Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

INTRODUCTION: Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. METHODS: We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. RESULTS: The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). CONCLUSION: A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

Transient Severe Functional Mitral Valve Regurgitation: An Extremely Rare Cause of Recurrent Pulmonary Edema.

A 79-year-old woman presented with recurrent pulmonary edema. Extensive testing spanning 5 admissions showed only mild mitral regurgitation (MR). A transthoracic echocardiogram with the patient in the supine position and passive leg raise showed severe MR. This suggested transient severe MR. She underwent mitral valve replacement and had an uneventful postoperative course without recurrence of symptoms. (Level of Difficulty: Intermediate.).

Diagnostic and antibiotic stewardship lessons: an outpatient assessment of symptomatic reflex urinalysis ordering accuracy using an electronic best-practice alert.

BACKGROUND: It is not well known how reliably clinicians order reflex urinalysis to microscopy and culture (rUA-cx) for outpatient urinary tract infection (UTI) workup. Antibiotic appropriateness cannot be fully appreciated until the prevalence of UTIs and asymptomatic bacteriuria (ASB) are realized. OBJECTIVE: This quality improvement study has two major aims, first to determine UTI symptom accuracy for rUA-cx ordering and second, to confirm UTI and ASB cases by integrating rUA-cx and cascaded urinalysis results. Antibiotic utilization and diagnostic coding were secondarily linked to UTIs and ASB. METHODS: An electronic best-practice alert informed the ordering of two rUA-cx options: symptomatic- rUA-cx specifically for dysuria, frequency, urgency, costovertebral pain, suprapubic pain or fever versus non-specific-rUA-cx for vague complaints. UTI symptoms were verified by chart review. Confirmed UTI was defined as a significant culture with UTI symptoms and ASB as a significant culture without UTI symptoms. RESULTS: rUA-cx (2065) were prospectively collected over 6 months from female patients at risk for uncomplicated UTIs. Symptomatic-rUA-cx and non-specific-rUA-cx were associated with UTI symptoms for 53% (809/1527) and 20% (107/538), respectively. Overall, 44% (916/2065) of all rUA-cx had UTI symptoms. rUA-cx were overordered by a factor of 9 (2065/225) for every confirmed UTI. The UTI-to-ASB relative ratio was 2.6 (225/86). Regarding UTI-relevant antibiotics, 39% (214/553) were appropriately associated with UTI whereas only 22% (74/339) of inappropriate antibiotics were captured by the ASB definition, underestimating the problem 4-fold. CONCLUSIONS: UTI and ASB remain challenging to categorize despite a meticulous method that applied acceptable criteria.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Adjuvant Therapy After Neoadjuvant Therapy for Esophageal Cancer: Who Needs It?

OBJECTIVE: We hypothesized that, on average, patients do not benefit from additional adjuvant therapy after neoadjuvant therapy for locally advanced esophageal cancer, although subsets of patients might. Therefore, we sought to identify profiles of patients predicted to receive the most survival benefit or greatest detriment from adding adjuvant therapy. BACKGROUND: Although neoadjuvant therapy has become the treatment of choice for locally advanced esophageal cancer, the value of adding adjuvant therapy is unknown. METHODS: From 1970 to 2014, 22,123 patients were treated for esophageal cancer at 33 centers on 6 continents (Worldwide Esophageal Cancer Collaboration), of whom 7731 with adenocarcinoma or squamous cell carcinoma received neoadjuvant therapy; 1348 received additional adjuvant therapy. Random forests for survival and virtual-twin analyses were performed for all-cause mortality. RESULTS: Patients received a small survival benefit from adjuvant therapy (3.2±10 months over the subsequent 10 years for adenocarcinoma, 1.8±11 for squamous cell carcinoma). Consistent benefit occurred in ypT3-4 patients without nodal involvement and those with ypN2-3 disease. The small subset of patients receiving most benefit had high nodal burden, ypT4, and positive margins. Patients with ypT1-2N0 cancers had either no benefit or a detriment in survival. CONCLUSIONS: Adjuvant therapy after neoadjuvant therapy has value primarily for patients with more advanced esophageal cancer. Because the benefit is often small, patients considering adjuvant therapy should be counseled on benefits versus morbidity. In addition, given that the overall benefit was meaningful in a small number of patients, emerging modalities such as immunotherapy may hold more promise in the adjuvant setting.

Comparison of Radiation Exposure Among Interventional Echocardiographers, Interventional Cardiologists, and Sonographers During Percutaneous Structural Heart Interventions.

