Diverse landscape of dermatologic toxicities from small-molecule inhibitor cancer therapy.

BACKGROUND: Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. METHODS: We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis. RESULTS: Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs. CONCLUSIONS: Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."

Localized cutaneous argyria: Review of a rare clinical mimicker of melanocytic lesions.

Localized cutaneous argyria is a rare cutaneous disorder that has been associated with occupational exposure, dental procedures, topical agents, acupuncture, earrings, and nasal piercings. In this paper, we review the current literature on localized cutaneous argyria, highlight its clinical and histologic diagnostic features, and then discuss the clinical and histological differential diagnoses for blue-gray skin and black dermal pigment, respectively. We also discuss the utility of ancillary techniques, such as deeper histologic levels, special stains, darkfield microscopy, and advanced micro-analytical techniques in helping diagnose localized cutaneous argyria. Furthermore, we emphasize that a thorough clinical history and astute clinico-pathologic correlation can be the most important diagnostic techniques in correctly diagnosing this rare disorder. Our review aims serve as a reminder to clinicians and pathologists of the importance of including localized cutaneous argyria in the clinical and histological differential diagnosis of pigmented lesions.

Cutaneous histoplasmosis with prominent parasitization of epidermal keratinocytes: report of a case.

Disseminated histoplasmosis most commonly occurs in immunosuppressed individuals and involves the skin in approximately 6% of patients. Cutaneous histoplasmosis with an intraepithelial-predominant distribution has not been described. A 47-year-old man was admitted to our institution with fever and vancomycin-resistant enterococcal bacteremia. He had been diagnosed with T-cell prolymphocytic leukemia 4 years earlier and had undergone matched-unrelated-donor stem cell transplant 2 years earlier; on admission, he had relapsed disease. His medical history was significant for disseminated histoplasmosis 6 months before admission, controlled with multiple antifungal regimens. During this final hospitalization, the patient developed multiple 2-5 mm erythematous papules, a hemorrhagic crust across the chest, shoulders, forearms, dorsal aspect of the fingers, abdomen and thighs. Skin biopsy revealed clusters of oval yeast forms mostly confined to the cytoplasm of keratinocytes and within the stratum corneum; scattered organisms were present in the underlying superficial dermis without any significant associated inflammatory infiltrate. Special stains and immunohistochemical studies confirmed these to be Histoplasma organisms. We highlight this previously unrecognized pattern of cutaneous histoplasmosis to ensure its prompt recognition and appropriate antifungal therapy.

Disseminated Mycobacterium avium Complex With Cutaneous Lesions.

BACKGROUND: Although most commonly encountered in patients with human immunodeficiency virus infection, disseminated Mycobacterium avium complex (MAC) is becoming more common in patients receiving immunosuppressive medications. Disseminated MAC with skin lesions may occur, and several presentations have been reported, including panniculitis, cutaneous granulomas, pustules, ulcerations, and erythematous skin lesions. OBJECTIVES: The objective of this report is to describe an unusual presentation of MAC that is unlikely to be encountered frequently in the outpatient dermatology setting, especially in a patient without human immunodeficiency virus infection. METHODS: The authors present a case of disseminated MAC infection with cutaneous manifestations in an iatrogenically immunocompromised patient. CONCLUSIONS: Diagnosis of MAC infection is challenging given the varied clinical presentations and the difficulty in culturing MAC. In addition, the acid-fast stain is nonspecific. Clinicians should remember to consider MAC infection in patients with acid-fast-positive skin lesions, as the selection of appropriate antibiotic therapy is species specific.

Emergency department use after stage II palliation for children with single ventricle lesions.

BACKGROUND: Infants born with a single cardiac ventricle require a 3-stage surgical palliation performed during the first few years of life for long-term survival. We aimed to determine the extent to which the emergency department services were used between the second and third surgical stages. METHODS: A retrospective chart review was performed on patients who underwent stage II palliation at our institution between 2006 and 2011. Data analyses were performed using Mann-Whitney U tests or χ tests as appropriate. RESULTS: Fifty patients underwent stage II palliation during the study period, 47 of which survived to hospital discharge. Thirty-one (66%) patients required 95 emergency department visits before stage III. The most common chief complaints were respiratory (n = 39) and gastrointestinal (n = 18 visits) in nature. Age and weight at time of stage II surgery, dominant ventricle, and data from discharge echocardiograms were not significantly different between patients who did and did not require emergency department visits. Median postoperative length of stay after stage II palliation was longer in patients using the emergency department, 11 (interquartile range, 6-17) versus 7 (interquartile range, 5-8) days, P = 0.015. Moreover, patients with lengths of stay greater than 10 days were 6 times more likely to require emergency department services (odds ratio, 6.0; 95% confidence intervals, 1.4-25.4). CONCLUSIONS: Emergency department use by patients with a single cardiac ventricle is common after their second surgical stage, especially in patients with more complicated postoperative courses. This study emphasizes the important role of the emergency department in the care of these challenging patients.

