United States

Background
Perioperative pain management for c-sections can be supplemented by adjuvant neuraxial opioids. However, opioids are not desirable for all patients, especially those with opioid use disorder or allergy. Meanwhile, dexmedetomidine is a highly specific and selective α2 agonist that is considered a safe and effective adjuvant. Currently, there is a need for a comprehensive systematic review that compares these medications in this setting but does not limit itself to either one opioid or a preidentified dose combination.

Methods
Embase, CENTRAL, Web of Science, and MEDLINE were searched on 08/29/24.1599 studies were imported to Covidence. Only randomized controlled trials (RCTs) that compared dexmedetomidine to opioids as neuraxial adjuvants during c-sections were eligible for inclusion with no restriction on local anesthetic, time of administration of adjuvant, or dosing. Two reviewers independently evaluated each article for abstract/full text screening, data extraction, and risk of bias. Conflicts were resolved by a third reviewer or mutual consensus. Pain outcomes, sedation, onset/duration of motor/sensory block, and adverse effects were recorded. A p-value of &lt; 0.05 represented statistical significance. Prospero number is CRD42024590544.

Results
The final analysis included 17 RCTs. 15 evaluated intrathecal administration with standard opioid dosing per SOAP guidelines while dexmedetomidine dosing was 2.5-10µg. For these intrathecal studies, the comparators were fentanyl/sufentanil in 13, morphine in 2, and meperidine in 1 (one compared fentanyl, morphine, and dexmedetomidine). Two studies compared patient-controlled epidural analgesia (PCEA) dexmedetomidine to morphine. Across dosing ranges and routes, dexmedetomidine had superior pain scores and analgesia duration in the majority of studies with these variables. None found inferiority. Dexmedetomidine prolonged motor block in the majority of studies with this variable. In a minority, it reduced shivering. It reduced pruritus vs morphine and meperidine. No adjuvant was consistently superior in onset of analgesia/motor block, hemodynamic effects, nausea/vomiting, or respiratory depression. For PCEA, dexmedetomidine produced deeper, less desirable sedation.

Conclusion
Neuraxial dexmedetomidine offers comparable-to-superior perioperative pain control vs standard dose fentanyl, sufentanil, morphine, or meperidine as c-section adjuvants. Its most common adverse effect is prolonged motor block. Therefore, intrathecal adjuvant dexmedetomidine at 2.5-10µg is a reasonable alternative in cases of contraindications to opioids or where further surgical intervention is expected such as tubal ligation.


AMA Research Challenge 2025 

Neuraxial Adjuvants for C-section Analgesia: A Systematic Review of Dexmedetomidine vs Opioids


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Background
Perioperative pain management for c-sections can be supplemented by adjuvant neuraxial opioids. However, opioids are not desirable for all patients, especially those with opioid use disorder or allergy. Meanwhile, dexmedetomidine is a highly specific and selective α2 agonist that is considered a safe and effective adjuvant. Currently, there is a need for a comprehensive systematic review that compares these medications in this setting but does not limit itself to either one opioid or a preidentified dose combination.

Methods
Embase, CENTRAL, Web of Science, and MEDLINE were searched on 08/29/24.1599 studies were imported to Covidence. Only randomized controlled trials (RCTs) that compared dexmedetomidine to opioids as neuraxial adjuvants during c-sections were eligible for inclusion with no restriction on local anesthetic, time of administration of adjuvant, or dosing. Two reviewers independently evaluated each article for abstract/full text screening, data extraction, and risk of bias. Conflicts were resolved by a third reviewer or mutual consensus. Pain outcomes, sedation, onset/duration of motor/sensory block, and adverse effects were recorded. A p-value of < 0.05 represented statistical significance. Prospero number is CRD42024590544.

Results
The final analysis included 17 RCTs. 15 evaluated intrathecal administration with standard opioid dosing per SOAP guidelines while dexmedetomidine dosing was 2.5-10µg. For these intrathecal studies, the comparators were fentanyl/sufentanil in 13, morphine in 2, and meperidine in 1 (one compared fentanyl, morphine, and dexmedetomidine). Two studies compared patient-controlled epidural analgesia (PCEA) dexmedetomidine to morphine. Across dosing ranges and routes, dexmedetomidine had superior pain scores and analgesia duration in the majority of studies with these variables. None found inferiority. Dexmedetomidine prolonged motor block in the majority of studies with this variable. In a minority, it reduced shivering. It reduced pruritus vs morphine and meperidine. No adjuvant was consistently superior in onset of analgesia/motor block, hemodynamic effects, nausea/vomiting, or respiratory depression. For PCEA, dexmedetomidine produced deeper, less desirable sedation.

