Allogeneic hematopoietic cell transplant (allo-HCT) is potentially curative for many hematologic diseases but complicated by acute graft-versus-host disease (aGVHD). While tacrolimus remains the cornerstone of aGVHD prophylaxis, regimens are increasingly including post-transplant cyclophosphamide (PTCy). This single-center study evaluated a previously published tacrolimus population pharmacokinetic (popPK) model developed from allo-HCT recipients administered standard (tacrolimus plus methotrexate) aGVHD prophylaxis for generalizability to PTCy recipients. Adult allo-HCT recipients treated with PTCy for aGVHD prophylaxis were included. Applicability of the established popPK model to the PTCy population was based on an evaluation of simulated to observed concentration ratios, and the distribution was interpreted with respect to a clinical equivalence range (0.8 to 1.25). The model was refit using data from both the standard and PTCy cohorts to describe the PK and support extrapolation to the PTCy population. Individual PK parameters from PTCy recipients were used to simulate steady-state concentrations (Ctrough, ss) using the current institutional weight-based dosing strategy and the proposed model-informed precision dosing (MIPD) algorithm. The proportion of patients predicted to experience a subtherapeutic Ctrough, ss (<5 ng/mL) was compared between dosing strategies. Five hundred and ninety-three tacrolimus Ctrough, ss values from 95 allo-HCT recipients who received PTCy were included. The previous model did not successfully predict tacrolimus Ctrough, ss values among PTCy patients, but highlighted similarities between clearance in PTCy and standard aGVHD prophylaxis patients who received reduced-intensity conditioning. Dosing simulations suggested a decreased proportion of PTCy patients would experience subtherapeutic tacrolimus Ctrough, ss with MIPD (3%) compared to conventional weight-based dosing (23%).

High doses of methotrexate are widely used, but its clinical application is limited by renal toxicity. The poorly soluble metabolite 7-hydroxymethotrexate contributes to renal injury, potentially through intratubular precipitation; however, its formation differs across species, complicating the evaluation of human-relevant toxicity in conventional animal models. In this study, methotrexate-induced renal toxicity was investigated using chimeric mice with humanized livers (humanized-liver mice). The pharmacokinetics of methotrexate and its major metabolite, 7-hydroxymethotrexate, were characterized in humanized-liver mice and compared with those in nontransplanted mice. Following the administration of a single oral dose, plasma concentrations and area under the curves of methotrexate and 7-hydroxymethotrexate were higher in humanized-liver mice than in control mice, and the urinary metabolite-to-parent ratio in humanized-liver mice was comparable to that reported in humans. Repeated methotrexate administration significantly increased blood urea nitrogen and creatinine levels, indicating impaired renal function. Necrosis of tubular epithelial cells and eosinophilic debris within the tubules were observed in the kidneys of humanized-liver mice, along with the accumulation of methotrexate and 7-hydroxymethotrexate, but not in control mice. Hepatic cytosolic methotrexate 7-hydroxylation activity in humanized-liver mice showed kinetic properties and inhibitor sensitivity consistent with human aldehyde oxidase, supporting this enzyme's role in metabolite formation. Thus, humanized-liver mice recapitulate key features of methotrexate-induced renal toxicity associated with human-relevant metabolism, providing a useful in vivo platform to evaluate organ toxicity in the context of human pharmacokinetics.

Eczema molluscatum refers to widespread molluscum contagiosum (MC) infection occurring in patients with atopic dermatitis (AD), a setting in which impaired skin barrier function and immune dysregulation both promote viral spread. We report the case of a 29-year-old man with longstanding, treatment-refractory AD who was well controlled on upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, and methotrexate when he developed multiple pink, dome-shaped papules with central umbilication across the cheeks and forehead over a six-month period. The lesions were unresponsive to topical clindamycin-benzoyl peroxide gel. The differential diagnosis included eczema coxsackium, eczema herpeticum, eruptive syringomas, and a refractory JAK inhibitor-associated acneiform eruption, but the absence of pain, systemic symptoms, vesiculation, and follicular morphology supported a diagnosis of eczema molluscatum. The patient was treated with cryotherapy for each lesion, with marked improvement at one-month follow-up. AD itself is a recognized risk factor for MC, reflecting the disease's inherent Th2-skewed, barrier-disrupted immune environment. However, this case raises the possibility that systemic immunosuppression with JAK1 inhibitors, particularly in combination with methotrexate, may further impair type I interferon-mediated antiviral defense and compound susceptibility to MC in patients with AD. Nonetheless, clinicians should maintain a high index of suspicion for eczema molluscatum in patients with AD on JAK inhibitor therapy who develop new facial papules, as these lesions are readily mistaken for a JAK inhibitor-associated acneiform eruption, potentially delaying appropriate treatment.

