Near-complete Remission Research Articles

Carbon Ion Beam Radiation Therapy as Part of a Trimodal Therapy for Non-small Cell Superior Sulcus Tumors: The INKA Study

Purpose/ObjectiveSuperior sulcus tumors are frequently treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery in a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiotherapy (C12-RT) in this regimen. Material/methodsThe prospective INKA-study included patients with locally advanced non-small cell superior sulcus tumors (<cN3 cM0). Patients received 2 cycles of cisplatin and vinorelbine as per local standard. During the second cycle, 39Gy(RBE) of hypofractionated C12-RT in 13 fractions were applied. Surgery following an FDG-PET/CT restaging was performed 2 weeks later. The primary endpoint was feasibility and safety measured by the incidence of CTCAE (v4.0) grade 3/4 toxicity and/or discontinuation due to any reason. Secondary endpoints included the morphological (RECIST 1.0), metabolic (PERCIST 1.0) and histopathological response after nCRT as well as Quality of Life measurement (QLQ-C30/LC13). ResultsBetween 2015 and 2020, 14 patients were included and received nCRT. No grade 3/4 toxicity occurred with no discontinuation due to toxicity. Before surgery, 8 patients (57%) showed a partial response on CT scan. Thirteen patients showed a metabolic response (mCR=1, mPR=12). Three patients were judged as inoperable after nCRT (21%). In patients with resection, a pathological CR was seen in 2 patients (19%) and near-complete remission (<10% vital tumor cells) in 6 patients (55%). Pain score was more than halved compared to baseline (mean: 69.2±26.2 vs. 30.6 ± 29.1; p=0.005) after completion of nCRT and before surgery. ConclusionThe INKA trial is the first study to evaluate nCRT with C12-RT and showed excellent response, low toxicity and rapid pain relief.

A case of hereditary breast and ovarian cancer syndrome of initially presented as cancer of unknown primary with lymph node metastases unveiled by genetic analysis

Cancer of unknown primary (CUP) is a heterogeneous disease concept involving various malignant tumors. Understanding its pathophysiology is often difficult, together with its treatment. Here, we present a case of CUP with abdominal lymph node enlargement and elevated carbohydrate antigen 125 levels. It initially resembled a favorable prognosis type similar to ovarian cancer, but metastases were observed in cervical lymph nodes, indicating a somewhat atypical CUP compared to the typical ovarian cancer-like CUP. We identified a germline Breast Cancer 1 (BRCA1) p.L63* variant through a family history inquiry and BRCA analysis, indicating hereditary breast and ovarian cancer syndrome. The patient achieved near-complete remission with platinum-based therapy followed by poly (ADP-ribose) polymerase (PARP) inhibitor. The variant has shown sensitivity in both clinical and pathogenic reports in the ClinVar database of the National Institutes of Health. No clinical studies reported on the efficacy of PARP inhibitors specific to this variant, but our case demonstrated the sensitivity of platinum-based therapy followed by PARP inhibitor. Reports of CUP in hereditary breast and ovarian cancer syndrome are very rare, with only a single report in the literature.

Definition of the Clinical Characteristics of Patients with Moderate and Severe Atopic Dermatitis for Whom Narrow-Band UVB (NB-UVB) and Medium-Dose UVA1 Phototherapies Are Still Valuable Treatment Options at the Age of Biologics.

Narrow-band (NB) UVB and UVA1 have been successfully used for the treatment of atopic dermatitis (AD) since the 1980s, but the clinical indications for their use "at the age of biologics" remain to be assessed. From 2013 to 2017, 145 patients underwent a first treatment cycle with phototherapy. They achieved a median final EASI score of 9.90 with UVA1 and 13.70 with NB-UVB. The rates of patients achieving an IGA score of 0/1 persistent for at least 6 months were 33% with UVA1 and 28% with NB-UVB, and the rates with an EASI90 improvement were 10.9% with UVA1 and 11.0% with NB-UVB. The cut-off baseline EASI values for a good probability to achieve a 0/1 IGA were 24.4 with UVA1 and 24.7 with NB-UVB. A 0/1 IGA persistent for at least 6 months was more likely to be achieved by patients with a history of flares interspersed with periods of mild or no disease. From 2018, we only enrolled patients with the above-mentioned characteristics. The number of treated patients was lower, but the final EASI score, the rate of patients achieving IGA 0/1 persistent for at least 6 months, and EASI90 were significantly higher. Medium-dose UVA1 and NB-UVB phototherapies remain useful for the treatment of AD patients with a baseline EASI score lower than 24.4 and 24.7, respectively, and a medical history of flares followed by prolonged periods of complete or near-complete remission.