Conclusion
Neuraxial dexmedetomidine offers comparable-to-superior perioperative pain control vs standard dose fentanyl, sufentanil, morphine, or meperidine as c-section adjuvants. Its most common adverse effect is prolonged motor block. Therefore, intrathecal adjuvant dexmedetomidine at 2.5-10µg is a reasonable alternative in cases of contraindications to opioids or where further surgical intervention is expected such as tubal ligation.


poster

Background:
FLT3-ITD mutation occurs in 25–30% of acute myeloid leukemia (AML) and is associated with a poor prognosis. FLT3 inhibitors (FLT3i), such as gilteritinib and quizartinib, improve initial response rates, but relapse is common. While on-target resistance via FLT3-TKD mutations is established, emerging evidence suggests that “collateral resistance,” characterized by the outgrowth of non-FLT3 subclones, contributes significantly to therapeutic escape. This review synthesizes current data on clonal evolution under FLT3i pressure, focusing on non-FLT3 subclonal emergence.

Methods:
We conducted a comprehensive review of published studies done up to June 2025, in PubMed, Web of Science, and Scopus. Studies were included if they involved FLT3-mutated AML patients treated with FLT3 inhibitors, reported paired genomic data at diagnosis and relapse. Data on FLT3i type, resistance mechanisms, mutation spectrum, and variant allele frequency (VAF) changes were extracted from clinical trials, retrospective cohorts, and preclinical models.

Results:
In a cohort of 41 relapsed patients treated with gilteritinib, 33% developed FLT3-TKD mutations (D835, F691L), 36.6% acquired NRAS/KRAS mutations, and 5% developed BCR-ABL1 fusions. Another study found off-target RAS/MAPK pathway mutations in 30–37% of relapses, frequently co-occurring with ASXL1, RUNX1, and PTPN11 mutations. Resistance to quizartinib was driven by FLT3-TKD mutations in 33–50% of cases, yet up to 50% of relapses lacked FLT3 mutations, suggesting alternative mechanisms such as microenvironmental signaling and off-target mutations. Three reported cases of BCR-ABL1 fusion following FLT3i failure showed partial responses to combined FLT3 and ABL1 inhibition. Single-cell DNA sequencing revealed that non-FLT3 subclones, undetectable at baseline by bulk sequencing, expanded under FLT3 inhibitor pressure, demonstrating polyclonal resistance and clonal selection as key drivers of relapse. These studies consistently demonstrate that non-FLT3 resistance, particularly involving the RAS/MAPK axis, is frequent and clinically relevant following targeted therapy.

Conclusion:
Collateral resistance to FLT3 inhibitors in AML is frequently mediated by the selection of pre-existing, low-frequency non-FLT3 mutant subclones, particularly those involving the RAS/MAPK pathway. These findings emphasize the importance of comprehensive genomic profiling for diagnosis and relapse. Future therapeutic strategies should prioritize rational drug combinations targeting FLT3 and non-FLT3 pathways to overcome resistance and improve patient outcomes.


REFERENCES
1.Smith, C. C., Levis, M. J., Perl, A. E., et al. (2022). Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Advances, 6(7), 2144–2155. https://doi.org/10.1182/bloodadvances.2021006489
2. Smith, C. C., Lin, K., Stecula, A., Sali, A., & Shah, N. P. (2015). FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia, 29(12), 2390–2392. https://doi.org/10.1038/leu.2015.165
3. Tarver, T. C., Hill, J. E., Rahmat, L., et al. (2020). Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations. Blood Advances, 4(3), 514–524. https://doi.org/10.1182/bloodadvances.2019000919


Collateral Resistance in FLT3-Mutated AML: Unraveling Non-FLT3 Subclonal Emergence and Therapeutic Escape Under FLT3 Inhibitor Pressure - A Comprehensive Literature Review

