Case report: Enfortumab vedotin induced refractory DKA and multi organ failure - a rare fatal adverse event.

There are very few therapeutic options to treat patients with locally advanced or metastatic Urothelial Cancer (UC). Enfortumab vedotin (EV) was recently approved by the FDA and has become a new therapeutic option for patients previously managed with conventional treatments. Despite its efficacy, EV carries the potential for infrequent yet severe adverse effects. In this report, we present a case of a patient undergoing EV treatment for urothelial carcinoma who developed refractory diabetic ketoacidosis (DKA) unresponsive to escalating insulin doses and necessitating continuous renal replacement therapy. While DKA was resolved, the patient eventually succumbed to progressive maculopapular skin rash, liver failure, and respiratory failure. Additionally, the study delves into a review of cases of EV-induced refractory DKA in the literature, shedding light on the similarities in patient profiles, timelines of adverse effects and the treatment strategies employed to manage the ensuing complications.

Incidence of pulmonary toxicity in bleomycin-containing regimens for testicular cancer with and without the use of growth factor.

INTRODUCTION: The concurrent use of bleomycin and granulocyte colony-stimulating factors (G-CSFs) has historically been debated as a risk factor for bleomycin-induced pulmonary toxicity in patients with both testicular cancer and Hodgkin's lymphoma. The purpose of this study is to evaluate the incidence of pulmonary toxicity in patients with testicular cancer who were treated with bleomycin and pegfilgrastim concurrently. METHODS: This is a retrospective study that includes male patients over the age of 18 years old diagnosed with testicular cancer who received bleomycin-containing chemotherapy regimens with and without the use of G-CSF agents. RESULTS: There were a total of 33 patients identified as receiving bleomycin, with 30 of those patients having received concurrent G-CSF therapy. Of the patients who received G-CSF therapy, 11 patients (36.6%) experienced pulmonary toxicity leading to discontinuation of bleomycin or changes in chemotherapy regimens altogether. CONCLUSION: There were no major differences in patient demographics or risk factors between those who received G-CSF and developed pulmonary toxicity and those who received G-CSF but did not develop pulmonary toxicity. Further studies are needed in order to fully assess the risk of pulmonary toxicity with this chemotherapy regimen.

Case-Based Clinical Guidance on Dosing and Management of the Hepatic Artery Infusion Chemotherapy Pump.

Hepatic artery infusion (HAI) delivers localized high-dose floxuridine directly to liver tumors through an implanted pump. While patients are undergoing active treatment, the pump is refilled with chemotherapy alternating with saline every 2 weeks using a specialized noncoring needle. Numerous clinical scenarios influence the dosing of floxuridine, which do not conform to the usual dose modification schema for systemic chemotherapy. This article aims to provide practical clinical management solutions to overcome the common challenges faced by oncologists in the real-world management of HAI pump therapy.

Starting a successful hepatic artery infusion pump program: A practical guide.

Implementation of a successful hepatic artery infusion pump program requires numerous factors to be in place, and the lack of any of these may lead to program failure. First and foremost, hepatic artery infusion pump programs must have adequate surgical expertise in the complex technical aspects of hepatic artery infusion pump implantation and postoperative management. Most new hepatic artery infusion pump programs are initiated by a surgeon and led in conjunction with a medical oncologist. Medical oncology experience in floxuridine dosing is critical in maximizing the treatment doses and the number of cycles administered while avoiding biliary toxicity. This is facilitated by collaboration with an engaged pharmacy team. To have adequate patient volume for a successful program, internal and external stakeholders must have buy-in, including surgical and medical oncology colleagues unfamiliar with hepatic artery infusion pumps, colorectal surgery, and other referring providers. Programmatic support must be obtained from the hospital, cancer center, and department administration. Day-to-day pump access for chemotherapy and maintenance saline fills must be performed by appropriately trained infusion nurses to avoid complications. Nuclear and diagnostic radiology experience is key to identifying extrahepatic perfusion and hepatic artery infusion pump-specific complications. Additionally, skilled interventional radiologists and gastroenterologists are necessary to identify and treat rare complications rapidly. Finally, given the current rapid expansion of hepatic artery infusion pump programs, new programs must identify engaged mentors to help guide patient selection, navigate the nuanced issues that may arise, and provide advice in the case of complications. Although hepatic artery infusion pump dissemination outside of several major tertiary centers previously had stalled, establishing a successful and active hepatic artery infusion pump is feasible with appropriate training, mentorship, and thoughtful assembly of a dedicated multidisciplinary team.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