Safety and utility of passive peritoneal drainage following Fontan palliation.

OBJECTIVE: Placement of peritoneal drainage catheters intra-operatively has been shown to help prevent fluid overload in children recovering from surgery for two-ventricle heart disease. We aimed to determine whether this practice is also helpful in children recovering from Fontan palliation. MATERIAL AND METHODS: A retrospective review was performed on children with single-ventricle anatomy undergoing Fontan palliation at our institution from 2007 to 2011. Variables in those with peritoneal drainage were compared with those without using t-tests, Mann-Whitney U-tests, chi-square tests, or analysis of variance for repeated measures as appropriate. Data were represented as mean with standard deviation unless otherwise noted. RESULTS: A total of 43 children were reviewed, 21 (49%) with peritoneal drainage catheters. No complications from catheter placement occurred. The groups did not differ with regard to cardiopulmonary bypass duration, dominant ventricle, pre-operative haemodynamic data, fenestration use, and initial intensive care unit ventilation index. Central venous pressures, vasoactive medication use, and diuretic use during the first 48 hours were also not statistically different. At 48 hours, the median fluid balance was -9 (interquartile range : -50, +20) in those with peritoneal drainage and +77 cc/kg (interquartile range : +22, +96) in those without (p < 0.001), yet median duration of mechanical ventilation was 40 hours (range: 19-326) in those with peritoneal drainage and 23 hours (range: 9-92) in those without, p = 0.01. CONCLUSION: Patients with peritoneal drainage recovering from Fontan palliation achieved negative fluid balance as compared with those without peritoneal drainage, although this difference was associated with a longer duration of mechanical ventilation.

UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors.

BACKGROUND: The UBE4B gene, which is located on chromosome 1p36, encodes a ubiquitin ligase that interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a protein involved in epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. The authors analyzed the roles of UBE4B in the outcomes of patients with neuroblastoma and in neuroblastoma tumor cell proliferation, EGFR trafficking, and response to EGFR inhibition. METHODS: The association between UBE4B expression and the survival of patients with neuroblastoma was examined using available microarray data sets. UBE4B and EGFR protein levels were measured in patient tumor samples, EGFR degradation rates were measured in neuroblastoma cell lines, and the effects of UBE4B on neuroblastoma tumor cell growth were analyzed. The effects of the EGFR inhibitor cetuximab were examined in neuroblastoma cells that expressed wild-type and mutant UBE4B. RESULTS: Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma. UBE4B overexpression reduced neuroblastoma tumor cell proliferation, and UBE4B expression was inversely related to EGFR expression in tumor samples. EGFR degradation rates correlated with cellular UBE4B levels. Enhanced expression of catalytically active UBE4B resulted in reduced sensitivity to EGFR inhibition. CONCLUSIONS: The current study demonstrates associations between UBE4B expression and the outcomes of patients with neuroblastoma and between UBE4B and EGFR expression in neuroblastoma tumor samples. Moreover, levels of UBE4B influence neuroblastoma tumor cell proliferation, EGFR degradation, and response to EGFR inhibition. These results suggest UBE4B-mediated growth factor receptor trafficking may contribute to the poor prognosis of patients who have neuroblastoma tumors with 1p36 deletions and that UBE4B expression may be a marker that can predict responses of neuroblastoma tumors to treatment.

Having Outpatient Major Elective (HOME) Robotic Colon Resection Protocol: A Safe Approach to Ambulatory Colon Resection.

BACKGROUND: Within the past decade, colorectal surgery length of stay (LOS) has decreased from an average of 5-6 days to 2-3 days. However, elective colon resections have yet to become a common procedure with the potential for same-day discharge. During the COVID pandemic, hospital capacity was exceptionally strained and colon resections were delayed due to the lack of inpatient beds available. PURPOSE: We sought to create a protocolized ERAS (enhanced recovery after surgery) pathway that would allow for safe and feasible ambulatory colon resections as well as decreasing overall hospital inpatient burden. RESEARCH DESIGN: Between November 2020 and March 2022, 15 patients were offered same-day discharges under the HOME protocol. Of the 15 patients, 11 patients agreed to be discharged home the day of surgery and followed prospectively for 30 days. All procedures were performed robotically. STUDY SAMPLE: Patients were selected based on level of preoperative health (ASA class 1 and 2), low-risk for loss to follow-up, ability for close family supervision for 3 days postoperatively, and type of procedure (partial colectomy). Close follow-up was achieved with daily telephonic or televideo visits for 3 days post-operatively, as well as a 2-week outpatient clinic follow-up. DATA COLLECTION: A total of 11 patient underwent same-day surgery utilizing the protocol, 5 females and 6 males, between the ages of 34 and 62. All patients were ASA class 2. Indications for colon resection were cecal volvulus (1), recurrent sigmmoid diverticulitis (9), and Crohn's disease (1). Primary outcome was readmission rates within the 30-days. RESULTS: There were no readmissions or complications during the perioperative 30-day period. There was one emergency department return for pain who was not admitted. Average operative time was 132.1 minutes. CONCLUSION: Using a novel enhanced recovery protocol, we demonstrated the feasibility and safety of ambulatory partial colectomy in a highly select small subset of patients.