Chinwe Ohanu, MD¹, Ana S. Rosado-Collazo, MD¹, Diane Mankin-Cruz, MD¹, Paco Diaz, MD²,
Frankie Alvarado, MD¹
¹Pavia Hospital, Internal Medicine Department, Pulmonology Section, Arecibo, Puerto Rico
²Pavia Hospital, Internal Medicine Department, Infectious Disease Section, Arecibo, Puerto Rico
Abstract title:
patient.
Trichosporon asahii induced sepsis secondary to bronchopneumonia in an immunocompromised
Background:
Opportunistic fungal infections are a significant concern in immunocompromised patients,
particularly those with hematologic malignancies. Trichosporon asahii is a rare but increasingly
recognized cause of invasive fungal infections. This yeast-like organism, commonly found in
soil, water, and normal human flora, can cause both superficial and systemic disease. Incidence
is estimated at 0.4–0.6% among immunocompromised individuals, especially those with
prolonged neutropenia or hematologic cancers. It is intrinsically resistant to echinocandins and
associated with high mortality rates up to 80% especially when diagnosis or appropriate therapy
is delayed. Diagnosis requires culture, microscopy, and molecular testing. Treatment should be
guided by susceptibility, with azoles being preferred.
Case Presentation:
A 76 year old hispanic female with chronic myelogenous leukemia on chemotherapy, coronary
artery disease, type 2 diabetes, and hypertension presented with progressive dyspnea,
hemoptysis, generalized weakness, and non-radiating chest pain. Vital signs revealed BP 120/45
mmHg, pulse 120 BPM, oxygen saturation at 88% on 3L NC, and fever of 38.1°C.
Chest X-ray showed haziness in the left lower lobe and increased perihilar markings suggestive
of bronchopneumonia. Infectious workup including testing for COVID-19, influenza, TB, PCP,
HIV , and Mycoplasma pneumoniae, was negative. She was initially treated with ceftriaxone and
azithromycin, later escalated to cefepime due to lack of clinical improvement.
Fiberoptic bronchoscopy revealed copious secretions bilaterally. Bronchoalveolar lavage was
negative for AFB and cryptococcus; however, KOH prep was positive for Trichosporon asahii.
Antibiotics were discontinued, and antifungal therapy with voriconazole was initiated. The
patient gradually improved with reduced oxygen requirements, resolution of fever and
respiratory distress.
Discussion:
Trichosporon asahii is an often overlooked fungal pathogen in immunocompromised hosts,
frequently mimicking bacterial pneumonia and delaying diagnosis. Early bronchoscopy and
fungal testing are critical in patients with non-resolving pneumonia. Prompt identification and
targeted antifungal therapy significantly improve outcomes. This case highlights the importance
of clinical vigilance and rapid escalation to fungal diagnostics in high-risk patients.

Trichosporon asahii induced sepsis secondary to bronchopneumonia in an immunocompromised patient

Neural oscillations categorized into specific frequency bands offer various cognitive functions. Gamma waves are the fastest brainwaves in the human brain, generated by synchronized electrical pulses from neurons ranging from 25 to 100 Hz. Decreased gamma oscillations have been associated with cognitive declines in neuropsychiatric diseases, such as memory loss in Alzheimer’s disease (AD). Inducing gamma oscillations using 40 Hz entrainment stimulation offers benefits in learning and memory by increasing the power of spontaneous gamma neural oscillations, modulating synaptic plasticity, and thereby reducing beta-amyloid plaques. This study aimed to investigate frequency-specific EEG responses to 40 Hz auditory stimulation using an open-source EEG study in healthy older adults and individuals with mild AD. 

This secondary analysis used an open-source EEG dataset from 26 participants (16 mild AD, 10 controls). Subjects received repeated cycles of 40-second 40 Hz auditory stimulation interleaved with 20-second rest periods. EEG was recorded from 19 channels. Power spectral density was computed across six frequency bands (delta, theta, alpha, beta, gamma, and gamma40). Linear mixed-effects models assessed stimulation-induced changes (stimulation minus rest), controlling for age and accounting for repeated measures.

Compared to its controls, AD participants demonstrated significantly greater theta power increases (β = 0.406, p = 0.008) during 40 Hz stimulation, with reduced beta, gamma, and gamma40 responses. Topographic mapping revealed widespread theta enhancement in AD, particularly over frontal, parietal, and occipital regions (e.g., AD × Occipital: β = 1.516, p < 0.001), whereas controls showed focal increases in posterior gamma. Notably, theta enhancement in AD did not significantly correlate with Mini-Mental State Examination (MMSE) scores, suggesting it was not exclusively driven by cognitive severity.

AD patients demonstrated a significant increase in theta power within the frontal, parietal, and occipital lobes. This widespread theta enhancement may reflect dysfunctional network entrainment or compensatory mechanisms in early AD. These findings underscore the importance of examining broader spectral responses beyond gamma and support the potential of theta activity as a biomarker of early AD-related neural networks.

Theta Dominance During 40 Hz Auditory Stimulation in Alzheimer’s Disease

Background 
Preterm birth (PTB) is defined as delivery prior to 37 weeks of gestation and is a significant cause of neonatal morbidity and mortality. PTB typically occurs due to spontaneous preterm labor without a known underlying maternal, fetal, or placental condition. Antenatal corticosteroids (ACS), like betamethasone and dexamethasone are commonly used in patients at risk of preterm delivery to enhance fetal lung development and reduce neonatal respiratory morbidity and mortality. A new glucocorticoid (ciclesonide and its active metabolite, desisobutyryl-ciclesonide) shows promise for treating or preventing brochopulmonary dysplasia in neonates without the adverse effects observed with dexamethasone. While glucocorticoids can prolong pregnancy and inhibit contractions in animal studies, human data is limited to one prospective study. This research aims to evaluate the effects of synthetic corticosteroids on the contractile activity of human myometrial tissue to explore their potential use as tocolytics for women at high risk of preterm delivery. 

Methods 
Myometrial biopsies were obtained from fully-informed and consenting patients undergoing cesarean deliveries at term. Strips (12 mm X 5 mm X 1 mm) were submerged in a heated, oxygenated organ baths with Kreb’s Bicarbonate Solution and subjected to 3 grams of tension. Rhythmic isometric contractions developed within ∼2–3 h. Cumulative concentrations (1 nM to 0.1 mM) of betamethasone, dexamethasone, ciclesonide, desisobutyryl-ciclesonide (Des-Cic), or vehicle were administered every 20 mins. The contractile activity was recorded and analyzed as the integral relative to baseline divided by the duration of each treatment period. All treatment data were expressed as a percent change of baseline spontaneous contractile activity. Statistical comparisons to vehicle-treated tissues were made using two-way ANOVA with post hoc Tukey’s test, and non-linear regression analyses produced concentration response curves. 

Results 

All the corticosteroids studied significantly (p<0.05) inhibited the ex vivo contractility of human myometrial tissue, compared to vehicle-treated controls, at the highest concentration examined. Notably, ciclesonide and des-ciclesonide were able to significantly (p<0.05) inhibit contractility at concentrations as low as 0.1mM. 

Conclusion 
Our findings suggest that commonly used ACS can serve a broader function by inhibiting uterine activity in patients experiencing spontaneous preterm labor. Currently, the standard use of ACS for fetal maturation is limited to two doses of 12mg administered 24 hours apart, which may not be sufficient to observe any tocolytic effect. Additionally, the enhanced tocolytic potency demonstrated by ciclesonide and desisobutyryl-ciclesonide, along with reports of their reduced toxicity, make these medications attractive alternatives to current corticosteroid options.

Evaluating the Tocolytic Potential of Synthetic Corticosteroids on Human Myometrial Contractility

Background
Total Knee Arthroplasty (TKA) is widely accepted as a successful procedure for treatment of knee arthritis, but the effects of robotic technology on functional outcomes following primary TKA remain mixed. Complications like infection, mechanical issues, instability, bearing surface wear, and mechanical loosening can lead to patients requiring a revision of their TKA. Robotic assistance in revision TKA is an evolving technology aimed at improving component positioning, gap symmetry, and early patient-reported outcomes. Obesity is a known risk factor in orthopaedic surgery, but its effect on outcomes in robotic-assisted revision total knee
arthroplasty (rarTKA) is still uncharted. This study examines the association between BMI and key perioperative and postoperative outcomes in rarTKA.
Methods
This retrospective, observational study analyzed 52 rarTKA patients at a single academic institution, stratifying them by BMI according to WHO classifications, with 33 (63.5%) having a BMI ≤35 kg/m² and 19 (36.5%) a BMI ≥35 kg/m² (obese). Perioperative and postoperative outcomes were assessed, and multivariable linear and logistic regression analyses were conducted to evaluate the relationship between BMI and each outcome.
Results
BMI ≥ 35 was independently correlated with only significantly longer operative times (B = 0.5, 95% CI:0.16 to 0.85, p=0.006). Obesity was positively associated with length of hospital stay, but this result was not significant (B= 6.18, 95% CI: -10.5, 22.86, p=0.46). Obesity did not have a significant effect on 30 and 90-day readmissions, but obese patients had over three times higher odds of readmission (OR = 3.35, 95% CI: 0.43–33.57, p=0.256). Mean 2-week postoperative
range of motion improvement was smaller in obese patients but was not significantly different (B= -0.65, 95% CI: -37.61, 36.31, p=0.97).
Conclusion
Higher BMI was associated with significantly longer operative times following rarTKA, but did not significantly affect other outcomes when controlling for age and sex. While average postoperative outcomes for obese patients tended to be worse than in non-obese patients, very few of them reached statistically significant differences, especially after adjusting for other variables. Our finding is consistent with some data published from primary conventional TKA which also did not show a significant difference between functional outcomes in obese and nonobese
patients. A post-hoc power analysis showed our study only has 30-50% power to detect moderate effect sizes with usual alpha thresholds (p < 0.05). Further studies with larger cohorts are warranted to confirm these findings and guide surgical planning in patients with elevated BMI.

BMI ≥35 Is Associated With Prolonged Operative Time in Robotic-Assisted Revision TKA

Introduction: Arbeitsgemeinschaft für Osteosynthesefragen (The AO Foundation) which translates from German to the Association for the Study of Internal Fixation created a thoracolumbar injury classification system. Type B thoracolumbar fractures result from distraction injuries (vertebrae are pulled apart from each other overstretching the muscles and ligaments that support the spine). These fractures are commonly treated surgically with open posterior spinal instrumentation (OPSI). Percutaneous pedicle screw fixation (PPSF) is a shorter, minimally invasive surgical technique that has demonstrated decreased length of hospital stay, blood loss, and infection rate. PPSF has largely been used to treat type A (compression) fractures while its use in type B fractures is currently less defined. The goal of this study is to evaluate outcomes of type B fractures treated with PPSF versus OPSI through comparing estimated blood loss, operative time, and need for reoperation. 
Methods: This retrospective case series collected patient data from February 1, 2016 through December 31, 2022. All patients were neurologically intact and treated at a level I trauma center. Data collected included operative time, estimated blood loss, early reoperation, and need for revision surgery.
Results: There were 45 patients included in this study, 11 PSF and 34 open. Median age at injury was 42 years old (range 18-77). Motor vehicle collision was the main mechanism of injury involving 22 patients (49%). The mean operative times were 167 minutes for OPSI versus 151 minutes for PPSF (p=0.71). Mean blood loss was 95 mL for PPSF versus 281 mL for OPSI (p=0.17). There was one reoperation for a PPSF patient for irrigation and debridement of a wound dehiscence at postoperative day 14. There were no revisions required in either cohort.
Conclusion: This study shows promising results of PPSF use for neurologically intact AO type B thoracolumbar fractures. Although the results are statistically insignificant, the advantages of PPSF including shorter operative time and less blood loss suggest it may extend beyond type A fractures to more complex type B fractures. Further research with a larger sample size is warranted to produce statistically significant results.

Percutaneous Fixation for AO Type B Thoracolumbar Fractures: A Retrospective Case Series

Background
Cognitive impairments are common but often neglected in Autism Spectrum Disorder (ASD). These deficits are particularly evident in domains such as working memory, processing speed, and short-term memory. Current pharmacological and behavioral interventions provide only limited improvements in cognition. Emerging research suggests that disrupted brain energy metabolism, including mitochondrial dysfunction and abnormalities in creatine-phosphocreatine systems, may contribute to these impairments. Creatine is a naturally occurring compound that supports ATP regeneration in high-demand brain regions and has shown cognitive benefits in other populations.

Objective
This commentary aimed to evaluate the rationale for using creatine as a cognitive enhancer in ASD by reviewing literature related to brain energy metabolism, creatine’s neurological functions, and cognitive outcomes in both clinical and preclinical studies.

Methods
We conducted a review of literature using PubMed, Google Scholar, and Scopus. Search terms included combinations of “creatine,” “cognition,” “autism,” “ASD,” “mitochondrial dysfunction,” “brain energy,” “working memory,” and “processing speed.” We selected peer-reviewed publications from the past two decades, including preclinical studies, clinical trials, case reports, and mechanistic reviews relevant to creatine and neuroenergetics in ASD.

Results
Multiple studies report that individuals with ASD show signs of mitochondrial dysfunction, altered oxidative stress responses, and reduced cerebral creatine levels. Preclinical models of creatine transporter deficiency replicate several features of ASD and demonstrate cognitive rescue with creatine analogs. In human populations, creatine supplementation has been associated with modest improvements in memory, attention, and processing speed. These effects are especially relevant to the cognitive domains most commonly affected in ASD.

Conclusion
Creatine supplementation may represent a low-risk and mechanistically plausible intervention for improving cognition in ASD. Based on the convergence of preclinical and translational evidence, we propose that future research should explore creatine as a cognitive enhancer in ASD, particularly in individuals with evidence of energy metabolism abnormalities. This commentary provides a foundation to guide the design of pilot studies targeting this promising yet understudied therapeutic pathway.


Thinking Creatively about Creatine- A New Direction for Cognitive Enhancement in Autism Spectrum Disorder


Background
Cardiac masses are rare but remain an important consideration in cardio-oncology
practice. The differentials for cardiac masses vary depending on clinical presentation and include tumors, thrombi, vegetations, and structural abnormalities. Of the heart’s four chambers, right atrial masses pose a diagnostic challenge due to anatomical variations and limitations in imaging modalities. We present a case of a pseudo–right atrial mass. 
Case Presentation
An 81-year-old woman with a past medical history of hypothyroidism, hypertension and erosive esophagitis presented with altered mental status, including dysarthria, weakness, and paresthesia. Initial concern was for a cerebrovascular accident (CVA). CT head and CT angiography showed no ischemia or large vessel occlusion. During hospitalization, a transthoracic echocardiogram (TTE) revealed a large right atrial mass. Review of imaging from two years prior showed no cardiac masses or anatomical abnormalities. Given recent weight loss and neurologic symptoms
concerning for micro-thrombotic lesions, a cardiac tumor was high on the differential. MRI of the brain revealed no acute CVA. Due to the patient’s agitation, transesophageal echocardiogram (TEE) was deferred. A contrast-enhanced CT of the heart was obtained but showed no clear evidence of a right atrial mass; however, the right atrium was poorly opacified, and a large hiatal hernia was noted. The patient's mental status gradually improved, and she was discharged with
outpatient cardiology follow-up. As an outpatient, TEE confirmed the absence of cardiac masses or anatomical abnormalities. The previously suspected right atrial mass was attributed to imaging artifact caused by the large hiatal hernia.
Discussion
Right atrial masses can be challenging to evaluate due to the chamber’s retrosternal position, which limits echocardiographic visualization. Misdiagnosis is possible due to anatomical variants or adjacent structures. This case illustrates how a large hiatal hernia may mimic a right atrial mass on imaging, particularly TTE. Comprehensive evaluation often requires multiple imaging modalities to differentiate true pathology from artifacts before proceeding with invasive workup. This case emphasizes the importance of considering non-cardiac causes, such as large hiatal hernias, in the differential for cardiac masses. Hiatal hernias can affect cardiac function
and rhythm, making their recognition vital in cardiac imaging. Reliance on multimodal imaging allows for a more accurate diagnosis, minimizes unnecessary interventions, and supports improved patient outcomes.

Echo Illusion: Hiatal Hernia Imitating a Right Atrial Mass

Background
Drug-Induced Liver Injury (DILI) is a heterogeneous clinical syndrome potentially caused by many pharmacological agents. DILI is typically benign and transient, improving after drug cessation; few cases progress to chronic liver disease or liver failure. We present a case of DILI following initiation of zoledronate and bicalutamide, resulting in persistent hyperbilirubinemia and acute renal failure due to suspected bile cast nephropathy. 

Case Presentation
An elderly man with metastatic prostate cancer presented with fatigue, dark urine, and jaundice. One month prior he initiated bisphosphonate and anti-androgenic therapy with zoledronate and bicalutamide, respectively. Workup revealed severe transaminitis, elevated alkaline phosphatase (ALP), and rising hyperbilirubinemia. A liver biopsy was obtained and was suggestive of DILI. He was treated with N-acetylcysteine and prednisone and discharged; follow-up labs showed initial improvement in transaminases, ALP, and bilirubin. However, weeks later he was readmitted with progressively increased bilirubin, ALP, and concomitant acute kidney injury. He was managed with fluids, electrolyte replacement, and supportive care. Weeks later, he was hospitalized again with electrolyte derangements, continued renal dysfunction, and persistently elevated bilirubin and ALP. Given persistent cholangiopathy and impending renal failure, with metastatic cancer, the patient enrolled in hospice care and passed away shortly after.
Discussion
Thousands of drugs have been potentially implicated in DILI with wide variations in presentation and severity. Causative drugs are typically identified by the temporal relationship of drug initiation with hepatotoxicity and improvement following cessation. Our patient developed DILI one month after starting zoledronate and bicalutamide, which have both been previously associated with rare reports of hepatotoxicity. Zoledronate has been more commonly implicated in prior reports and is the more likely causative agent – notably, these reports specify transient hepatotoxicity with swift recovery. Our case is unique in that neither bicalutamide nor zoledronate has been previously associated with such severe, prolonged, and progressive liver injury.
Both drugs, particularly zoledronate, have long mechanisms of action and are eliminated slowly – this may help explain the prolonged course of hepatotoxicity seen in our patient. While typical treatment of DILI involves immediate cessation of the offending agent, drugs with long durations of action can present a unique challenge since toxic effects can also persist. We suspect the prolonged period of hyperbilirubinemia resulted in renal failure secondary to bile cast nephropathy, however this was not confirmed with biopsy. Ultimately, the prolonged duration and severity of this case highlight the challenge of managing complex and rare hepatotoxic effects.


Prolonged Cholestatic Drug-Induced Liver Injury with Acute Renal Failure in a Patient with Metastatic Cancer

Background: Microscopic polyangiitis (MPA) is a rare ANCA-associated small vessel vasculitis that primarily affects adults. Pediatric cases are rare and frequently present with non-specific or atypical symptoms. Early recognition can be difficult, as initial symptoms may resemble more common pediatric gastrointestinal or renal conditions.
Case Presentation: A previously healthy 15-year-old male developed progressive vomiting, significant weight loss, and persistent hypertension over several months. Initial outpatient gastrointestinal workup, including imaging and endoscopy, was unrevealing. He was admitted for worsening symptoms and found to have acute kidney injury with abnormal renal ultrasound findings. After temporary improvement with fluid repletion, he was readmitted for recurrent nausea, rising creatinine, and new-onset hematuria and proteinuria. Further history revealed prior episodes of epistaxis and rash. Renal biopsy demonstrated pauci-immune necrotizing and crescentic glomerulonephritis, and serologic testing revealed elevated MPO-positive p-ANCA titers, confirming MPA. He was treated with high dose intravenous steroids and rituximab for induction, with supportive care and antihypertensive therapy. He responded to immunosuppressive treatment with early improvement in symptoms and renal function.
Discussion: This case highlights the diagnostic challenge of MPA in pediatric patients, particularly when presenting with a non-classical, gastrointestinal predominant presentation. ANCA-associated vasculitis should remain on the differential for adolescents with evolving signs of glomerular disease, particularly if early signs are subtle or suggest alternative diagnoses. Early consideration and prompt biopsy confirmation are critical for timely initiation of immunosuppressive therapy and prevention of irreversible organ damage.

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