John Kirkwood | University of Pittsburgh (original) (raw)

Papers by John Kirkwood

Journal of Neurosurgery, 1993

To determine local tumor control rates and survival of patients with melanoma metastases to the b... more To determine local tumor control rates and survival of patients with melanoma metastases to the brain, the authors reviewed the results of 23 consecutive patients with a total of 32 tumors (19 patients had a solitary tumor and four had multiple tumors) who underwent adjuvant stereotactic radiosurgery. Tumor locations included the cerebral hemisphere (24 cases), brain stem (four cases), basal ganglia (two cases), and cerebellum (two cases). Fifteen patients had associated cranial symptomatology and eight had incidental metastases. All patients had tumors of 3 cm or less in diameter (mean tumor volume 2.5 cu cm), and all received fractionated whole-brain radiation therapy (30 Gy) in addition to radiosurgery (mean tumor margin dose 16 Gy). Nineteen patients were managed with both modalities at the time of diagnosis; four underwent radiosurgery 3 to 12 months after fractionated whole-brain radiotherapy. The mean patient follow-up period was 12 months (range 3 to 38 months). After radiosurgery, eight patients improved, 13 remained stable, and two deteriorated. One patient subsequently required craniotomy because of intratumoral hemorrhage; this patient and three others are living 13 to 38 months after radiosurgery. Nineteen patients died, 18 from progression of their systemic disease and one from another hemorrhage into a new brain metastasis. The local tumor control rate was 97%. Only two patients subsequently developed new intracranial metastases. The median survival period after diagnosis was 9 months (range 3 to 38 months). The authors believe that stereotactic radiosurgery coupled with fractionated whole-brain irradiation is an effective management strategy for cerebral metastases from a melanoma. Multi-institutional trials are warranted to confirm that stereotactic radiosurgery results equal or surpass the outcome achieved with craniotomy and tumor resection.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2009

This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the ... more This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3...

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-g... more Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activ- ity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small

Clinical Epigenetics, 2015

Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-... more Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-20 % in unselected chemotherapy-naïve patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index. Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree-guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [2] for network inference. T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease. This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection.

Oncoimmunology

A promising vaccine strategy for the treatment of cancer involves the use of vaccines incorporati... more A promising vaccine strategy for the treatment of cancer involves the use of vaccines incorporating tumor antigen-derived synthetic peptides that can be coordinately recognized by specific CD4(+) and CD8(+) T-cells. Previously, we reported that a MAGE-A6-derived peptide (MAGE-A6172-187) and its highly-immunogenic and cross-reactive homolog derived from Mycoplasma penetrans HF-2 permease (HF-2216-229) are promiscuously presented by multiple HLA-DR alleles to responder CD4(+) T-cells obtained from healthy donors and melanoma patients. Here, we investigated whether these same peptides could concomitantly stimulate cross-reactive MAGE-A6-specific CD8(+) T-cell responses in vitro using cells isolated from HLA-A*0201 (HLA-A2)(+) healthy individuals and patients with melanoma. We now show that MAGE-A6172-187 and, even more so, HF-2216-229, induce memory CD8(+) T cells that recognize HLA-A2(+) MAGE-A6(+) tumor target cells. The immunogenicity of these peptides was at least partially attribu...

European Journal of Cancer Supplements, 2006

Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1... more Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1alpha (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone. In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with (15)O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30 micro g/kg given i.v. over 2 h. At 4 h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400 mg/m(2). Treatment was repeated every 28 days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24 h after IL-1 initiation. Mean measured pretreatment tumor blood flow was 1.82 ml/min per g. At 2, 4 and 24 h it was 1.35, 1.67 and 1.62 ml/min per g respectively. Tumor blood flow was significantly decreased ( P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.008) at 2 h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2 h after initiation ( n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2 h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated. We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with (15)O water at 2 h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.

Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-128... more Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-1282, was undertaken by the Eastern Cooperative Oncology Group (ECOG) to determine whether the combined use of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy improved the disease-free survival and overall survival of patients with carcinoma of the esophagus, compared to those who received radiation therapy alone. Two- and 5-year survivals were 12% and 7% in the radiation alone arm and 27% and 9% in the chemoradiation arm. Patients treated with chemoradiation had a longer median survival (14.8 months), compared to patients receiving radiation therapy alone (9.2 months). This difference was statistically significant. The same pattern of survival was noted in almost all subgroups independent of whether surgical resection was performed.

Cancer Institute instituted a pilot study employing high dose methotrexate with leucovorin rescue... more Cancer Institute instituted a pilot study employing high dose methotrexate with leucovorin rescue (35 7.5 g/m') as an adjuvant to aggressive radiotherapy and surgery. A high response rate of 60% (9/E) with no compromise of definitive therapy indicates such cooperation multimodality trials may hold promise for an increase in cure rates in these patients.

European Journal of Cancer, 2004

Since dacarbazine was approved for treating metastatic melanoma in the 1970s, numerous studies ha... more Since dacarbazine was approved for treating metastatic melanoma in the 1970s, numerous studies have evaluated whether different schedules and dacarbazine-based combinations improve clinical outcomes. This evidence-based review shows that combining dacarbazine with other drugs having single-agent activity and/or hormonal or immunotherapeutic compounds fails to provide clinically meaningful improvements in survival, and may increase toxicity. In patients with metastatic melanoma, dacarbazine

Cytokine & Growth Factor Reviews, 2002

Interferon-alpha (IFN-α) is a pleiotropic cytokine belonging to type I IFN, currently used in can... more Interferon-alpha (IFN-α) is a pleiotropic cytokine belonging to type I IFN, currently used in cancer patients. Early studies in mouse tumor models have shown the importance of host immune mechanisms in the generation of a long-lasting antitumor response to type I IFN. Recent studies have underscored new immunomodulatory effects of IFN-α, including activities on T and dendritic cells, which may

Melanoma research, 2004

Ocular melanoma has a unique metastatic predilection for the liver and is refractory to most form... more Ocular melanoma has a unique metastatic predilection for the liver and is refractory to most forms of therapy. The dual blood supply of the liver with differential perfusion of metastatic lesions and normal hepatocytes by the hepatic artery and portal vein, respectively, has led to the evaluation of intrahepatic chemotherapy and chemoembolization in this disease. Despite suggestion of efficacy in phase II trials, this therapy has not been systematically evaluated. We conducted a randomized phase I/II trial evaluating escalating doses of intrahepatic chemotherapy with cisplatin with or without polyvinyl sponge (PVS) in 19 patients with ocular melanoma and liver metastases. The cisplatin dose was initiated at 100 mg/m and was increased in 25% increments. Patients were randomized to receive cisplatin alone or cisplatin plus PVS. Seven patients were treated with intrahepatic cisplatin at 100 mg/m: four with PVS, and three without. The dose was escalated to 125 mg/m with or without PVS i...

Stereotactic and functional neurosurgery, 2005

The role of stereotactic radiosurgery in treating metastatic melanoma involving the spine has pre... more The role of stereotactic radiosurgery in treating metastatic melanoma involving the spine has previously been limited. Conventional external beam radiotherapy lacks the precision to allow delivery of large single-fraction doses of radiation and simultaneously to limit the dose delivered to radiosensitive structures such as the spinal cord. This study evaluated the clinical efficacy of radiosurgery for the treatment of melanoma spinal metastases in 28 patients. Thirty-six melanoma spine metastases were treated with a single-session radiosurgery technique (1 cervical, 11 thoracic, 13 lumbar, and 11 sacral) with a follow-up period of 3-43 months (median 13 months). Tumor volume ranged from 4.1 to 153 cm3 (mean 47.6 cm3). Twenty-three of the 36 lesions had received prior external beam irradiation. Maximum tumor dose was maintained at 17.5-25 Gy (mean 21.7 Gy). Spinal cord volume receiving > 8 Gy ranged from 0.0 to 0.7 cm3 (mean 0.26 cm3); spinal canal volume at the cauda equina level...

Pigment cell & melanoma research, 2009

The following meeting highlights are from the Perspectives in Melanoma XII conference, held in Sc... more The following meeting highlights are from the Perspectives in Melanoma XII conference, held in Scheveningen/The Hague, the Netherlands, on October 2-4, 2008. Selected reviews are included but further discussions of these and other presentations are posted at http://www.MelanomaCare.org.

PloS one, 2014

We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced mela... more We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associa...

The Journal of investigative dermatology, 2015

Over the preceding two decades, sophisticated sequencing techniques have been used to characteriz... more Over the preceding two decades, sophisticated sequencing techniques have been used to characterize the genetic drivers of adult melanoma. However, our understanding of pediatric melanomas is still rudimentary. In this report, we comment on a thorough multi-platform analysis of common pediatric melanoma subsets, including pediatric conventional melanoma (CM), congenital nevus-derived melanoma (CNM), and Spitzoid melanoma (SM), contributed by Lu et al.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014

Sorafenib is an inhibitor of VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGF... more Sorafenib is an inhibitor of VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel ± sorafenib (CP vs. Pretreatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed. Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes. Statistical analysis was performed using Fisher exact test, logistic regression, and Cox proportional hazards models. Progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier methods. BRAF and NRAS mutations were found at frequencies consistent with other metastatic melanoma cohorts. BRAF-mutant melanoma was associated with worse performance status, increased number of disease sites, and younger age at diagnosis. NRAS-muta...

Aquatic Mammals, 2006

We developed a method to rapidly and safely live capture wild dugongs based on the "rodeo method"... more We developed a method to rapidly and safely live capture wild dugongs based on the "rodeo method" employed to catch marine turtles. This method entails close pursuit of a dugong by boat until it is fatigued. The dugong is then caught around the peduncle region by a catcher leaping off the boat, and the dugong is restrained at the water surface by several people while data are collected. Our sampling protocol involves a short restraint time, typically < 5 five min. No ropes or nets were attached to the dugong to avoid the risk of entanglement and subsequent drowning. This method is suitable for shallow, open-water captures when weather and water conditions are fair, and may be adapted for deeper waters.

Cancer discovery, Jan 26, 2014

Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that dr... more Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibiti...

JAMA, Jan 5, 2014

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival i... more Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-...