Hyaluronic acid filler for a depressed scar.

The use of filler for depressed scars has been documented but is rare in the literature. We present a case of a patient treated with hyaluronic acid fillers at the site of a long-standing depressed scar.

Effectiveness of pulsed dye laser in the treatment of recalcitrant warts in children.

BACKGROUND: To determine the efficacy and safety of the 585-nm pulsed dye laser (PDL) in the treatment of recalcitrant warts in children. METHODS AND MATERIAL: Retrospective survey of the medical records of children with recalcitrant warts who were treated with PDL between March 1995 through January 1999 at the Children's Memorial Hospital outpatient subspecialty center, Chicago, Illinois. RESULTS: Sixty-one children with recalcitrant warts were treated with PDL; 75% of them had total clearance of warts after an average of 3.1 treatment sessions. Overall success rates were 100% for both perineal and perianal and face-only warts, 93% for hands, 69% for plantar warts, 67% when both face and extremities were involved, and 60% when multiple extremities were involved. Pain and other side effects were minimal. Mild scarring occurred in 2% of patients; 75% of patients remained free of warts after a follow-up period of 24 months or longer. CONCLUSION: PDL therapy is an effective, safe alternative therapy for treatment of recalcitrant warts in children, with few side effects and a low long-term recurrence rate.

Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo.

Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPIArg189Gln/TPIGlu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.

Problems in pattern alopecia.

Female pattern hair loss (FPHL) was originally described as synonymous with androgenetic alopecia. However, the role of androgens in FPHL has not been proven, and the etiology is not yet defined. Several patterns of hair loss in women have been described, in addition to descriptions of scarring alopecias mimicking FPHL. In this paper, we discuss FPHL as an entity other than androgenetic alopecia and suggest that de-emphasizing the physicians reliance on pattern in the diagnosis of hair loss in women, and instead utilizing other tools including dermoscopy and histopathology, would benefit clinician's efforts in treating alopecias.

Twenty-four-month persistence of hyaluronic acid filler for an atrophic scar.

A 24-month follow up of a previously reported case of successful hyaluronic acid filler use in steroid atrophy is presented. The patient had persistence of the volume and appearance of her scar with sustained satisfaction 24 months after hyaluronic acid treatment, without the need for repeat injection. This case suggests expansion of the use of hyaluronic acid fillers to include scar atrophy, as persistence of a desired cosmetic appearance for 2 years is demonstrated.

Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo.

BACKGROUND: ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. METHODS: The authors examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot, and quantitative real time polymerase chain reaction (Q-PCR). Response to ERBB inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements. RESULTS: A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with HER-2 in some tumors. HER-4 mRNA was expressed predominantly in cleavable isoforms. Whereas EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, although CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. CONCLUSIONS: Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, although EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma.

Dermatologic surgery and the pregnant patient.

BACKGROUND: Because of concerns about potential harm to the mother or fetus, dermatologic surgeons are frequently hesitant to perform cutaneous surgery on pregnant patients. OBJECTIVE: To review the relevant physiologic changes during pregnancy, appropriate preparation for and timing of procedures, and drug safety. METHODS: A literature review was performed of dermatologic and nondermatologic journals discussing physiology, surgery, and drug safety in the pregnant patient. RESULTS: Special positioning is required for the pregnant patient during surgery. Low doses of most local anesthetics with epinephrine as well as nitrous oxide less than 50% are safe to use during pregnancy. Sedatives and opioids are potential teratogens and should be avoided. Safe antibiotics to use during skin surgery in pregnancy include penicillins, cephalosporins, and nonestolate erythromycin. If necessary, lymph node dissections under general anesthesia in the pregnant melanoma patient should occur during the second trimester. CONCLUSION: With appropriate preparation, safe and successful cutaneous surgery can be performed on the pregnant patient.