Alopecia areata (AA) is an immune-mediated non-scarring hair loss disorder. Severe forms, including alopecia totalis and alopecia universalis (AU), are rare in children and often refractory. Psychosocial stress has been implicated as a trigger, and pigmentary changes may occur during regrowth. We report a 9-year-old girl from Honduras with AU involving the scalp, eyebrows, eyelashes, and forearms, with nail pitting following a significant psychosocial stressor. Laboratory studies showed normal thyroid function and low vitamin D levels. Initial treatment included topical clobetasol propionate 0.05% for 6 months, topical minoxidil 5% for 12 months, and oral vitamin D supplementation for 6 months, with minimal response. Systemic therapy was initiated with oral corticosteroids (1 mg/kg/day) tapered over 4 months, followed by oral methotrexate (12 mg/m[2]/week) for 1 year; topical therapies were maintained concurrently throughout systemic treatment. Hair regrowth began at 3 months of methotrexate, initially as diffuse poliosis, followed by complete terminal hair regrowth and normalization of nail changes. Psychological support was provided throughout management. This case highlights psychosocial stress as a potential contributor in pediatric AU and supports a multidisciplinary approach. Methotrexate was effective and well tolerated, and poliosis may be a marker of follicular recovery.

Primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder (PCSMLPD) is a rare indolent cutaneous lymphoid proliferation accounting for approximately 2% of all cutaneous lymphomas. It typically presents as a solitary nodule on the face, neck, or upper trunk and is associated with an excellent prognosis. This review evaluates current treatment options for PCSMLPD and discusses outcomes reported in the literature. Management strategies include watchful waiting, surgical excision, low-dose radiotherapy, topical or intralesional steroids, and, in selected cases, systemic therapies such as methotrexate or doxycycline. Spontaneous regression following diagnostic biopsy has also been documented. Analysis of the largest published series demonstrates that complete surgical excision provides the highest rate of complete remission and the lowest risk of recurrence, making it the preferred first-line treatment for localized disease. Low-dose radiotherapy is highly effective for patients that are unsuitable for surgery, for recurrent lesions, or for lesions on the face, whereas topical or intralesional steroids may achieve remission in selected cases but are associated with a higher likelihood of requiring additional treatment. Relapses are uncommon and generally occur within the first 2 years after diagnosis, supporting regular clinical follow-up during this period. Staging examinations are no longer recommended in patients with a typical clinicopathological presentation. Overall, PCSMLPD has an excellent prognosis, and conservative skin-directed therapies are usually sufficient to achieve durable disease control, with surgical excision remaining the treatment of choice.

Background/Objectives: Methotrexate (MTX) is an effective antineoplastic and immunosuppressive agent whose clinical use can be limited by nephrotoxicity. Increasing evidence suggests that dysregulated angiotensin II-mediated signaling contributes to MTX-induced renal injury. Olmesartan (OLM), an angiotensin II type 1 receptor (AT1R) blocker, possesses renoprotective properties; however, its therapeutic efficacy may be limited by suboptimal pharmacokinetics and tissue deli\very. This study aimed to develop OLM-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (OLM-PLGA) and investigate their nephroprotective efficacy and underlying molecular mechanisms in MTX-induced nephrotoxicity. Methods: OLM-PLGA nanoparticles were prepared and evaluated for their physicochemical characteristics. The in vivo nephroprotective effects of OLM-PLGA were investigated in male Sprague-Dawley rats, which were allocated into four groups: OLM (10 mg/kg), OLM-PLGA (10 mg/kg), MTX-treated, and normal control. Renal function, oxidative stress, inflammation, apoptosis, and fibrosis were assessed, together with renal gene expression of AT1R and extracellular signal-regulated kinase 1/2 (ERK1/2). Results: Compared with free OLM, OLM-PLGA provided superior protection against MTX-induced renal dysfunction and oxidative stress, as evidenced by improved renal function and enhanced antioxidant defense. OLM-PLGA also exerted greater anti-inflammatory and anti-apoptotic effects and attenuated renal fibrotic changes, accompanied by reduced renal expression of α-smooth muscle actin and collagen. These protective effects were associated with decreased AT1R gene expression and suppression of downstream ERK1/2 signaling. Conclusions: PLGA-based nanoencapsulation enhanced the nephroprotective efficacy of OLM against MTX-induced nephrotoxicity and was associated with the modulation of the AT1R/ERK1/2 signaling axis. OLM-PLGA may therefore represent a promising nanotherapeutic approach for improving OLM delivery and renal protection during MTX treatment.