PURPOSE: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. EXPERIMENTAL DESIGN: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. RESULTS: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). CONCLUSION: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. METHODS: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. RESULTS: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. CONCLUSIONS: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Case Report: Safety and Efficacy of Enfortumab Vedotin in a Patient With Metastatic Urothelial Carcinoma Undergoing Peritoneal Dialysis.

The clinical management of metastatic urothelial carcinoma has significantly evolved with the emergence of monoclonal antibodies and antibody-drug conjugates (ADCs). Enfortumab vedotin (EV) was granted approval by the FDA in 2021 for patients with locally advanced or metastatic urothelial carcinoma who have received prior immunotherapy and platinum-containing chemotherapy. Little to no data exist for the use of EV in patients with concurrent end-stage renal disease (ESRD) using either hemodialysis or peritoneal dialysis (PD). Here, we present the case of a patient with metastatic urothelial carcinoma on PD who failed multiple lines of treatment but demonstrated an impressive response to EV without significant toxicity. We discuss the possible impact of peritoneal dialysis on the pharmacokinetics of ADCs and the potential for safe administration based on known pharmacokinetic data.

A Case Report of Metastatic Castration-Resistant Prostate Cancer Harboring a PTEN Loss.

The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has dramatically improved over the last decade; however, patients with visceral metastases are still faced with poor outcomes. Phosphatase and tensin homolog (PTEN) loss is observed in 40%-60% of mCRPC patients and is also associated with a poor prognosis. Several PI3K/AKT/mTOR pathway inhibitors have been studied, with disappointing anti-tumor activity. Here, we present a case of a patient with heavily treated mCRPC who had a modest tumor response to concurrent carboplatin, abiraterone acetate/prednisone, and liver-directed radiation therapy. We discuss the potential rationale supporting the use of this combination therapy and its safety in mCRPC. While the underlying basic mechanism of our patient's anti-tumor response remains uncertain, we suggest that further prospective studies are warranted to evaluate whether this combination therapy is effective in this population of patients with pre-treated mCRPC and PTEN loss.

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

UNLABELLED: Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. INTRODUCTION: Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. METHODS: To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. RESULTS: +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. CONCLUSIONS: Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization.