Abstract A014: Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment

Abstract Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) patients harbor an oncogenic KRAS mutation, with Gly-to-Asp mutations (KrasG12D) being most common. PDAC is characterized by a robust, immunosuppressive tumor microenvironment that is rich in myeloid-derived suppressor cells (MDSCs) and has a paucity of T cells. The majority of therapeutic interventions in PDAC are ineffective, in part, due to this immunosuppressive TME. We aimed to examine the efficacy of a small molecule KrasG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14d. MRTX1133 treatment additionally reduced metastatic burden after 7d of treatment. An increase in tumor cell death was identified after only 36h of treatment, with concomitant loss of tumor cell proliferation. Inhibition of KrasG12D led to marked shifts in the TME composition. MRTX1133-treated tumors had an increase in fibroblasts, collagen deposition, and blood vessel density. There was a robust increase in M1-like macrophages after MRTX1133 treatment. Further, there was a loss of MDSCs, along with an increase in cytotoxic T cells. Proteome profiling on tumor cells treated with MRTX1133 identified a loss of tumor cell-derived GM-CSF (a MDSC recruiter), as well as an increase in CCL2 (a macrophage recruiter), providing evidence that MRTX1133 alters the TME through tumor secreted factors. T cells were necessary for MRTX1133’s full anti-tumor effect, and T cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KrasG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Citation Format: Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger. Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A014.

Case Series of Patients with Brainstem Inflammation Causing Paroxysmal Movement Disorders (P4-5.016)

<h3>Objective:</h3> We describe five patients with various neuroinflammatory diseases who developed Paroxysmal Movement Disorders (PMD). <h3>Background:</h3> PMD are a rare phenomenon that has been described in patients with multiple sclerosis since the 1940s. PMD are typically responsive to carbamazepine. One subtype of PMD is paroxysmal dysarthria and ataxia syndrome (PDA), characterized by stereotyped episodes of dysarthria and ataxia, lasting seconds and recurring several times per day. This is thought to be due to transverse ephaptic transmission between demyelinated axons in the brainstem. Recently, cases of PDA in other neuroinflammatory diseases such as Behcet’s disease, MOG-antibody disease (MOGAD), Bickerstaff encephalitis, and anti-NMDA encephalitis have been described but the spectrum of PMD in neuroinflammatory diseases has not been sufficiently studied. <h3>Design/Methods:</h3> Case report series. <h3>Results:</h3> We describe in detail five patients with CNS inflammatory diseases who developed PMD. Underlying diseases were chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), MS, MOGAD, and post-infectious encephalitis (COVID and LaCrosse virus). Four patients developed PDA, while one presented with paroxysmal esophageal contractions. Paroxysms were brief (less than 10 seconds) and frequent (up to hundreds of times a day). On MRI, four patients had lesions in the medial midbrain and one had a lesion in a cerebellar peduncle. In four cases paroxysms were treated successfully with carbamazepine. All patients had complete or near-complete remission of their PMD. <h3>Conclusions:</h3> This series highlights that different neuroinflammatory disorders can cause PMD. This is the first report of PDA in CLIPPERS or post-COVID encephalitis, and the second report in MOGAD. Most patients had lesions in the dorsal midbrain below the red nucleus, a site commonly reported to cause PDA. Treatment with carbamazepine was successful. PMD in neuroinflammatory disease is important to recognize as symptoms can be debilitating but successfully treated. This case series can help improve awareness of this rare condition. <b>Disclosure:</b> Dr. Luxenberg has nothing to disclose. The institution of Dr. Wang has received research support from Genentech. The institution of Dr. Wundes has received research support from Benaroya Research Institute . The institution of Dr. Von Geldern has received research support from Novartis. The institution of Dr. Von Geldern has received research support from National MS Society. Dr. Von Geldern has received personal compensation in the range of $0-$499 for serving as a DSMB member with NIH, NINDS. Dr. Von Geldern has a non-compensated relationship as a editorial board member with MS and Related Disorders Journal that is relevant to AAN interests or activities.

