Recurrent Metastatic Melanoma Research Articles

Chronic inflammatory demyelinating polyradiculopathy as a paraneoplastic manifestation of metastatic melanoma

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that leads to proximal greater than distal weakness. It follows a relapsing course and requires treatment with chronic immune suppressing therapy such as steroids or intravenous immunoglobulin infusions. The vast majority of cases are idiopathic. However, there has been an established association with malignancy. Hematologic malignancies are the most commonly associated, but solid tumors are implicated as well. CIDP associated with melanoma has been reported in several previous case reports. Despite these reports, this association is not widely known. We report a case of a patient with a remote history of resected melanoma who developed severe refractory CIDP. He was found to have a recurrent metastatic melanoma. He experienced sustained clinical improvement with treatment of both the CIDP and malignancy. We then compare the characteristics of this case with others reported in the literature. This case along with other reports highlights the importance of being aware of this association and emphasizes that treatment of both the neuropathy and malignancy leads to maximal clinical effect.

S1806 Ipilimumab and Nivolumab-Induced Colitis in a Patient With Recurrent Metastatic Melanoma

INTRODUCTION: Drug induced colitis is historically in reference to a reaction to nonsteroidal anti-inflammatory and antibiotic medications. More recently immune checkpoint inhibitors have been recognized as a cause of immune mediated colitis. Ipilimumab and Nivolumab are monoclonal antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), respectively. They increase activity of T cells against cancerous cells but can simultaneously result in stimulation of T cells against non-cancerous tissues such as the GI tract. Reported incidence of colitis is about 5 times greater with ipilimumab compared to Nivolumab and is 13.6% with combination therapy. CASE DESCRIPTION/METHODS: A 51-year-old Caucasian woman with relapsed metastatic melanoma presented with intractable nausea, vomiting, abdominal pain, and copious diarrhea. Diarrhea began about 4 weeks prior to presentation following the second cycle of ipilimumab and nivolumab. After the third cycle, diarrhea worsened with more than 7 episodes of non-bloody diarrhea per day, unresponsive to loperamide and diphenoxylate. Physical exam was benign without abdominal tenderness. On admission, serum Na and K were 132 mMol/L and 2.3 mMol/L, respectively. The patient underwent aggressive fluid and electrolyte replacement. Stool culture and Clostridioides difficile DNA amplification stool test were negative. Colonoscopy revealed significant, severe colitis in transverse and descending colon. Mild-moderate colitis in sigmoid colon with erythema, friable scattered punched out ulcers and proctitis were also observed. Multiple biopsies were taken which showed mild architectural abnormality with ulceration, crypt abscess, apoptotic bodies, and inflammatory cells in lamina propria. No granuloma or dysplasia were observed histologically. IV steroid was initiated and followed by oral steroid therapy; her symptoms subsequently improved. Steroids were tapered over the course of 8 weeks and she has not had any recurrence to date. DISCUSSION: Immune mediated colitis is one of the side effects of immune checkpoint inhibitors. Patients with worsening symptoms and negative infectious workup who do not respond to conservative treatment need to be admitted and evaluated promptly with colonoscopy. Once the diagnosis is reached, conservative treatment with steroid therapy should be started. Patients should be monitored closely to avoid complications such as bowel perforation and toxic megacolon.Figure 1.: Left sided colon micrograph, obtained by colonoscopy, demonstrating friable scattered punched out ulcers in the colon.Figure 2.: Biopsy from a colon lesion (x200 magnification, Hematoxylin and Eosin staining) demonstrating inflammatory cells in lamina propria, crypt abscess (hollow arrow), and crypts destruction and dropout (solid arrow).

A phase II trial of nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with mutations in BRCA or BRCAness.

