A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil in Metastatic Colorectal Adenocarcinoma.

INTRODUCTION: This study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: Single institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed. RESULTS: Fifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%. CONCLUSION: The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC. CLINICALTRIALS: GOV: NCT04868773.

Plants as vectors for environmental prion transmission.

Prions cause fatal neurodegenerative diseases and exhibit remarkable durability, which engenders a wide array of potential exposure scenarios. In chronic wasting disease of deer, elk, moose, and reindeer and in scrapie of sheep and goats, prions are transmitted via environmental routes and the ability of plants to accumulate and subsequently transmit prions has been hypothesized, but not previously demonstrated. Here, we establish the ability of several crop and other plant species to take up prions via their roots and translocate them to above-ground tissues from various growth media including soils. We demonstrate that plants can accumulate prions in above-ground tissues to levels sufficient to transmit disease after oral ingestion by mice. Our results suggest plants may serve as vectors for prion transmission in the environment-a finding with implications for wildlife conservation, agriculture, and public health.

A Machine Learning Model for Predicting Mortality within 90 Days of Dialysis Initiation.

Background: The first 90 days after dialysis initiation are associated with high morbidity and mortality in end-stage kidney disease (ESKD) patients. A machine learning-based tool for predicting mortality could inform patient-clinician shared decision making on whether to initiate dialysis or pursue medical management. We used the eXtreme Gradient Boosting (XGBoost) algorithm to predict mortality in the first 90 days after dialysis initiation in a nationally representative population from the United States Renal Data System. Methods: A cohort of adults initiating dialysis between 2008-2017 were studied for outcome of death within 90 days of dialysis initiation. The study dataset included 188 candidate predictors prognostic of early mortality that were known on or before the first day of dialysis and was partitioned into training (70%) and testing (30%) subsets. XGBoost modeling used a complete-case set and a dataset obtained from multiple imputation. Model performance was evaluated by c-statistics overall and stratified by subgroups of age, sex, race, and dialysis modality. Results: The analysis included 1,150,195 patients with ESKD, of whom 86,083 (8%) died in the first 90 days after dialysis initiation. The XGBoost models discriminated mortality risk in the nonimputed (c=0.826, 95% CI, 0.823 to 0.828) and imputed (c=0.827, 95% CI, 0.823 to 0.827) models and performed well across nearly every subgroup (race, age, sex, and dialysis modality) evaluated (c>0.75). Across predicted risk thresholds of 10%-50%, higher risk thresholds showed declining sensitivity (0.69-0.04) with improving specificity (0.79-0.99); similarly, positive likelihood ratio was highest at the 40% threshold, whereas the negative likelihood ratio was lowest at the 10% threshold. After calibration using isotonic regression, the model accurately estimated the probability of mortality across all ranges of predicted risk. Conclusions: The XGBoost-based model developed in this study discriminated risk of early mortality after dialysis initiation with excellent calibration and performed well across key subgroups.

Development of a Visualization Tool for Healthcare Decision-Making using Electronic Medical Records: A Systems Approach to Viewing a Patient Record.

Healthcare delivery systems are widely accepted as socio-technical systems. Unlike other socio-technical systems, healthcare systems leave very little decision-making to technical automation and control. Instead, the healthcare delivery system relies on human healthcare resources for decision-making. Human decision-making is imperative to the clinical delivery of care to patients and to the operational processes that support care delivery, quality improvement, and other organizational management activities. For these clinical and operational activities, human resources make healthcare decisions using healthcare data typically housed in electronic medical records (EMRs). Unfortunately, EMR systems were first designed with the functional capability to store data, and, second to a lesser degree, to retrieve data. The literature recognizes the need to improve the retrieval of information from EMR systems. More specifically, there remains the need to directly view a patient's holistic health and healthcare trajectory. At this time, decision-makers are left to mentally build this holistic picture in their mind by sequentially clicking through many sections of the EMR. Therefore, in this paper, we develop a visualization tool to organize and present an individual's health and healthcare trajectory by describing a patient record holistically from a system architecture perspective. This approach is based on a previously developed system model for healthcare delivery and individual health outcomes.

Heterozygous Alpha-1 Antitrypsin Deficiency Causing Pulmonary Emboli and Pulmonary Bullae.