Remission of Persistent Negative Symptoms and Psychosocial Consequences by Combined Clozapine and Cariprazine Treatment in a Patient With Long-Standing Treatment-Resistant Schizoaffective Disorder.

This patient case report describes a 45-year old white unmarried man with disability pension due to schizoaffective disorder, diagnosed at the age of 24. He lives in an apartment and has housing support. Retrospectively, the patient displayed prodromal markers of a disorder within the schizophrenia spectrum many years before the onset of frank psychosis, indeed since childhood. Over the years several symptoms and signs across schizophrenia domains have been manifest: positive, negative, cognitive, and affective, among which the negative and affective symptoms and signs were the earliest to appear. While the positive, disorganized, and catatonic symptoms responded to treatment – when duly tested and complied with – the negative and affective symptoms have been notoriously difficult to handle. We now report on the successful introduction of cariprazine (CAR) to his ongoing clozapine (CLZ) medication, the result of which has been a near-complete remission of his persistent negative and psychosocial issues. We interpret this remarkable alleviation of the patient's disease – and concomitant improvement of his quality of life – in terms of neuroreceptor target complementarity between CLZ and CAR, with particular emphasis on the contributions from the D3 and D2 receptor partial agonist components of the latter agent.

Topical diphenylcyclopropenone in the treatment of alopecia areata: A 10-year follow-up of 86 cases in a single center

Background: Diphenylcyclopropenone (DPCP) is a topical contact allergen used for contact immunotherapy in alopecia areata (AA). Objectives: We aimed to evaluate the treatment effectiveness and prognostic factors in Taiwanese patients with AA treated with topical DPCP. Methods: We performed a retrospective study of all consecutive patients with AA affecting more than 10% of scalp area treated with topical DPCP for more than 90 days. Results: Eighty-six patients were assessed in the study. The greatest hair regrowth percentages of 0%, 1%–25%, 26%–50%, 51%–75%, and 76%–100% were 26.7% (23/86), 7.0% (6/86), 2.3% (2/86), 10.5% (9/86), and 53.5% (46/86) of patients, respectively. 32.6% (28/86) of patients achieved near-complete remission (with or without maintenance DPCP therapy), defined as more than 90% sustainable hair regrowth. Positive prognostic factors include older age of onset, shorter duration of AA before DPCP treatment, less severity of hair loss, and no nonscalp hair loss. Multivariate logistic regression analysis showed that more than a 2-year duration of AA before DPCP treatment (P = 0.015) and more than 90% of hair loss (P = 0.032) had a poorer treatment outcome. Factors including eczematous sensitization reaction, history of atopy, adverse reactions, or concentrations of DPCP do not predict treatment effectiveness. Pigmentary change may cause cosmetic concerns in Chinese ethnicity. Conclusion: Topical DPCP is effective for AA. Various factors were associated with the clinical outcomes. Monitoring the possible adverse events is warranted.

The Case | Severe hypophosphatemia in a patient with lymphoma

The patient was an 82-year-old man known for hypertension, hyperlipidemia, and gout who was diagnosed with follicular lymphoma 5 years before nephrology consultation. His lymphoma did not require therapy until 2 years before presentation, when his disease progressed clinically and radiographically with worsening lymphadenopathy. At that time, he completed 8 cycles of rituximab, cyclophosphamide, vincristine, and prednisolone, with near-complete remission. Three weeks before the nephrology consultation, a repeat computed tomography scan showed a significant progression of abdominal lymphadenopathy and a lymph node biopsy confirmed transformation into diffuse large B-cell lymphoma.