TPS10082 Background: Melanoma has a response rate of 10-15% with anti-PD-1 re-challenge in the refractory setting. Newer targeted therapies in melanoma are needed, especially once patients progress on immune checkpoint inhibitor (ICI) therapy. Analysis of TCGA and the Cleveland Clinic’s Gross Family Melanoma Registry reveals that a significant proportion (~40%) of melanoma patients possess somatic (31.6%) or germline (TCGA: 4.2%; Registry: 8.3%) mutations in homologous recombination repair genes, which may serve as a therapeutic target. PARP inhibitors, specifically talazoparib, have demonstrated synthetic lethality, potent PARP trapping activity, and increased immunogenicity of tumor cells by promoting T cell and NK cell infiltration in vitro and in vivo. Moreover, augmentation of the STING pathway via PARP inhibition modulates the tumor microenvironment, impacting PD-L1 expression and type I interferon production. Therefore, the use of talazoparib in combination with the ICI, nivolumab, may have a synergistic immunomodulatory and antitumor effect. Methods: This phase II, single arm, open label trial aims to enroll 37 primary or recurrent unresectable or metastatic melanoma patients harboring a somatic or germline mutation or deletion in BRCA or BRCAness (genes including ARID1A/B/2, ATM, ATR, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK4/12, CHEK1/2, DSS1, EMSY, ERCC3, FANCA/D2, HDAC2, IDH1, LIG3/4, MDC1, MLH1/3, MRE11, NBN, PALB2, PRKDC, RAD50/51/54, XRCC6) who have progressed on prior ICI therapy. Patients will be treated with nivolumab 480mg IV every 4 weeks and talazoparib 1mg PO daily. The primary objective is to determine clinical efficacy of the combination therapy, as measured by the objective response rate. The trial is designed to test the null hypothesis that ORR ≤ 10% and is powered to detect an effect size of ORR ≥ 30%. Secondary objectives include PFS, OS, immune-related objective response rate (irORR), irPFS, and treatment-related adverse events. Associations with clinical response will be assessed with correlative studies of PD-L1 expression, ctDNA, tumor mutational burden, copy number variation, and the phenotypic and functional characterization of circulating and tumor infiltrating immune cells. The study is currently open and enrolling patients. Clinical trial information: NCT04187833.

Dynamic Evolution of Clonal Composition and Neoantigen Landscape in Recurrent Metastatic Melanoma with a Rare Combination of Driver Mutations

In melanoma, initiating oncogenic mutations in BRAF or NRAS are detected in premalignant lesions that accumulate additional mutations and genomic instability as the tumor evolves to the metastatic state. Here we investigate evolution of clonal composition and neoantigen landscape in an atypical melanoma displaying recurrent cutaneous lesions over a 6-year period without development of extracutaneous metastases. Whole exome sequencing of four cutaneous lesions taken during the 6-year period identified a collection of single nucleotide variants and small insertions and deletions shared among all tumors, along with progressive selection of subclones displaying fewer single nucleotide variants. Later tumors also displayed lower neoantigen burden compared to early tumors, suggesting that clonal evolution was driven, at least in part, by counter selection of subclones with high neoantigen burdens. Among the selected mutations are a missense mutation in MAP2K1 (F53Y) and an inversion on chromosome 7 generating a AKAP9-BRAF fusion. The mutant proteins cooperatively activate the MAPK signaling pathway confirming they are potential driver mutations of this tumor. We therefore describe the long-term genetic evolution of cutaneous metastatic melanoma characterized by an unexpected phenotypic stability and neoantigen-driven clonal selection.

Recurrent metastatic occult melanoma - Long-term remission after detection of the primary tumor by FDG-PET/CT.

Recurrent metastatic occult melanoma - Long-term remission after detection of the primary tumor by FDG-PET/CT.

Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy

BackgroundImmune checkpoint inhibitors have transformed the treatment landscape for many cancers, including metastatic melanoma, but have also opened the door for a diverse variety of immune-related adverse effects.Case presentationWe describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. The patient was noted to develop clinical signs consistent with systemic sarcoidosis shortly after the initiation of treatment and underwent a biopsy of hilar lymphadenopathy that confirmed sarcoidosis and after which immunotherapy was discontinued. His melanoma remained stable on surveillance imaging for the next year after which time he developed neurological symptoms and was found to have MRI brain abnormalities without evidence of intracranial metastatic disease, consistent with probable neurosarcoidosis given biopsy-proven systemic sarcoidosis and lack of evidence of CNS infection or malignancy. He underwent treatment with high dose steroids, followed by infliximab, and then methotrexate with both clinical and radiographic improvement within 4 months of starting treatment.ConclusionsImmune-related adverse effects often occur within 3–6 months of receiving immune checkpoint inhibitor therapy, with some reports of late toxicity. This report highlights a case of probable neurosarcoidosis nearly a year after discontinuation of immune checkpoint therapy. The potential for durable responses after discontinuation of therapy also likely underscores a potential for late toxicity. In patients presenting with new or unexplained symptoms after checkpoint inhibitor therapy, the index of suspicion for an immune-related adverse effect should remain high, irrespective of timing.