Importance: Transesophageal echocardiography during percutaneous left atrial appendage closure (LAAO) and transcatheter edge-to-edge mitral valve repair (TEER) require an interventional echocardiographer to stand near the radiation source and patient, the primary source of scatter radiation. Despite previous work demonstrating high radiation exposure for interventional cardiologists performing percutaneous coronary and structural heart interventions, similar data for interventional echocardiographers are lacking. Objective: To assess whether interventional echocardiographers are exposed to greater radiation doses than interventional cardiologists and sonographers during structural heart procedures. Design, Setting, and Participants: In this single-center cross-sectional study, radiation doses were collected from interventional echocardiographers, interventional cardiologists, and sonographers at a quaternary care center during 30 sequential LAAO and 30 sequential TEER procedures from July 1, 2016, to January 31, 2018. Participants and study personnel were blinded to radiation doses through data analysis (January 1, 2020, to October 12, 2021). Exposures: Occupation defined as interventional echocardiographers, interventional cardiologists, and sonographers. Main Outcomes and Measures: Measured personal dose equivalents per case were recorded using real-time radiation dosimeters. Results: A total of 60 (30 TEER and 30 LAAO) procedures were performed in 60 patients (mean [SD] age, 79 [8] years; 32 [53.3%] male) with a high cardiovascular risk factor burden. The median radiation dose per case was higher for interventional echocardiographers (10.6 µSv; IQR, 4.2-22.4 µSv) than for interventional cardiologists (2.1 µSv; IQR, 0.2-8.3 µSv; P < .001). During TEER, interventional echocardiographers received a median radiation dose of 10.5 µSv (IQR, 3.1-20.5 µSv), which was higher than the median radiation dose received by interventional cardiologists (0.9 µSv; IQR, 0.1-12.2 µSv; P < .001). During LAAO procedures, the median radiation dose was 10.6 µSv (IQR, 5.8-24.1 µSv) among interventional echocardiographers and 3.5 (IQR, 1.3-6.3 µSv) among interventional cardiologists (P < .001). Compared with interventional echocardiographers, sonographers exhibited low median radiation doses during both LAAO (0.2 µSv; IQR, 0.0-1.6 µSv; P < .001) and TEER (0.0 µSv; IQR, 0.0-0.1 µSv; P < .001). Conclusions and Relevance: In this cross-sectional study, interventional echocardiographers were exposed to higher radiation doses than interventional cardiologists during LAAO and TEER procedures, whereas sonographers demonstrated comparatively lower radiation doses. Higher radiation doses indicate a previously underappreciated occupational risk faced by interventional echocardiographers, which has implications for the rapidly expanding structural heart team.

Acellular mucin in lymph nodes isolated from treatment-naïve colorectal cancer resections: a clinicopathologic analysis of 16 cases.

Lymph nodes with acellular mucin harvested from treated colorectal cancers (CRC) are staged as pN0. However, there is variability among pathologists while reporting the pN stage when acellular mucin is found within nodes of untreated CRCs. While the UICC guidelines suggest staging them as pN1, the AJCC and CAP do not offer any recommendations. In order to characterize their clinicopathologic features and outcome, we compared 16 untreated CRCs (study group; mean age: 68 years) harboring nodes with acellular mucin with 34 pN0 and 25 pN1 untreated CRC controls. All tumors were unifocal; 12 (75%) were right-sided lesions. Most cases (75%) showed one node with acellular mucin (range: 1-3). MMR-deficient tumors were significantly more common in the study group (83%) compared to pN0 (33%; p = 0.006) and pN1 controls (8%; p < 0.001). The overall survival of study group patients was closer to pN0 compared to pN1 controls; however, this difference was not statistically significant. In conclusion, untreated CRC that harbor acellular mucin within lymph nodes commonly present as right-sided, MMR-deficient tumors in older women that show a non-mucinous phenotype. While the limited number of cases precludes us from making any formal recommendations about staging, we suggest that the finding of acellular mucin in a node should prompt evaluation of deeper levels (with or without cytokeratin immunohistochemistry) and submission of all pericolonic fat for additional lymph node harvest. Whether acellular mucin in nodes of untreated CRCs is related to the indolent biology of the disease, a robust local immune response or MMR deficiency requires further investigation.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Cardiac Rehabilitation and Resting Blood Pressure: MONTANA OUTCOMES PROJECT CARDIAC REHABILITATION REGISTRY FINDINGS.

PURPOSE: Exercise-based cardiac rehabilitation (CR) is essential for treating cardiovascular disease, and modifying risk factor modification, including hypertension. Because the causes of hypertension and benefits of CR are faceted, we examined the influence of phase II CR on resting blood pressure (BP). METHODS: Outcomes straddle the release of the updated BP guidelines, and study emphases included CR session number, sex, race/ethnicity, insurance provider, and referring diagnosis. RESULTS: Patient files of 31 885 individuals uploaded to the Montana Outcomes Project registry indicated that lowered systolic and diastolic BP were further improved after the release of the revised BP guidelines. The CR session number was proportional to improvements in diastolic BP. Blood pressure improved independent of sex, although female patients exhibited lower diastolic BP before and after CR. Race/ethnicity analyses indicated that Asian and White patients experienced drops in systolic and diastolic BP, while diastolic BP was improved in Hispanic patients. Neither American Indian nor Black patients exhibited statistically altered BP. Medicare, Veterans Administration, and privately insured patients had lowered systolic and diastolic BP, while Medicaid patients had lower diastolic BP, and the uninsured had lower systolic BP. Blood pressure outcomes were generally improved independent of the primary referring diagnosis, while those with peripheral artery disease showed no improvements. CONCLUSIONS: Findings demonstrate that phase II CR is highly effective in the control of BP, although improvements are not equally distributed to all individuals according to differences in sex, race/ethnicity, and access to insurance-funded health care.

Robotic-assisted Resection of a Diaphragmatic Metastasis of a Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumors (GISTs) are relatively rare mesenchymal tumors. The treatment of these tumors has drastically changed based on molecular treatment methods, namely tyrosine kinase inhibitors, which have led to impressive survival benefits. While medical management has enhanced patient outcomes, surgery is still the standard of care for stable, completely resectable primary tumors or metastases that are >2 cm. This case presents the resection of a diaphragmatic metastasis of a tyrosine kinase inhibitor-controlled GIST in a 51-year-old male. The surgery was collaboratively approached from both the thoracic and abdominal cavities, utilizing the da Vinci robotic system. Prior data is limited regarding patient outcomes after robotic-assisted resection of GISTs. However, small case series have shown it to be a safe and effective surgical option. Our patient's quick recovery and return to normal function demonstrate the successful use of robotic-assisted surgery for GIST resection.

Worsening of Behcet Syndrome Symptoms During Pregnancy.

Behcet disease is a rare, chronic multisystem vasculitis of unknown etiology. It commonly causes oral and genital ulcers, eye lesions, and vascular lesions. There are limited published reports on this condition in pregnant patients and the data that does exist shows remission of the disease in most pregnant patients. Arterial and venous thrombotic events appear to be a major comorbidity in patients with Behcet disease. This is a case report of a 24-year-old pregnant woman who presented with worsening Behcet disease symptoms during her second pregnancy. Her first pregnancy was not affected by the disease. Worsening of symptoms must be considered in pregnant women with Behcet disease and treated promptly due to potential life-threatening consequences.

Target Lesion Lipid Content Detected by Near-Infrared Spectroscopy After Stenting and the Risk of Subsequent Target Lesion Failure.

[Figure: see text].

Recurrent Cardiogenic Syncope From Extrinsic Organ Anomaly.

CASE PRESENTATION: A 40-year-old woman presented with recurrent syncope. She reported multiple (>20) episodes of non-prodromal loss of consciousness, periodically provoked by physical exertion. One episode resulted in a nasal fracture due to the abrupt nature of her syncope. The characterization of each episode was inconsistent with a neurogenic seizure. Other causes of syncope (vasovagal, situational, carotid hypersensitivity, and orthostasis) were also deemed unlikely. On physical examination, a low-pitched, brief adventitious sound was appreciated after each S2 sound in the right lower sternal border. The remainder of the physical examination was unremarkable. Initial workup, including complete blood count, comprehensive metabolic panel, cardiac enzymes, and ECG yielded normal results. The chest radiograph did not show any gross cardiac or pulmonary parenchymal pathologic condition (Fig 1). Telemetry did not demonstrate any malignant arrhythmias, and video-guided EEG did not document any seizure activity.

Is Opioid-free Post-Vasectomy Analgesia a Pain? A Single Surgeon Experience.