2000 - MONOLINEAGE ORIGIN OF RELAPSE FOLLOWING MULTILINEAGE DIFFERENTIATION THERAPY OF ACUTE MYELOID LEUKEMIA

Acute myeloid leukaemia (AML) is characterized by the accumulation of transformed immature myeloid blasts. While most AML patients treated with standard therapy have poor outcomes, in the APL disease subtype retinoic acid induces leukaemia maturation and can be curative in combination with arsenic trioxide. Recently approved mutant IDH1/2 inhibitors also induce AML maturation, renewing interest in AML differentiation therapy. To examine differentiation therapy dynamics in vivo we have generated a novel mouse AML model driven by reversible RNAi-mediated knockdown of the myeloid transcription factor PU.1. Restoration of endogenous PU.1 in established AML in vivo triggers synchronous differentiation of leukemic blasts and disease clearance. However, despite near-complete remission, mice reproducibly relapse with immature AML. Notably, in vivo time course studies reveal that one week after PU.1 restoration leukemic blasts differentiate into two mature myeloid lineages with distinct immunophenotype and morphology. AML-derived SSClowLy6G+ cells resembling neutrophils initially predominate but are rapidly eradicated in vivo. In contrast, high resolution flow and imaging indicates that mature AML-derived SSChighF4/80+SigF+ eosinophil-like cells persist at low numbers in specific organs during disease remission and appear to seed relapse. In mice transplanted with AML blasts lacking the essential eosinophil lineage transcription factor GATA1, in vivo PU.1 restoration triggers neutrophil but not eosinophil lineage differentiation and thereby eliminates residual disease. These results demonstrate that AML differentiation therapy can produce long-lived sublineages of mature AML-derived cells from which relapse can originate. Understanding the multilineage potential of AML blasts in individual patients may inform new strategies to improve differentiation therapy outcomes.

Local excision in mid-to-low rectal cancer patients who revealed clinically total or near-total regression after preoperative chemoradiotherapy; a proposed trial

BackgroundPreoperative chemoradiotherapy (pre-CRT) followed by total mesorectal excision (TME) is currently a standard therapy for locally advanced mid-to-low rectal cancer. Less aggressive, organ-preserving option such as local excision (LE) or watchful wait can alternatively be used for patients who respond well to pre-CRT. High-resolution rectal magnetic resonance imaging (MRI) is one of the most useful methods to assess pre-CRT response, and the MERCURY group has shown that the MR tumor regression grade (mrTRG) correlated with the pathologic TRG. The aim of this study is to compare postoperative complication and oncologic outcomes between LE and TME in mid-to-low rectal cancer patients whose tumors are mrTRG grade 1 (radiological complete remission) or 2 (predominant fibrosis; near-complete remission) after pre-CRT.MethodsA prospective, double-arm, randomized, open-labeled, single center, clinical trial will be conducted in patients with mid-to-low rectal cancer whose tumors are mrTRG 1/2 after pre-CRT at the Asan Medical Center, Seoul, Korea, after approval from the Institution Review Board. Patient medical records will be de-identified using a serial number to protect personal information. Inclusion criteria will include rectal adenocarcinoma with an inferior border < 8 cm from the anal verge, mrTRG 1/2, age > 20, and provision of informed consent. Postoperative complications will be assessed by Clavien-Dindo Classification Grade. Oncologic and functional outcomes will be collected and risk factors related to these outcomes will be investigated.DiscussionWe believed that the rate of postoperative complication of LE will be comparable to that of TME in mid-to-low advanced rectal cancer patients with a favorable response after pre-CRT.Trial registrationKCT0002579 (https://cris.nih.go.kr) Dec-2017.