The plasminogen activation system (PAS) and its principal inhibitor, plasminogen activator inhibitor-1 (PAI-1), are recognized modulators of matrix. In addition, the PAS has previously been implicated in the regulation of bone homeostasis. Our objective was to study the influence of active PAI-1 on geometric, biomechanical, and mineral characteristics of bone using transgenic mice that over-express a variant of human PAI-1 that exhibits enhanced functional stability. Femora were isolated from male and female, wildtype (WT) and transgenic (PAI-1.stab) mice at 16 and 32 weeks of age (n=10). Femora were imaged via DEXA for BMD and muCT for cortical mid-slice geometry. Torsional testing was employed for biomechanical properties. Mineral composition was analyzed via instrumental neutron activation analysis. Female femora were further analyzed for trabecular bone histomorphometry (n=11). Whole animal DEXA scans were performed on PAI-1.stab females and additional transgenic lines in which the functional domains of the PAI-1 protein were specifically disrupted. Thirty-two week female PAI-1.stab femora exhibited decreased mid-slice diameters and reduced polar moment of area compared to WT, while maintaining similar cortical bone width. Greater biomechanical strength and stiffness were demonstrated by 32 week PAI-1.stab female femora in addition to a 52% increase in BMD. PAI-1.stab trabecular bone architecture was comparable to WT. Osteoid area was decreased in PAI-1.stab mice while mineral apposition rate increased by 78% over WT. Transgenic mice expressing a reactive-site mutant form of PAI-1 showed an increase in BMD similar to PAI-1.stab, whereas transgenic mice expressing a PAI-1 with reduced affinity for vitronectin were comparable to WT. Over-expression of PAI-1 resulted in increased mineralization and biomechanical properties of mouse femora in an age-dependent and gender-specific manner. Changes in mineral preceded increases in strength/stiffness and deterred normal cross-sectional expansion of cortical bone in females. Trabecular bone was not altered in PAI-1.stab mice whereas MAR increased significantly, further supporting mineral changes as the underlying factor in strength differences. The primary influence of PAI-1 occurred during a period of basal bone remodeling, attributing a role for this system in remodeling as opposed to development. Comparison of transgenic lines indicates that PAI-1's influence on bone is dependent on its ability to bind vitronectin, and not on its proteolytic activity. The impact of PAI-1 on mouse femora supports a regulatory role of the plasminogen activation system in bone homeostasis, potentially elucidating novel targets for the treatment of bone disease.

The effect of cold-induced increased metabolic rate on the rate of 13C and 15N incorporation in house sparrows (Passer domesticus).

Animals with high metabolic rates are believed to have high rates of carbon and nitrogen isotopic incorporation. We hypothesized that (1) chronic exposure to cold, and hence an increase in metabolic rate, would increase the rate of isotopic incorporation of both 13C and 15N into red blood cells; and (2) that the rate of isotopic incorporation into red blood cells would be allometrically related to body mass. Two groups of sparrows were chronically exposed to either 5 or 22 degrees C and switched from a 13C-depleted C3-plant diet to a more 13C-enriched C4-plant one. We used respirometry to estimate the resting metabolic rate (VO2) of birds exposed chronically to our two experimental temperatures. The allometric relationship between the rate of 13C incorporation into blood and body mass was determined from published data. The (VO2) of birds at 5 degrees C was 1.9 times higher than that of birds at 22 degrees C. Chronic exposure to a low temperature did not have an effect on the rate of isotopic incorporation of 15N save for a very small effect on the incorporation of 13C. The isotopic incorporation rate of 13C was 1.5 times faster than that of 15N. The fractional rate of 13C incorporation into avian blood was allometrically related to body mass with an exponent similar to -1/4. We conclude that the relationship between metabolic rate and the rate of isotopic incorporation into an animal's tissues is indirect. It is probably mediated by protein turnover and thus more complex than previous studies have assumed.

Continuous and bilevel positive airway pressure in the treatment of acute cardiogenic pulmonary edema.

Patients with acute cardiogenic pulmonary edema (ACPE) are commonly seen in the emergency department (ED). Although the majority of patients respond to conventional medical therapy, some patients require at least temporary ventilatory support. Traditionally, this has been accomplished via endotracheal intubation and mechanical ventilation, an approach that is associated with a small but significant rate of complications. The past 2 decades have witnessed increasing interest in methods of noninvasive ventilatory support (NVS), notably continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). We review the physiological consequences, clinical efficacy, and practical limitations of CPAP and BiPAP in the management of ACPE.

Emergency medical care: types, trends, and factors related to nonurgent visits.

OBJECTIVES: To describe and compare national trends in ED use by statistical analyses on data from the 1992 to 1996 National Hospital Ambulatory Medical Care Survey (NHAMCS) with a special interest in factors related to nonurgent visits. METHODS: The NHAMCS collects data for ED visits using a four-stage national probability sample. Data from 135,723 ED visits in 1992-1996 were analyzed using the chi-square test for proportions with logistic regression modeling for multivariate analysis. RESULTS: More than half of the ED visits were considered nonurgent. There was a decreasing trend for nonurgent ED visits over the first three years of the sample (54.0% to 52.1%, p < 0.05). The proportion of ED visits for nonurgent care bounced back in 1995 (54.7%) and 1996 (54.1%). Significant variation existed in the proportion of nonurgent care visit based on disease category, age, race, and insurance coverage status. Marked variation in nonurgent visits also existed among geographic regions and types of hospital ownership. CONCLUSIONS: Analyses of data from the NHAMCS identify trends in ED use. The study of nonurgent ED visits with this database has inherent methodologic problems such as retrospective coding and geographic coding inconsistency. Since the nonurgent visit is clearly linked to certain social-demographic factors, addressing these underlying issues by establishing a comprehensive health care system is a priority.

Helicopter loading time study: hot versus cold.

INTRODUCTION: Historically our program has used the practice of hot-loading at scenes as a time-saving measure. This practice potentially exposes patients and health care personnel to a variety of risks. Currently no data exist supporting the use of hot-loading as a time-saving technique. We prospectively studied load times and scene times for both hot- and cold-loading methods. METHODS: Hot- or cold-loading methods were randomized according to odd or even days of the month for scene runs. Both loading times and total scene times were recorded. An ANOVA was used to compare the times, taking into consideration the aircraft in use (BO 105 or BK 117). RESULTS: A total of 104 flights were entered into the study. For loading time, hot-loading showed a statistically significant difference (F [1,100] = 112.84, P = 0.000). Means for hot- and cold-loading times are 3.071 and 5.033 minutes, respectively. The interaction effect of aircraft and loading method also was significant (F [1,100] = 4.637, P = 0.034). The BO 105 (on high skids) was slower to hot-load. In contrast, the BK 117 (additional pretakeoff system checks) was slower to cold-load. The type of aircraft alone showed no effect on loading time. Total scene times were evaluated using the same procedures. A statistically significant difference also was found for the effect of hot-loading on total scene time (F [1,100] = 11.391, P = 0.001). Means for hot and cold total scene times are 10.54 and 13.615 minutes, respectively. CONCLUSION: Hot-loading does decrease our program's overall scene times. The clinical significance of this procedure was not evaluated.

Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache.

STUDY OBJECTIVE: To evaluate intramuscular dihydroergotamine in direct comparison with opioid analgesia in the treatment of acute migraine headache. METHODS: This was a prospective, multicenter, double-blind trial performed in the emergency departments of 11 general hospitals in the United States. One hundred seventy-one patients between the ages of 18 and 60 years who presented to the ED with acute migraine headache were enrolled. Patients were randomly assigned to receive either 1 mg dihydroergotamine (DHE) or 1.5 mg/kg meperidine (MEP) by intramuscular injection. The anti-nauseant hydroxyzine (H) was coadministered in both treatment groups. RESULTS: One hundred fifty-six patients were evaluable. Treatment groups were comparable in sample size, demographics, and baseline measurements of headache pain. Reduction of headache pain as measured on a 100-mm visual analog scale was 41+/-33 mm (53.5% reduction) for the DHE group, and 45+/-30 mm (55.7% reduction) for the MEP group at 60 minutes after treatment (difference=2.2%; 95% confidence interval [CI] -10%, 14.5%; P=.81). Reduction in the severity of nausea and improvement in functional ability were similar between treatment groups. Central nervous system adverse events were less common in the DHE group (DHE 23.5% versus MEP 37.6%, difference-14.1%: 95% CI -28%, 0%). In particular, dizziness was reported less commonly with DHE than MEP (2% versus 15%, difference=-13%: 95% CI -21%, -5%). CONCLUSION: In this prospective, double-blind trial of a convenience sample of ED patients randomly assigned to one of two treatment regimens, DHE and MEP were comparable therapies for acute migraine. The use of DHE avoids several problems associated with opioid analgesia, including dizziness.