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review

BackgroundWhile data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response.Case presentationCase #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy.Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease.ConclusionsThese cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow “unmasks” previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.

New NCCN Guidelines for Uveal Melanoma and Treatment of Recurrent or Progressive Distant Metastatic Melanoma.

The NCCN Guidelines Panel for Melanoma debuted new guidelines for uveal melanoma at the NCCN 23rd Annual Conference. Although uveal melanoma and cutaneous melanoma share the same name, they do have different characteristics and treatments. The NCCN Guidelines describe how tumor size guides therapeutic options, which for most tumors is radiotherapy. Predictors of melanoma-related mortality include advanced age, larger tumor size, and histopathologic and molecular features. The NCCN Guidelines for Cutaneous Melanoma have not changed notably, but adjuvant therapy with immunotherapies is now recommended. The best second-line treatment in the metastatic setting remains unclear.

Pembrolizumab‐induced auto‐immune type‐1 diabetes in a patient with metastatic melanoma

AbstractBackgroundImmunotherapy for metastatic melanoma has improved response rates and progression‐free survival significantly compared to traditional chemotherapy. However, our understanding of their unique side‐effect profile remains limited given the novelty of these treatments. Unlike traditional cytotoxic chemotherapy, immunotherapy is often associated with autoimmune‐related toxicities, including colitis, thyroiditis, pneumonitis or hepatitis. However, autoimmune endocrinopathies are much less well described. These experiences are concerning as the use of these agents is becoming more widespread in other cancer subtypes and they require very different approaches in regard to toxicity management. We report a case of pembrolizumab‐induced auto‐immune diabetes and hepatitis in a patient undergoing treatment for metastatic melanoma.Clinical detailsA 79‐year‐old Caucasian man was referred by his general practitioner to the emergency department with hyperglycaemia and elevated liver function tests on a background of recurrent metastatic melanoma on pembrolizumab treatment. The patient had a long history of hypertension but no other significant past medical history. The patient did not have a personal or family history of diabetes or autoimmune disease.OutcomesThe patient was treated with a basal‐bolus insulin regimen for his new‐onset diabetes and a reducing dose of prednisolone for hepatitis.ConclusionNew emerging immunotherapy treatments are changing the outcomes of patients with metastatic melanoma; however, their side effect profile differs from traditional chemotherapeutic agents and has not been fully explored. Healthcare professionals and patients should be aware that autoimmune side effects, such as diabetes and hepatitis, do occur in the context of these new treatments.

Small bowel obstruction: a recurrence of melanoma during the second trimester of pregnancy

Background: The incidence of melanoma is on the rise in the United States and is particularly prevalent among women of childbearing age. Obtaining a complete history and understanding the unpredictable behavior of melanoma is essential to make the diagnosis of recurrent disease during pregnancy. Case: A 35-year-old G2P1 at 23 weeks and 1 days’ gestation with a remote history of (treated) cutaneous melanoma underwent an exploratory laparotomy for small bowel obstruction. Pathology was consistent with recurrent metastatic melanoma. Conclusion: Metastatic melanoma diagnosed during pregnancy is rare. There are no guidelines on how or when to proceed with treatment of metastatic disease or delivery of the fetus. Immunotherapy is changing the management of melanoma and is extending life expectancy. The significant survival benefits for mother with immunotherapy may outweigh the risks of preterm delivery for the baby.