Heavy chain disease: a rare case report of adult nephrotic syndrome

Monoclonal immunoglobulin deposition disease is a systemic disorder characterized by the deposition of immunoglobulins as nonfibrillar material in various organs. Three subtypes have been reported: light chain deposition disease, light and heavy chain deposition disease and heavy chain deposition disease. Among these, light chain deposition disease is the most prevalent. Reports of light and heavy chain and heavy chain disease are rare, with fewer than two dozen documented cases in the world literature and very few from India. Heavy chain disease is characterized by glomerular, tubular, and vascular wall deposition of monoclonal heavy chains without associated light chains. We present the case of a 51-year man, who presented with a 3-month history of pedal edema, hypertension detected 3 months ago, and mild renal failure Estimated Glomerular filteration rate (eGFR) 66 ml/min/1.73 m2; histopathology showed heavy chain deposition disease. The case emphasizes the need for a thorough workup for plasma cell dyscrasias when we see membranoproliferative pattern in adult patients. This patient was treated with bortezomib-based regimen and after 3 months achieved near-complete remission of proteinuria with improvement in serum creatinine.

Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

AbstractAmong 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm–relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of RUNX1 mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of RUNX1 mutations.

Survival and side effects from novel alternative regimen for squamous cell head and neck cancer.

e17515 Background: Toxicity of the standard regimens is a major limitation in treatment of head/neck cancer which impacted about 61,000 persons in 2016 in USA of which 13,000 died. We present data herein with low dose chemotherapy (metronomic) using commonly used drugs Taxols, Platins, 5-Flurouracil and EGFR inhibitors. We achieved equal or better outcomes as compared to standard dosing with minimal side effects (level 3/4). Methods: This is a retrospective study on squamous cell head and neck cancer patients where standard first line therapies were started at ½ normal dosing and was increased until the emergence of side effects and titrated thereafter. Results: Patient population consisted of 32 patients with 87% males and with median age 65.2 years where 59% had recurrent disease, 71% locally advanced and 28% had metastatic disease. Total 270 chemotherapy cycles were delivered among these 32 patients with median of 9 cycles. Median dose for Cispatin was 45mg/m2, Paclitaxol was 80mg/m2, 5-FU was 360mg/m2/day. Cetuximab was used at standard doses. 6 patients who achieved long-term disease control were then placed on immunotherapy with either Nivolumab (median dose of 3mg/kg) or Pembrolizumab (median dose of 2mg/kg) and got median of 7 cyles. Out of 32, 9 patients (28%) achieved complete remission, 3 patients (9%) achieved near-complete remission with more than 95% reduction in tumor size. Overall disease control rate was 68% and overall response rate was 59%. Out of 9 patients who achieved complete remission 5 underwent surgical exploration and 1 went for cryo-ablation and no residual tumor was found. Measuring tumor volume in patients who achieved disease control showed volume reduction of 53%, 62% and 78% in 1st, 2nd and 3rdfollow up surveillance studies at mean interval of 101 , 186 and 331 days showing steady response. Median Progression free survival was 17.8 months and overall survival at 40 months was 54%. Notable high-grade toxicities were generalized fatigue in 12.5% (n = 4), grade 3 neutropenia in 18% (n = 6) and grade 4 neutropenia in 1 patient. Conclusions: These excellent results, low toxicity and subsequent good quality of life encourage patient tailored approach rather than one-size fits all approach.

A Case of Cyclosporine-Induced Sebaceous Hyperplasia in a Renal Transplant Patient Successfully Treated with Isotretinoin.