OBJECTIVE: To determine the impact of transitioning from opioid to non-opioid analgesia post-vasectomy on unplanned opioid prescriptions and health encounters. METHODS: A retrospective review for patients who underwent vasectomy from October 2018 through December 2019 was performed. Beginning February 1st, 2019, patients were counseled to take scheduled acetaminophen and ibuprofen in lieu of acetaminophen with codeine, with an opioid prescription only provided upon request. Analysis was performed comparing 200 consecutive patients before and after this transition. Baseline patient characteristics, unplanned postoperative encounters for pain within 30 days of vasectomy, and associated narcotic prescriptions were compared between groups. RESULTS: 400 patients were included, consisting of 200 patients pre and 200 patients postintervention. There were no differences in socioeconomic characteristics between groups. No differences between the pre- and postintervention groups were observed in terms of generating telephone calls to clinic (9% vs 11%, P = .5), clinic visits (2.5% vs 2.5%, P = 1), or ED visits (0% vs 1%), P = .5) for the pre and postintervention cohorts, respectively. CONCLUSIONS: Patients that are not prescribed opioids after vasectomy do not generate additional phone calls, clinic, or ED visits compared to those that were routinely prescribed prior to our institutional change. We have permanently discontinued the routine use of opioids for post-vasectomy analgesia. Other physicians performing vasectomy should consider making this change as well.

Stationary and portable multipollutant monitors for high-spatiotemporal-resolution air quality studies including online calibration.

The distribution and dynamics of atmospheric pollutants are spatiotemporally heterogeneous due to variability in emissions, transport, chemistry, and deposition. To understand these processes at high spatiotemporal resolution and their implications for air quality and personal exposure, we present custom, low-cost air quality monitors that measure concentrations of contaminants relevant to human health and climate, including gases (e.g., O3, NO, NO2, CO, CO2, CH4, and SO2) and size-resolved (0.3-10 µm) particulate matter. The devices transmit sensor data and location via cellular communications and are capable of providing concentration data down to second-level temporal resolution. We produce two models: one designed for stationary (or mobile platform) operation and a wearable, portable model for directly measuring personal exposure in the breathing zone. To address persistent problems with sensor drift and environmental sensitivities (e.g., relative humidity and temperature), we present the first online calibration system designed specifically for low-cost air quality sensors to calibrate zero and span concentrations at hourly to weekly intervals. Monitors are tested and validated in a number of environments across multiple outdoor and indoor sites in New Haven, CT; Baltimore, MD; and New York City. The evaluated pollutants (O3, NO2, NO, CO, CO2, and PM2.5) performed well against reference instrumentation (e.g., r = 0.66-0.98) in urban field evaluations with fast e-folding response times (≤1 min), making them suitable for both large-scale network deployments and smaller-scale targeted experiments at a wide range of temporal resolutions. We also provide a discussion of best practices on monitor design, construction, systematic testing, and deployment.

Siewert III Adenocarcinoma: Still Searching for the Right Treatment Combination.

It remains uncertain whether Siewert III tumors should be treated as esophageal or gastric cancers. Neoadjuvant therapy has been shown to improve survival in both esophageal and gastric trials. Randomized control trials comparing neoadjuvant chemotherapy versus chemoradiation should help define the most optimal treatment regimen. Surgical treatment follows general oncology principals: resect to negative margins with complete lymph node dissection, and, the extent of resection often extends more proximal onto the esophagus in addition to the total/subtotal gastrectomy.

Occipital artery to p3 segment of posterior inferior cerebellar artery bypass in treating a complex fusiform aneurysm.

We provide a case report of a 58-year-old man who presented with a ruptured fusiform dissecting aneurysm located at the junction of the vertebral artery and posterior inferior cerebellar artery (PICA). Due to the lesion's complexity, a two-step approach was planned for revascularisation of PICA using the occipital artery (OA) prior to coiling embolisation. An end-to-side OA-PICA bypass was performed with implantation at the caudal loop of the p3 PICA segment. Fifteen days after the procedure, the aneurysm underwent stent-assisted coiling for successful obliteration of the aneurysm. The patient tolerated this procedure well and now at 1.5 years of follow-up remains free from any neurological deficits (modified Rankin Score 0). This case report illustrates one of the unique scenarios where both the vascular territory involved and morphological features of the aneurysm prohibited the use of more conventional means, necessitating the use of an arterial bypass graft for successful treatment of this lesion. As open vascular surgery is becoming less common in the age of endovascular coiling, our article uniquely reports on the combined use of both endovascular and microsurgical techniques to treat a complex aneurysm of the posterior circulation.

NKTR-214 immunotherapy synergizes with radiotherapy to stimulate systemic CD8+ T cell responses capable of curing multi-focal cancer.

BACKGROUND: High-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+ T cell and natural killer cell stimulation compared with IL-2. METHODS: Animals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray. RESULTS: We demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+ T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors. CONCLUSIONS: Given the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.