Recurrent Metastatic Melanoma Presenting as a Bleeding Gastric Polyp

Gastrointestinal metastases of melanomas are uncommon; however, in a patient with a history of melanoma, seemingly benign lesions found on endoscopy warrant a low threshold for tissue analysis. A 64 year old female with hypertension, diabetes mellitus type 2, chronic kidney disease, heart failure, multifactorial normocytic anemia, and stage IIa malignant melanoma of the left ear was admitted for heart failure exacerbation. On hospital day 1, her hemoglobin dropped from 7.1g/dl (baseline 8g/dl) to 5.3g/dl. She was hemodynamically stable and there was no evidence of active bleeding. Her hemoglobin increased to 7.8g/dl after transfusion with 3 units of packed RBCs. Esophagogastroduodenoscopy (EGD) revealed an asymmetric, friable sessile 5 mm polyp in the body of the stomach which was removed by snare electrocautery. A similar polyp was described on EGD in 2013, which was not removed due to GI bleed at that time. Endoscopic examination was otherwise unremarkable. The patient's hemoglobin remained stable and she was discharged with colonoscopy to be done as an outpatient. Analysis of the polyp revealed poorly differentiated adenocarcinoma. Immunohistochemistry was positive for S100, Melan-A, and HMB45 which was consistent with melanoma. PET/CT showed evidence of disease in the right adrenal gland, stomach, duodenum, and multiple nodal stations throughout the small bowel consistent with metastatic melanoma. BRAF and KIT mutations were negative. Dual immunotherapy with Ipilimumab and Nivolumab is the first line treatment for metastatic melanoma. She was started on only nivolumab due to multiple comorbidities and concerns for toxicities. She tolerated therapy and had an excellent response as shown by increased energy and decreased disease burden on her 3 month surveillance PET scan. The recurrence of melanoma with metastasis is suspected given that the resected gastric polyp is likely the same polyp seen on the prior EGD in 2013. Chemotherapy for metastatic melanoma is not very effective, and the patient's significant comorbidities would have precluded chemotherapy. With the emergence of immunotherapy, the potential for prolonged survival measured in years is now a possibility. This case illustrates the importance of pursuing complete evaluation in patients with significant comorbidities as meaningful prolongation of life may be possible in the era of immunotherapy for advanced malignancy.

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.

e21072Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-...

Recurrent Metastatic Melanoma Despite Multiple Surgical Interventions and Biological Targeted Therapy

A 40 year old Caucasian male was referred to our plastic surgery unit with a rapidly growing mass in his left groin. A biopsy was taken which showed the lesion was metastatic amelanotic melanoma. No primary was identified. He had a history of a halo naevus on his lower back that had fully regressed

Bayesian Analysis of a Patient with either Recurrent Metastatic Melanoma or Ipilimumab-Induced Sarcoidosis

A patient with metastatic melanoma received treatment with adjuvant Ipilimumab and subsequently developed signs of sarcoidosis 6 weeks post completion of treatment. 18 F FDG PET CT was completed which described FDG avid hilar and mediastinal adenopathy and bilateral FDG avid lung nodules with low-grade bilateral uptake in the lower limbs. Differential diagnosis was either recurrent melanoma or sarcoidosis arising as an immune related adverse event attributable to Ipilimumab. Prior to initiation of anti- PD-1 treatment we assessed the merit of undertaking a biopsy to confirm a second relapse of metastatic melanoma. We approached a quantitative appraisal of the clinical dilemma arising in this case using Bayes' theorem and a meta-analysis of published literature of the accuracy of PET detection of recurrent cutaneous melanoma. Partly on this rationale a bronchoscopic biopsy of two lymph nodes was undertaken. Results found abundant histiocytic aggregates focally forming granuloma giving a diagnosis of Ipilimumab induced sarcoidosis. Therefore, positive findings on PET imaging in patients with melanoma treated with Ipilimumab can represent other entities including iatrogenic sequelae from immunotherapy. With the emergence immunotherapy. With the emergence of novel immunotherapy treatment for metastatic melanoma and an increase in the popularity of PET imaging as a modality for diagnosing metastatic disease this article highlights two important issues; the traditional role of biopsies in confirming metastatic disease and immune related adverse events associated with novel therapies.