Alpha-1 antitrypsin deficiency is an autosomal co-dominant disease known for different genetic alterations in the serine protease inhibitor enzyme by which different disease phenotypes can manifest. The lung and the liver are the most common organs involved. The severity of the disease depends on the phenotypes involved. However, emerging evidence shows that this disease can impact multiple organ systems and may even develop regardless of the phenotype. We describe a case of a young man with a known history of the MS phenotype who presented with chest pain and was found to have pulmonary emboli and bullae. His past medical history was relevant for a gastric ulcer and elevated liver enzymes. Due to this young man's age and lack of risk factors for the aforementioned diseases, we propose that these findings were manifestations of his MS phenotype. This case raises multiple questions challenging the presumed benign nature of the MS phenotype. We propose a closer follow-up and lower threshold for diagnostic studies in patients with the heterozygous form.

Primary Clear Cell Carcinoma of the Pancreas: A Systematic Review.

Over the years, the world has witnessed many advances in diagnosing and treating multiple types of cancers. These breakthroughs have revolutionized the understanding of the molecular drive behind these neoplasms, leading to tangible therapeutic evolution and promising prognostic implications. However, pancreatic cancer remains a highly lethal disease. With recent discoveries, modern medicine has been able to delineate histopathologic subtypes of pancreatic cancer in hopes of improved diagnosis and treatment to improve survival. A once vague entity, clear cell adenocarcinoma of the pancreas, in particular, has been better characterized on a histopathological and molecular level over the past two decades. With novel technological support, this disease has become less inconspicuous, and more researchers have reported its occurrence. Its diagnosis relies heavily on a mix of histological and immunohistochemical clues such as a clear cell cytoplasm and positivity for cytokeratins and other markers. However, new molecular markers, such as hepatocyte nuclear factor 1 beta, have been associated with this entity and may aid in further diagnostic and therapeutic strategies. This review article aims to portray how the identification and description of clear cell adenocarcinoma of the pancreas have evolved over the past few decades and how this may impact future treatment strategies.

A 64-year-old woman with rapid neurologic decline diagnosed with Toxoplasma encephalitis after presumed metastatic cancer.

In an era of fragmented medical care, concurrent clinical features that ultimately lead to a unified diagnosis may not be prioritized appropriately. We present a case of a 64-year-old woman referred to hematology clinic for anemia, with recent memory loss and gait disturbance. Two months later, she developed pneumonia; imaging workup showed a left renal mass. Neurologic function continued to decline precluding definitive nephrectomy. She then presented with new-onset seizure and initial neuro-imaging was reported as unremarkable. One month later, outpatient neurologic workup demonstrated new left-sided weakness which prompted hospitalization and repeat neuro-imaging, which showed a 1.7-cm right frontal lobe mass lesion with surrounding vasogenic edema. The patient ultimately underwent craniotomy with resection of the mass lesion; pathology did not show metastatic renal cell cancer, the provisional clinical diagnosis. Rather, immunostaining revealed a parasite and ultimately led to a diagnosis of Toxoplasma encephalitis, an infection whose clinical presentation had been interpreted by healthcare providers for months to be a result of metastatic cancer.

Machine learning of EEG spectra classifies unconsciousness during GABAergic anesthesia.

In current anesthesiology practice, anesthesiologists infer the state of unconsciousness without directly monitoring the brain. Drug- and patient-specific electroencephalographic (EEG) signatures of anesthesia-induced unconsciousness have been identified previously. We applied machine learning approaches to construct classification models for real-time tracking of unconscious state during anesthesia-induced unconsciousness. We used cross-validation to select and train the best performing models using 33,159 2s segments of EEG data recorded from 7 healthy volunteers who received increasing infusions of propofol while responding to stimuli to directly assess unconsciousness. Cross-validated models of unconsciousness performed very well when tested on 13,929 2s EEG segments from 3 left-out volunteers collected under the same conditions (median volunteer AUCs 0.99-0.99). Models showed strong generalization when tested on a cohort of 27 surgical patients receiving solely propofol collected in a separate clinical dataset under different circumstances and using different hardware (median patient AUCs 0.95-0.98), with model predictions corresponding with actions taken by the anesthesiologist during the cases. Performance was also strong for 17 patients receiving sevoflurane (alone or in addition to propofol) (median AUCs 0.88-0.92). These results indicate that EEG spectral features can predict unconsciousness, even when tested on a different anesthetic that acts with a similar neural mechanism. With high performance predictions of unconsciousness, we can accurately monitor anesthetic state, and this approach may be used to engineer infusion pumps to intelligibly respond to patients' neural activity.

Testicular Germ Cell Tumors: Paraneoplastic Syndromes and the Role of Beta-Human Chorionic Gonadotropin.