Dear Editor: Sebaceous hyperplasia (SH) is a benign proliferation of the sebaceous glands that develops as a result of intrinsic aging, photo-aging, exposure to ultraviolet radiation, and genetic predisposition. Organ transplant recipients are susceptible to SH particularly on the face, where multiple large lesions may cause cosmetic concern. Several studies in the literature report SH being induced by cyclosporine due to immunosuppression of patients undergoing organ transplant. Oral isotretinoin and topical photodynamic therapy has previously been reported as a treatment for SH in immunocompetent individuals1,2,3. Other options include electrodesiccation, shave excision and carbon dioxide laser. However, only three cases of cyclosporine-induced SH in a kidney transplant population treated with oral isotretinoin have been reported in the English literature2,3. Therefore, we report a case of cyclosporine-induced SH in a renal transplant recipient successfully treated with oral isotretinoin, along with a review of the literature. A 40-year old Korean man presented in 2013 with multiple skin-colored papules on his face. He had undergone renal transplantation surgery in 1996, following which, he was immunosuppressed with oral cyclosporine and prednisolone for 11 years. He started to notice the facial lesions during this period. The initial doses were cyclosporine 350 mg (5.0 mg/kg body weight) and prednisolone 7.5 mg. The initial dosage was tapered and the patient eventually stopped taking the immunosuppressants in 2007. The patient then started taking tacrolimus 6 mg and prednisolone 5 mg for 4 years. Examination of his face revealed approximately a hundred skin-colored, umbilicated papules, 2 to 4 mm in size, which had increased in number for several years (Fig. 1A). Histological examination of the lesion demonstrated a peculiar superficial localization of the enlarged sebaceous glands in the upper dermis. The patient was diagnosed with SH. He was treated with daily oral isotretinoin 20 mg (0.29 mg/kg) for two months which resulted in near-complete remission without any side effect (Fig. 1B). Two months after discontinuing oral isotretinoin, a few new lesions started to develop. Oral isotretinoin 20 mg was restarted for two months. The lesions cleared without recurrence for nine months. Fig. 1 (A) Prominent multiple hyperplastic sebaceous glands seen as skin-colored papules (arrows) scattered on the right side of the face after treatment of cyclosporine for 11 years and tacrolimus for 4 years. (B) Sebaceous hyperplasia almost completely cleared ... Cyclosporine-induced SH has been reported in several series of organ transplant recipients. Among renal transplant recipients, 7 out of 67 (10%) and 5 out of 82 patients (6%) developed SH. In all cases, the patients were taking cyclosporine4. In an earlier report of 151 kidney transplant recipients who were not taking cyclosporine, SH did not occur5. These studies suggest that cyclosporine is a direct and causative factor of SH. Both tacrolimus and cyclosporine are calcineurin inhibitors sharing similar physicochemical properties and a common mechanism of action - inhibition of proinflammatory cytokines. In addition, both drugs are highly soluble in lipids allowing for cutaneous accumulation of the drugs and leading to dysplastic epithelial proliferation. Therefore, in this patient, it is possible to that oral tacrolimus might have played a role in developing SH. Sebaceous glands are mostly considered by dermatologists in association with acne and seborrhea; thus, the antiproliferative and sebostatic effects of isotretinoin have been extensively studied. Isotretinoin causes cell cycle arrest in human staphylococcal enterotoxin B-1 sebocytes in vitro, and apoptosis in human sebaceous glands in vivo2. To our knowledge, there are two other reports of renal transplant recipients receiving treatment for SH with isotretinoin (Table 1)2,3. Other reported effective treatments for cyclosporine-induced SH in patients undergoing renal transplant include carbon dioxide laser and topical photodynamic therapy. Table 1 Summary of previously reported cases of kidney transplant recipient receiving treatment for sebaceous hyperplasia with isotretinoin In conclusion, our case provides additional support for the safe and effective use of oral isotretinoin for cyclosporine-induced SH in patients undergoing renal transplant. However, further studies are needed to establish a treatment protocol for cyclosporine-induced SH in patients undergoing renal transplant.

Apremilast and adalimumab: a novel combination therapy for recalcitrant psoriasis

Psoriasis is a chronic immune-mediated inflammatory condition that affects 2-3% of the population. Apremilast was FDA-approved in March 2014 for the treatment of psoriatic arthritis and in September 2014 for the treatment of moderate to severe plaque psoriasis. Apremilast appears to have lower efficacy than some biologic agents such as adalimumab and ustekinumab, which achieve a PASI-75 in approximately 70% of patients after 12-16 weeks of therapy. However, its ease of administration as an oral agent coupled with a mild side effect profile make it an attractive option for psoriasis treatment. Herein, we present a patient with a 17-year history of plaque type psoriasis recalcitrant to topical, oral, and biologic mediations who attained near-complete remission after therapy with a combination of adalimumab and apremilast.

Efficacy of Intermittent Combined RAF and MEK Inhibition in a Patient with Concurrent BRAF- and NRAS-Mutant Malignancies

Vemurafenib, a RAF inhibitor, extends survival in patients with BRAF(V600)-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAF(V600K)-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma.

Multiple Successful Desensitizations to Brentuximab Vedotin: A Case Report and Literature Review

Brentuximab vedotin is an antibody-drug conjugate FDA-approved for the treatment of systemic anaplastic large-cell lymphoma (ALCL) that has relapsed after multiagent chemotherapy. At least 2 cases of hypersensitivity reactions to brentuximab vedotin have been reported, without attempted desensitization. This report describes a morbidly obese 32-year-old woman with ALCL that relapsed after autologous stem cell transplantation, who was treated on a phase II clinical study with brentuximab vedotin. After 1 dose, she experienced near-complete remission, but therapy was stopped because of severe drug-related toxicity. She then received 5 cytotoxic treatments and radiation, and ultimately experienced disease progression. The patient was rechallenged with brentuximab vedotin approximately 28 months after initial exposure and tolerated the dose well, but experienced a significant allergic reaction with the next dose. High-dose steroid and antihistamine prophylaxis administered 50 minutes before the subsequent brentuximab vedotin infusion was unsuccessful in mitigating this reaction. Brentuximab vedotin was successfully infused according to a rapid desensitization protocol. With progressive dose titration and supportive care, the patient tolerated this therapy. She received 11 doses through a rapid desensitization protocol and experienced a durable disease remission.

Sustained remission and reversal of end-organ dysfunction in a patient with anaplastic myeloma

Dear Editor, Anaplastic myeloma (AM) is a rare, aggressive, and poor risk form of myeloma characterized by dedifferentiated plasma cells and extensive extramedullary disease [1]. Since myeloma presenting with severe end-organ damage and poor performance status are excluded from clinical trials, treatment paradigms for these patients are not usually guided by clinical trial data. Combinations of cyclophosphamide (Cy) and bortezomib have been successfully used in the treatment of myeloma [2–4]. Since hepatic dysfunction secondary to myeloma is rare, there is paucity of data regarding the use of bortezomib and Cy in this setting. In this paper, we describe the efficacy of a Cy- and bortezomib-based induction in a patient with anaplastic myeloma who presented with fulminant hepatic and renal failure. A 59-year-old woman presented with 3–4 weeks of easy bruising, abdominal pain, 20-lb weight loss, and jaundice. She was admitted for acute liver failure (MELD score 42), anemia (Hb 7.6 g/dL), thrombocytopenia (Plt 44×109/L), abnormal coagulation markers (INR 3.2, aPTT 47.3 s), metabolic acidosis (lactate acid 16.1 mmol/L), hyperbilirubinemia (TBil 11.4 mg/dL, peaked at 61 mg/dL), transaminitis (AST 242 U/L, ALT 78 U/L), elevated LDH (1,527 U/L), gross hepatosplenomegaly, and acute kidney injury (Cr 4.2 mg/dL) requiring continuous venovenous hemodialysis (CVVHD). A bone marrow biopsy showed infiltration with atypical kappa-restricted plasma cells. Serum protein electrophoresis (SPEP) demonstrated three spikes in the gamma region adding to 0.44 g/dL. The serum-free kappa light chain was elevated (7, 220 mg/L), lambda light chain (0.5 mg/L). Liver biopsy showed infiltrating CD138+, kappa-restricted, atypical plasmacytoid cells (Fig. 1). Fig. 1 The atypical plasmacytoid cells were confirmed as plasma cells with strong CD138 immunoreactivity (a CD138, ×200). Moreover, these lesional cells displayed kappa restriction, demonstrating hepatic involvement by the neoplastic plasma cells (b ... Initial treatment consisted of Cy (1,500 mg/m2 IV) on day 1 and dexamethasone 20 mg on days 1–4, followed by bortezomib at 1 mg/m2 IV (dose reduced for hepatic dysfunction) and dexamethasone 40 mg on days 9, 12, 15, 18 post Cy. This was followed by two cycles of Cy 300 mg/m2, bortezomib 1 mg/m2 IV (dose reduced for hepatic dysfunction), and dexamethasone 40 mg (CyBorD) on a weekly schedule days 1, 8, 15, and 22 of a 28-day cycle as reported previously [4]. Renal function normalized (Cr 1.0 mg/dL) during the second cycle of CyBorD. Her liver function normalized in 7 months after initiation of therapy. For the last 30 months, she has been in a near-complete remission (nCR) with normal free light chains and her bone marrow biopsy shows no evidence of myeloma. Due to convenience of an oral regimen, she was switched to lenalidomide and dexamethasone. Her ECOG performance score is 0, and she has maintained normal renal and hepatic function. Although Cy does not appear to be hepatotoxic, it is activated by the hepatic cytochrome P-450 enzyme system [5]. In severe hepatic failure, there is uncertainty regarding the clinical efficacy of Cy. Bortezomib undergoes hepatic clearance and is metabolized by CYP3A4 and CYP2C19 [6]. Although there are case reports of bortezomib-induced hepatic dysfunction [7], the majority of patients with normal liver function do not experience hepatic dysfunction with bortezomib [8, 9]. In an organ dysfunction study in solid tumors, the systemic exposure to bortezomib was found to be increased in patients with moderate to severe hepatic dysfunction [10] but the frequency of adverse events was not increased with increasing degree of hepatic impairment or with increasing dose of bortezomib. The efficacy and long-term follow-up in patients with myeloma and hepatic dysfunction are lacking. We report the long-term outcome in a patient with aggressive anaplastic myeloma presenting with extensive extramedullary disease leading to multiorgan failure. Induction with Cy, bortezomib, and dexamethasone led to a rapid remission and reversal of hepatic and renal dysfunction. The remission has been sustained with lenalidomide and dexamethasone. This case demonstrates that myeloma can rarely present with fulminant hepatic failure, and rapid initiation of treatment may lead to reversal of organ dysfunction.