Multiple Structural and Epigenetic Defects in the Human Leukocyte Antigen Class I Antigen Presentation Pathway in a Recurrent Metastatic Melanoma Following Immunotherapy

Scant information is available about the molecular basis of multiple HLA class I antigen-processing machinery defects in malignant cells, although this information contributes to our understanding of the molecular immunoescape mechanisms utilized by tumor cells and may suggest strategies to counteract them. In the present study we reveal a combination of IFN-γ-irreversible structural and epigenetic defects in HLA class I antigen-processing machinery in a recurrent melanoma metastasis after immunotherapy. These defects include loss of tapasin and one HLA haplotype as well as selective silencing of HLA-A3 gene responsiveness to IFN-γ. Tapasin loss is caused by a germ-line frameshift mutation in exon 3 (TAPBP(684delA)) along with a somatic loss of the other gene copy. Selective silencing of HLA-A3 gene and its IFN-γ responsiveness is associated with promoter CpG methylation nearby site-α and TATA box, reversible after DNA methyltransferase 1 depletion. This treatment combined with tapasin reconstitution and IFN-γ stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses. These results represent a novel tumor immune evasion mechanism through impairing multiple components at various levels in the HLA class I antigen presentation pathway. These findings may suggest a rational design of combinatorial cancer immunotherapy harnessing DNA demethylation and IFN-γ response.

Abstract IA22: Modeling recurrent metastatic melanoma in the mouse

Abstract Recurrence and metastasis following resection and therapy are the most critical problems in progressive cancers and the main causes of cancer-related death. This problem is magnified in cutaneous malignant melanoma, which is highly metastatic in advanced stages and generally resistant to chemotherapy. Although new drugs such as Vemurafenib successfully target BRAFV600E and typically demonstrate a significant clinical response, progressive melanomas recur resulting in near uniform patient mortality. Dissection of processes underpinning recurrent and metastatic melanoma is certain to identify new therapeutic targets for more efficacious treatment. However, current preclinical studies do not model progressive recurrent disease, but rather rely on the growth response of human melanoma cell lines subcutaneously xenografted into immunocompromised mice as the efficacy endpoint; these studies have shown poor predictive power for clinical activity. Therefore we have designed new and improved genetically engineered mouse (GEM) models of progressive melanoma. These are being used to test targeted and immune-based therapies singly and in combination, and to study mechanisms associated with the resistance of recurrent/metastatic melanoma to promising clinical drugs. To identify novel targets for advanced disease we hypothesized that metastatic melanomas can exploit hard-wired pathways employed by migratory embryonic melanocytes, but not mature melanocytes, to achieve a more aggressive malignant phenotype. We had previously generated a GEM model (iDCT-GFP) that expresses Green Fluorescent Protein specifically in all melanocytic cells in a doxycycline-regulatable manner. The iDCT-GFP mouse was used in concert with FACS to isolate melanoblasts from key developmental stages, sequence their transcriptomes using RNA-Seq, and identify genes/pathways common to metastatic melanoma cells. We have thus generated a full library of the genes expressed during embryonic development of the melanocyte. A detailed comparative analysis of mouse melanoblast gene expression profiles with human metastatic melanoma cells was then performed, identifying what we believe to be a small number of critical genes common to both. We anticipate that this approach will enhance our understanding of this fatal disease at both mechanistic and prognostic levels, and facilitate the identification of novel therapeutic targets for the treatment of metastatic melanoma. Citation Format: Glenn T. Merlino, Chi-Ping Day, Pravin Mishra, Theresa Guo, Raza Zaida, Sean Davis, Paul Meltzer, Frances Noonan, Edward De Fabo, Zoe Ohler-Weaver, Terry Van Dyke. Modeling recurrent metastatic melanoma in the mouse. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA22.

Longitudinal Study of Recurrent Metastatic Melanoma Cell Lines Underscores the Individuality of Cancer Biology

Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed 8 patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (p<0.001) and RNA gene expression level (p<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations, such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which dramatically turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent step-wise process.