Choriocarcinoma syndrome is a rare phenomenon that occurs in male patients with testicular choriocarcinoma. Male patients who have a testicular non-seminomatous germ cell tumor (TNSGCT) with at least partial choriocarcinoma histology, and metastases to the lungs and/or other extragonadal sites, as well as a markedly elevated beta-human chorionic gonadotropin (HCG), have been prone to pulmonary bleeding, hypoxia, and acute respiratory distress syndrome (ARDS). The respiratory complications occur immediately after chemotherapy is administered or, in some cases, spontaneously. Paraneoplastic hyperthyroidism is another entity described in patients with testicular choriocarcinoma, whereby high levels of HCG (typically >50,000 mIU/ml) induce clinical and laboratory characteristics of hyperthyroidism. We present the case of a male patient diagnosed with TNSGCT and found to have both choriocarcinoma syndrome and paraneoplastic hyperthyroidism in the setting of only mildly elevated HCG levels. We compare our case with similar cases published previously while questioning the quantitative role of HCG.

Primary Refractory Catastrophic Antiphospholipid Syndrome Masquerading as Buerger's Disease.

Catastrophic antiphospholipid syndrome (CAPS) is a lethal disease with up to 30% mortality rate. It can occur as a primary disease or secondary to an underlying autoimmune disease. Current treatment focuses on disease control with anticoagulation and steroids. Plasma exchange and intravenous immunoglobulin (IVIG) have shown some benefit when added. Monoclonal drugs such as rituximab have shown some benefit in refractory cases, and eculizumab, a drug approved for use in atypical hemolytic uremic syndrome, has demonstrated disease control in a few case reports. We describe a unique case of primary refractory CAPS with an unusual presentation that was treated with five lines of therapy before disease control was established.

Small-Cell Lung Cancer Cavities: Primary or Secondary?

Although non-small-cell lung cancer occasionally presents as cavitary lesions, it is rare for small-cell lung cancer (SCLC) to present or progress in such a manner. If a cavitary lesion is seen in the setting of small-cell lung carcinoma, infectious etiologies must be excluded first. We present the case of a 43-year-old man with refractory SCLC that progressed despite two lines of therapy, and who was ultimately found to have recurrent adenopathy and numerous widespread cavitary lung nodules. Fine-needle aspiration of a hilar lymph node revealed extensively necrotic SCLC, while bronchoalveolar cultures grew Aspergillus fumigatus and Candida albicans. The patient was subsequently treated with voriconazole; however, despite these measures, his overall clinical course deteriorated and the patient ultimately succumbed to his illness. Aspergillosis is a major cause of cavitary lung lesions, especially in immunocompromised patients. Our patient with refractory stage four SCLC was found to have several cavitary lung lesions. Before assuming that cavitary lesions are neoplastic, evaluation for aspergillosis should be conducted, particularly in SCLC patients. Although invasive fungal infections are often missed, it may be prudent to conduct such testing because aspergillosis is a treatable condition and the treatment can improve a patient's hospitalization and overall clinical course.

Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome.

Pembrolizumab and other immunotherapies now play a prominent role in the treatment of metastatic colon cancer. Clinicians have achieved significant response rates even in heavily pretreated patients, particularly those with mismatched repair deficiencies. The endpoint of pembrolizumab treatment for patients who enjoy a strong response remains unclear. Herein, we present the case of a 33-year-old man with pretreated metastatic colon cancer and a prolonged treatment response of over three years to single-agent pembrolizumab even after treatment discontinuation in July 2018. Prior to pembrolizumab, he was found to have lung and liver metastases despite multiple lines of chemotherapy. With pembrolizumab, there was a persistent downtrend in CEA level and uptrend in weight. After nearly three years of pembrolizumab treatment from October 2015 through July 2018, PET scan showed no FDG-avid disease, and further treatment was placed on hold. He remains under surveillance, with CT scan in February 2019 again showing no evidence of local or metastatic disease. In patients whose treatment duration and disease course are not defined by toxicities/progressive disease but rather by sustained treatment responses, we propose that immunotherapy treatment duration be guided by close monitoring of CEA levels, weight, and clinical exams in addition to traditional imaging.

Age-dependent overall survival benefit of androgen deprivation therapy for metastatic prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) remains a standard of care in metastatic prostate cancer. Recent prospective trials have explored addition of chemotherapy to ADT. We retrospectively examined overall survival in metastatic prostate cancer patients treated with ADT, chemotherapy plus ADT (C + ADT), or observation from 2004 to 2010 using National Cancer Database data. METHODS: Using the National Cancer Database, 21,977 patients with metastatic prostate cancer diagnosed from 2004 to 2010 were identified. Multivariate logistic regression, Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were implemented, with overall survival as the primary endpoint. RESULTS: Five-year overall survival was 13.6% in patients aged ≥ 75 years vs. 30.1% (age 65-74) and 34.5% (age 18-64). Subgroup analysis of age-based cohorts (<65 and ≥65 years) showed poor overall survival for C + ADT vs. ADT alone, both in younger (HR 1.35, 95% CI 1.21-1.50; p < 0.0001) as well as older (HR 1.21, 95% CI 1.08-1.34; p = 0.0006) populations. Younger patients had no significant difference in overall survival for observation vs. ADT (HR 0.99, 95% CI 0.92-1.08; p = 0.9121). Besides age, other factors impacting overall survival included race, rural/urban settings, comorbidity score, income, PSA and radiation. DISCUSSION: Younger patients had no significant difference in overall survival between observation or ADT. This implies a group of younger patients in whom ADT does not confer any overall survival benefit. Future clinical trials with genetic and biologic markers are needed to delineate which subgroups would not benefit from C + ADT or ADT alone. This is of utmost clinical importance given the negative impact of ADT on quality of life and comorbidities.

Late-onset robust curly hair growth in a patient with BRAF-mutated metastatic melanoma responding to dabrafenib.

Development of curly hair has been infrequently described in association with BRAF inhibitors in clinical trials, and usually affects patients between 6 and 24 weeks of therapy. The curly hair is typically preceded by initial hair thinning or even diffuse alopecia. We report herein an occurrence of late-onset robust curly head hair growth in a patient with metastatic melanoma responding well to dabrafenib, without being preceded by hair thinning. The curly hair in our patient developed at 11 months of therapy with dabrafenib. Occurrence of late-onset, robust curly hair might represent a prognostic marker of clinical response to these agents. If our hypothesis is correct, we expect more reports of late-onset, robust curly hair growth with the use of this class of pharmaceuticals. Moreover, newer generations of BRAF inhibitors may expand the armory of hair care products in the future.

Severe phototoxic reaction secondary to subcutaneous 5-azacitidine.

Phototoxicity occurs when the effects of sunlight and certain drugs converge at the skin level. Various pharmacologic agents have been linked to photosensitivity, including agents used in hematology and oncology. We describe herein a severe phototoxic response to subcutaneous 5-azacitidine. There are no previous reports of phototoxicity reactions to this agent in the published literature. As 5-azacitidine is frequently used to treat patients with myelodysplastic syndromes and acute myeloblastic leukemia, familiarity with this side effect is important for the medical and scientific community at large.

Strategy to reduce bortezomib-induced paralytic ileus in patients with myeloma and impaired renal function.

While bortezomib is known to cause adverse effects involving the autonomic nervous system, gastrointestinal side effects are typically mild. We describe herein a series of patients with myeloma and impaired renal function who developed severe paralytic ileus secondary to bortezomib use. Our patients had other risk factors for paralytic ileus including electrolyte abnormalities and opiate use. The striking commonality in our patients is the development of paralytic ileus with intravenous bortezomib in the setting of reduced renal function, followed by ileus resolution with bortezomib dose reduction. We discuss the existing literature on this subject and propose a strategy in order to reduce the risk of paralytic ileus in these patients. Upfront bortezomib dose reduction to 1 mg/m2 intravenously in patients with myeloma with a glomerular filtration rate (GFR) of <30 mL/min may prevent paralytic ileus, while not compromising the clinical outcomes. Our conclusions will have to be validated in larger studies.

Audit of anesthetic trainees' 'hands-on' operating room experience in an Australian tertiary children's hospital.

BACKGROUND: There are no internationally accepted guidelines about what constitutes adequate clinical exposure during pediatric anesthetic training. In Australia, no data have been published on the level of experience obtained by anesthetic trainees in pediatric anesthesia. There is, however, a new ANZCA (Australian and New Zealand College of Anaesthetists) curriculum that quantifies new training requirements. AIM: To quantify our trainees' exposure to clinical work in order to assess compliance with new curriculum and to provide other institutions with a benchmark for pediatric anesthetic training. METHODS: We performed a prospective audit to estimate and quantify our anesthetic registrars' exposure to pediatric anesthesia during their 6-month rotation at our institution, a tertiary pediatric hospital in Perth, Western Australia. RESULTS: Our data suggest that trainees at our institution will achieve the new ANZCA training standards comfortably, in terms of the required volume and breadth of exposure. Experience, however, of some advanced pediatric anesthetic procedures appears limited. CONCLUSIONS: Experience gained at our hospital easily meets the new College requirements. Experience of fiber-optic intubation and regional blocks would appear insufficient to develop sufficient skills or confidence. The study provides other institutions with information to benchmark against their own trainee experience.