Abstract C139: Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response.

Abstract Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma who was treated with sorafenib demonstrated a near-complete clinical and radiographic remission for five years. Whole-genome sequencing and RNA sequencing on primary tumor and normal samples from this patient identified a somatic mutation, encoding ARAF S214C, present in the cancer genome and expressed at high levels. ARAF S214 binds 14-3-3 proteins when phosphorylated, and, by analogy to the paralogous residue of RAF1, presumably interferes with binding of ARAF to activated Ras. Mutation of S214 impaired the ability of ARAF to bind 14-3-3ξ, likely contributing to the oncogenic activity of ARAF S214C. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF and RAF1 mutants transformed immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity. These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C139. Citation Format: Heidi E. Greulich, Marcin Imielinski, Bethany Kaplan, Luiz Araujo, Joseph Amann, Leora Horn, Miguel Villalona, Matthew Meyerson, David Carbone. Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C139.

Treatment of Darier disease with oral alitretinoin

Darier disease (DD) is an autosomal dominant skin disease. Treatment is often difficult and unsatisfactory because of the chronic nature of the condition and the irritant potential of various therapeutic agents. Systemic vitamin A derivatives such as acitretin and isotretinoin are the treatment of choice, but their use is often limited by class-specific side-effects. Alitretinoin (9-cis-retinoic acid), has antiproliferative and anti-inflammatory potential, and is licensed for the systemic treatment of chronic hand eczema in a number of countries. Unlike acitretin, alitrenoin requires contraception in women of childbearing age to be extended for only 1 month after the end of treatment. There is evidence that alitretinoin might be a well-tolerated alternative for the systemic treatment of various retinoid-responsive skin diseases. We present two cases of women with refractory DD successfully treated with alitretinoin without marked side-effects, who both obtained near-complete remission of their skin lesions.