A Case of Severe Enterocolitis Secondary to a Novel Biological Agent

Introduction: Ipilimumab is a recombinant human IgG1 immunoglobulin monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen, used in the treatment of metastatic melanoma. We present a case of severe enterocolitis associated with the use of ipilimumab in a patient with recurrent metastatic melanoma. Case Presentation: A 67-year-old female with history of recurrent metastatic melanoma presented with a four-week history of loose, non-bloody watery stools, associated nausea, vomiting, and lower abdominal pain, following four cycles of chemotherapy with ipilimumab. Physical examination revealed diffuse lower abdominal wall tenderness with no peritoneal signs. Laboratory testing showed acute pre-renal kidney injury secondary to dehydration. Stool studies ruled out an infectious etiology. Flexible sigmoidoscopy with biopsy revealed a continuous area of ulcerated mucosa in the descending colon with no active bleeding, and biopsies showed moderately active colitis/proctitis with ulceration. The patient was started on prednisone for the colitis. In the interim, an elective chest X-ray showed free air under the diaphragm, and a follow-up CT abdomen/pelvis showed diffusely dilated loops of small and large bowel, with free air in the abdomen. Exploratory laparotomy revealed perforated sigmoid colon and distal ileum, and the patient underwent resection of terminal ileum, cecum, and left colon with end ileostomy and transverse colostomy. Histopathological analysis of the resected bowel showed severe transmural acute inflammation with extensive necrosis. The patient eventually succumbed to her illness, in spite of aggressive supportive management. Discussion: Ipilimumab, a new promising tool for the treatment of metastatic melanoma, is reported to cause new types of toxicities called “immune- related adverse events” due to prolonged activation of cytotoxic T lymphocytes. Gastrointestinal side effects include nausea, vomiting, abdominal pain, and even severe colitis. Treatment includes supportive measures, including fluid and electrolyte replacement, intravenous high dose steroids, infliximab for steroid-resistant cases, and ileostomy or colectomy for cases unresponsive to medical therapy. Conclusion: Even though ipilimumab has emerged as a promising tool in the treatment of metastatic malignant melanoma, clinicians should be aware of its severe side effects, including enterocolitis.

Biomarkers of treatment effect in a phase II trial of velimogene aliplasmid in patients with metastatic melanoma.

e19058 Background: Velimogene aliplasmid (Allovectin, A) is a plasmid-based immunotherapeutic that encodes human leukocyte antigen-B7 and β-2 microglobulin. A is designed to induce allogeneic and tumor-antigen-specific T-cell responses against tumor cells. In a phase II trial, 127 patients with stage III or IV recurrent metastatic melanoma were treated in cycles of 6 weekly intralesional injections of 2 mg/dose. Complete (CR) or partial responses (PR) were observed in 15 patients (11.9%, 95% CI: 6.2-17.4), stable disease (SD) in 32 (25.2%), and progressive disease (PD) in 80 (63.0%). Methods: Serum collected before treatment and 3 weeks after each cycle from 29 patients who showed clinical benefit (CB: 15 CR or PR patients and 14 patients with SD for &gt;4 months) and 62 with PD (progressed by the end of the first cycle) were evaluated for 45 inflammation biomarkers in a quantitative multiplex immunoassay. Changes in analyte concentrations relative to baseline were evaluated by paired t-test or Wilcoxon signed-rank test. Results: Overall, 52% of patients had decreases in serum IL-10 after treatment; however, decreases were more prevalent in CB patients (71.4% for CB, 44.4% for PD; p=0.036; Chi-square test). At week 8, mean serum IL-10 concentration within a group was reduced relative to baseline in CB (p=0.008) but not PD patients suggesting greater treatment effect in CB patients. In CB patients, IL-10 remained at lower levels relative to baseline through week 26. CCL-3 decreased in CB patients by week 26 (p=0.021) and von Willebrand factor (a biomarker of vascular endothelium dysfunction) was increased at week 26 (p=0.007). In PD patients, by week 8, several biomarkers associated with metastatic melanoma (TIMP-1, VCAM-1, and TNF-R2) or inflammation (haptoglobin) increased (p=0.001, 0.022, &lt;0.001, 0.004, respectively) consistent with tumor progression, whereas others (IL-8 and stem cell factor) decreased (p=0.007, 0.013, respectively). Conclusions: Consistent with A’s proposed mechanism of action, treatment was associated with a decrease in the production of the T-cell suppressive cytokine, IL-10. Furthermore, biomarker profiles in the two groups were markedly different and analogous with treatment outcomes.

Melphalan in Regional Chemotherapy for Locally Recurrent Metastatic Melanoma

In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor α has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated.