitted to recipients during solid organ transplants carry significant morbidity and mortality. We present 2 cases of adenocarcinoma of donor lung origin transmitted via liver and kidney transplant from a single donor. Both recipients developed metastatic adenocarcinoma of lung origin with p.L858R mutation in the epidermal growth factor receptor gene and a microsatellite signature of donor origin. Osimertinib was trialed in the liver recipient; however, it was discontinued because of hepatotoxicity and disease progression. Standard donor screening protocols limit malignancy transmission but do not include multicancer detection assays. As these technologies evolve, they may be implemented in donor screening.

Informing youth-centred opioid agonist treatment: Findings from a retrospective chart review of youths' characteristics and patterns of opioid agonist treatment engagement in a novel integrated youth services program.

AIM: Youth ages 12-24 account for approximately 20% of overdoses and yet are poorly reached by opioid agonist treatment (OAT), the most widely recommended treatment for opioid use disorder (OUD). This study contributes to understanding this critical gap by describing youths' patterns of OAT engagement at a novel integrated youth-specific OAT program. METHODS: A retrospective chart review was carried out on electronic medical records of n = 23 youth with OUD accessing a community-based integrated youth services (IYS) centre. Data abstraction focused on four domains: sociodemographic, social determinants of health, patterns of OAT engagement, and other services utilized. RESULTS: Youths' mean age was 22.6 years (SD = 2.1), with a mean age of first opioid use of 17.4 (SD = 2.7). Youth reported extensive histories of adverse childhood experiences, concurrent mental and physical health complications, and poly-substance use. All youth were offered OAT and 83% initiated treatment with buprenorphine/naloxone, methadone, or slow-release oral morphine. Among those initiating OAT, 42.1% were considered stable on OAT. CONCLUSIONS: To our knowledge, this is the first empirical study to describe youths' OAT engagement in an integrated youth-specific OAT program. Our findings demonstrated that a high proportion of youth with OUD initiated OAT in this novel program with varying degrees of OAT stability. These findings can be used to inform the development and implementation of youth-specific and integrated OAT. To account for the novelty of this area of study and small sample sizes, future collaborative efforts across IYS initiatives should be considered, including mixed method approaches to understand outcomes and experiences.

Circumstances of Hospitalization Impact Outcomes of Pulmonary Embolism.

Clinical tools that stratify risk of acute pulmonary embolism (PE) are useful in guiding therapeutic decision making, although may neglect pragmatic and potentially impactful characteristics of hospitalization during care of venous thromboembolism (VTE). Using a retrospective cohort design, consecutive patients discharged after inpatient care for acute PE were retrospectively evaluated for features of hospitalization, including patient characteristics, treatment efficiency, and circumstances of hospitalization. A proportional hazards model incorporated nontraditional risk factors to assess their association with a primary composite endpoint of in-hospital bleeding or death after adjusting for conventional PE risk estimators, including the Pulmonary Artery Severity Index (PESI) and right ventricular/left ventricular (RV/LV) ratio. From January 2016 to December 2018, 822 patients were discharged after treatment for acute PE, including high-risk (5.0%), intermediate-risk (64.2%), and low-risk (30.8%) PE. In-hospital death was 10-fold higher among those with high-risk PE compared to intermediate risk PE (36.6% vs 3.0%, P < 0.001). Overall, 60.4% of hospitalizations were primarily attributed to presentation with VTE. High risk PE was observed more frequently as a secondary event during hospitalizations ostensibly unrelated to VTE (26.8%). After adjustment for PESI score and RV/LV ratio, hypoalbuminia, IVC filter, and non-VTE hospitalization had strong associations with the primary composite outcome. Along with known markers of risk associated with PE, hypoalbuminia, IVC filter placement, and PE complicating hospitalization for circumstances not primarily related to VTE had strong associations with bleeding and death. These findings highlight the complex circumstances of acute PE care and need to refine practical risks.

A novel portable and cost-efficient wheelchair training roller for persons with disabilities in economically disadvantaged settings: the EasyRoller.

PURPOSE: Stationary training rollers enable wheelchair users to maintain physical health and train as athletes, which serves to treat and prevent immobility-associated chronic disease and improve cardiorespiratory fitness required for sports performance. However, conventional exercise equipment is largely inaccessible for persons with disabilities in low-resource areas, primarily due to cost. The aim of this study was to prototype, develop, and test a portable, cost-efficient stationary training device for wheelchair users in low-resource settings - The EasyRoller. MATERIALS AND METHODS: Stakeholder input from wheelchair athletes, trainers, and potential commercial manufacturers was solicited and utilized to conceptualize The EasyRoller design. The device was constructed from easily sourced, low cost components, following which it was user-tested with Para athletes. Feedback was analysed and incorporated into newer versions of the prototype.Results and conclusions: The EasyRoller creatively combines easily-sourced components to significantly cut down cost and ease both manufacture and repair for use in low-resource settings. The device is portable with a total weight of 34 pounds and total size of 42 linear inches while also affordable with a total cost of USD$199. Hereby, The EasyRoller has the potential to increase physical activity participation in populations with impairment who live in socioeconomically deprived world regions.Implications for rehabilitationExercise and physical activity are key aspects of health and quality of life for persons with disabilitiesStationary training rollers, devices that enable wheelchair users to train, are often bulky and expensive and therefore inaccessible for populations in socio-economically disadvantaged settingsThe EasyRoller is a portable and affordable training device that increases access to exercise and physical activity for these populations.

In-Hospital Mortality and Related Outcomes for Elevated Risk Acute Pulmonary Embolism Treated With Mechanical Thrombectomy Versus Routine Care.

PURPOSE: To compare in-hospital mortality and other hospitalization related outcomes of elevated risk patients (Pulmonary Embolism Severity Index [PESI] score of 4 or 5, and, European Society of Cardiology [ESC] classification of intermediate-high or high risk) with acute central pulmonary embolism (PE) treated with mechanical thrombectomy (MT) using the Inari FlowTriever device versus those treated with routine care (RC). MATERIALS AND METHODS: Retrospective data was collected of all patients with acute, central PE treated at a single institution over 2 concurrent 18-month periods. All collected patients were risk stratified using the PESI and ESC Guidelines. The comparison was made between patients with acute PE with PESI scores of 4 or 5, and, ESC classification of intermediate-high or high risk based on treatment type: MT and RC. The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included intensive care unit (ICU) length of stay, total hospital length of stay, and 30-day readmission. RESULTS: Fifty-eight patients met inclusion criteria, 28 in the MT group and 30 in the RC group. Most RC patients were treated with systemic anticoagulation alone (24 of 30). In-hospital mortality was significantly lower for the MT group than for the RC group (3.6% vs 23.3%, P < .05), as was the average ICU length of stay (2.1 ± 1.2 vs 6.1 ± 8.6 days, P < .05). Total hospital length of stay and 30-day readmission rates were similar between MT and RC groups. CONCLUSION: Initial retrospective comparison suggests MT can improve in-hospital mortality and decrease ICU length of stay for patients with acute, central PE of elevated risk (PESI 4 or 5, and, ESC intermediate-high or high risk).

The Perry Initiative's Impact on Gender Diversity Within Orthopedic Education.

PURPOSE OF REVIEW: Orthopedic surgery lags behind the other surgical specialties in terms of reaching gender equality, and women remain underrepresented in the field. The reason for this disparity is multifaceted, with lack of exposure and mentorship frequently cited as two key reasons women fail to choose orthopedic surgery as a specialty. Recognizing these gender differences, The Perry Initiative was founded to increase young women's exposure to the field, provide mentorship opportunities, and recruit women into orthopedic surgery and related engineering fields. The purpose of this article is to describe the measurable impact of The Perry Initiative on increasing the number of women matriculating into orthopedic residencies. RECENT FINDINGS: Though roughly half of medical school graduates today are women, only 16% of active orthopedic surgery residents are women. To date, The Perry Initiative has reached over 12,000 women in high school and medical school, and of the program participants who are eligible to match into any residency program, 20% matched into orthopedic surgery residencies. This indicates that the women who participated in Perry Initiative outreach programs are entering orthopedic surgery at a rate that is higher than the current rate of women entering orthopedic surgery. The model behind The Perry Initiative's outreach efforts can be scaled and expanded, ideally reaching more women and making progress towards closing the gender gap within orthopedic surgery and achieving greater gender diversity.

Safety and Efficacy of Acute Pulmonary Embolism Treated via Large-Bore Aspiration Mechanical Thrombectomy Using the Inari FlowTriever Device.

PURPOSE: To report initial experience with safety and efficacy in the treatment of pulmonary embolism (PE) using the FlowTriever device. MATERIALS AND METHODS: A single-center retrospective study was performed in all patients with acute central PE treated using the FlowTriever device between March 2018 and March 2019. A total of 46 patients were identified (massive = 8; submassive = 38), all with right ventricular (RV) strain and 26% with thrombolytic contraindications. Technical success (according to SIR reporting guidelines) and clinical success (defined as mean pulmonary artery pressure intraprocedural improvement) are reported, as are major device and procedure-related complications within 30 days after discharge. RESULTS: Technical success was achieved in 100% of cases (n = 46). Average mean pulmonary artery pressure improved significantly from before to after the procedure for the total population (33.9 ± 8.9 mm Hg before, 27.0 ± 9.0 mm Hg after; P < .0001; 95% confidence interval [CI], 5.0-8.8), submassive cohort (34.7 ± 9.1 mm Hg before, 27.4 ± 9.2 mm Hg after; P < .0001; 95% CI, 5.2-9.5) and massive cohort (30.4 ± 6.9 mm Hg before, 25.4 ± 8.2 mm Hg after; P < .05; 95% CI:0.4-9.6). Intraprocedural reduction in mean pulmonary artery pressure was achieved in 88% (n = 37 of 42). A total of 100% of patients (n = 46 of 46) survived to hospital discharge. In total, 71% of patients (n = 27 of 38) experienced intraprocedural reduction in supplemental oxygen requirements. Two major adverse events (4.6%) included hemoptysis requiring intubation, and procedure-related blood loss requiring transfusion. No delayed procedure-related complications or deaths occurred within 30 days of hospital discharge. CONCLUSIONS: Initial clinical experience using the FlowTriever to perform mechanical thrombectomy showed encouraging trends with respect to safety and efficacy for the treatment of acute central, massive, and submassive pulmonary embolism.

Multimodality Imaging of Focal and Diffuse Fibrosing Mediastinitis.

Fibrosing mediastinitis is a rare benign but potentially life-threatening process that occurs because of proliferation of fibrotic tissue in the mediastinum. The focal subtype is more common and typically is associated with an abnormal immunologic response to Histoplasma capsulatum infection. Affected patients are typically young at presentation, but a wide age range has been reported, without a predilection for either sex. The diffuse form may be idiopathic or associated with autoimmunity, usually affects middle-aged and/or elderly patients, and is more common in men. For both subtypes, patients present with signs and symptoms related to obstruction or compression of vital mediastinal structures. The most common presenting signs and symptoms are cough, dyspnea, recurrent pneumonia, hemoptysis, and pleuritic chest pain. Patients with the diffuse subtype may have additional extrathoracic symptoms depending on the other organ systems involved. Because symptom severity is variable, treatment should be individualized with therapies tailored to alleviate compression of the affected mediastinal structures. Characteristic imaging features of fibrosing mediastinitis include infiltrative mediastinal soft tissue (with or without calcification) with compression or obstruction of mediastinal vascular structures and/or the aerodigestive tract. When identified in the appropriate clinical setting, these characteristic features allow the radiologist to suggest the diagnosis of fibrosing mediastinitis. Careful assessment is crucial at initial and follow-up imaging for exclusion of underlying malignancy, assessment of disease progression, identification of complications, and evaluation of treatment response. Online supplemental material is available for this article. ©RSNA, 2019.

Automated Breast Ultrasound Interpretation Times: A Reader Performance Study.

RATIONALE AND OBJECTIVES: This study aimed to determine the average time for breast radiologists of varied experience to interpret automated breast ultrasound (ABUS) examinations. MATERIALS AND METHODS: A reader performance study was conducted on female patients, with ACR BI-RADS 4 breast density classifications of C or D, who received both an ABUS screening examination and a digital mammogram from 2013 to 2014 at an academic institution. Three faculty breast radiologists with varied levels of ABUS experience (advanced, intermediate, novice) read all ABUS examinations, with interpretation times and final impressions (categorized as "normal" or "abnormal") recorded for each examination. RESULTS: Ninety-nine patients were included, with all readers demonstrating an average ABUS interpretation time of less than 3 minutes. Compared to the other two readers, the intermediate reader had a significantly longer mean interpretation time at 2.6 minutes (95% confidence interval 2.4-2.8; P < .001). In addition to having the shortest mean interpretation time, the novice reader also demonstrated reduced times in subsequent interpretations, with a significant decrease in interpretation times of 3.1 seconds (95% confidence interval 0.4-5.8) for every 10 ABUS examinations interpreted (P < .05). CONCLUSIONS: Overall, mean ABUS interpretation time by radiologists of all experience levels was short, at less than 3 minutes per examination, which should not deter radiologists from incorporating ABUS examinations into a busy clinical environment.

A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta).

The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

The Australian baby boomer population--factors influencing changes to health-related quality of life over time.

OBJECTIVE: Identify factors associated with changes to health-related quality of life (HRQoL) in baby boomers. METHODS: Panel data were collected on baby boomers at two time points, 2000-2002 and 2004-2006. A fixed-effects model was used to identify associations between changes in the dependent variable (SF-36 summary scales) and changes in independent variables (health indicators/employment status). RESULTS: Mental health problems, being out of labor force, sedentary behavior, and severe lung disease were associated with deterioration in physical and mental HRQoL. Obesity was associated with deterioration in physical HRQoL whereas cardiovascular disease was associated with deterioration in mental HRQoL. Unemployment, full-time employment, and absence of lung disease symptoms were associated with improvements in physical and mental HRQoL. DISCUSSION: If we are to maximize the future labor participation, and HRQoL, of this cohort, it will be necessary to reduce obesity and sedentary behavior and to further investigate the association between health and employment.

The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.

Baby boomers, obesity, and social change.

SUMMARY: Baby boomers are currently in mid-life and over the next several decades they will swell the ranks of those aged 65 and over. Their entry into this age group will have a significant impact in a number of areas but particularly in relation to the type and extent of health services required. Obesity is a major health issue for this cohort as its members are significantly over-represented in both the overweight and obese categories compared to the rest of the population. In addition, they are significantly more likely to have multiple risk factors. This review considers how alterations to lifestyle, initiated by the rapid social changes of the last half century, might have contributed to obesity within this cohort. In providing this broad overview it focuses on how increased affluence and changes to everyday institutions have affected the cultures around food consumption. This includes a consideration of both the internal and external ways in which eating environments are now constructed. This review suggests that further research is needed to identify the factors which facilitate or constrain healthy ageing in the baby boom cohort. Research along these lines also needs to consider both macro- and micro-level changes to the social context within which these factors arise. This is essential as the high levels of obesity in this cohort may reflect both an individual and a structural lag in adapting lifestyles and policies to meet the needs of this very different social environment.: