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Patients with advanced cutaneous squamous cell carcinoma (CSCC) have a poor prognosis. Blocking the PD-1–PD-L1 axis has shown promising activity in this patient population. We assessed the safety and antitumor activity of PD-1 inhibitor pembrolizumab in patients with refractory advanced CSCC. This was a prespecified subgroup analysis of patients with advanced CSCC who enrolled in an open-label, phase II clinical trial for pembrolizumab in patients with refractory rare cancers during 2016–2018. Patients received pembrolizumab 200 mg intravenously every 21 days until progressive disease, unacceptable adverse event, or completion of 24 months of treatment. The primary endpoint was nonprogression rate (NPR) at 27 weeks; secondary endpoints included safety, objective response rate (ORR) per irRECIST, clinical benefit rate (CBR), progression-free survival, and overall survival. Twenty patients with refractory CSCC enrolled; 19 were evaluable for efficacy. Median follow-up time was 44.1 months. The NPR at 27 weeks was 37% (95% CI 0.16–0.62). Three patients had a complete response (CR), three had a partial response, and one had stable disease, for an ORR of 32% and a CBR of 37%; median duration of response was 27.3 months. All three patients with a CR remained free of recurrence at the time of writing. Severe treatment-related adverse events (grade ≥ 3) occurred in 10% of patients (2/20). PD-L1 expression was not correlated with response to pembrolizumab. A long-term follow-up confirms pembrolizumab’s antitumor activity and safety profile in patients with refractory CSCC. Patients with a CR may experience cure. ClinicalTrials.gov, NCT02721732, Registered March 29, 2016.

Background Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. Methods Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2–124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. Results Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. Conclusions Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. Trial registration PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011. Electronic supplementary material The online version of this article (10.1186/s40425-019-0567-3) contains supplementary material, which is available to authorized users.

Human papillomaviruses (HPV) establish persistent infections because of evolved immune evasion mechanisms, particularly HPV-mediated suppression of the immune functions of Langerhans cells (LC), the antigen presenting cells of the epithelium. Polyinosinic-polycytidilic acid (Poly-I:C) is broadly immunostimulatory with the ability to enhance APC expression of costimulatory molecules and inflammatory cytokines resulting in T cell activation. Here we investigated the activation of primary human LC derived from peripheral blood monocytes after exposure to HPV16 virus like particles followed by treatment with stabilized Poly-I:C compounds (s-Poly-I:C), and their subsequent induction of HPV16-specific T cells. Our results indicate that HPV16 particles alone were incapable of inducing LC activation as demonstrated by the lack of costimulatory molecules, inflammatory cytokines, chemokine-directed migration, and HPV16-specific CD8+ T cells in vitro. Conversely, s-Poly-I:C caused significant upregulation of costimulatory molecules and induction of chemokine-directed migration of LC that were pre-exposed to HPV16. In HLA-A*0201-positive donors, s-Poly-I:C treatment was able to induce CD8+ T cell immune responses against HPV16-derived peptides. Thus, s-Poly-I:C compounds are attractive for translation into therapeutics in which they could potentially mediate clearance of persistent HPV infection., Graphical abstract

Cardiotoxicity is an emerging concern with a new class of drugs known as targeted agents, which include trastuzumab and sunitinib. Sunitinib is a small molecule that inhibits multiple tyrosine kinase receptors. This drug was approved by the United States Food and Drug Administration in 2006 for the treatment of clear cell metastatic renal cell carcinoma and advanced gastrointestinal stromal tumors. We describe a 65-year-old woman who was treated with sunitinib for metastatic clear cell renal cell carcinoma. After 5 months of therapy, she developed acute heart failure requiring hospitalization; sunitinib was immediately discontinued. The patient had classic symptoms of heart failure, including pleural effusion. An echocardiogram revealed a left ventricular ejection fraction of 30%. She received standard treatment for heart failure, including a beta-blocker, an angiotensin-converting enzyme inhibitor, and diuretics. Within 1 month, the patient's symptoms resolved, and subsequent cardiac evaluation showed that her left ventricular ejection fraction returned to normal. According to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute, her cardiac event associated with sunitinib was defined as grade III toxicity. One month later, sorafenib, another tyrosine kinase inhibitor, was started with the aim of continuing her previous response to sunitinib. After 7 months of sorafenib therapy, the patient had no evidence of heart failure, and her condition was responding to treatment. Clinicians should be aware that sunitinib-induced heart failure occurs occultly and that many--but not all--cases resolve with discontinuation of the drug. Use of sorafenib after sunitinib-induced heart failure appears to be safe and effective, which suggests that cardiotoxicity is not a general class effect of the tyrosine kinase inhibitors.

Sarcomas are a heterogeneous group of tumors that respond poorly to conventional cytotoxic chemotherapy. Sarcomas possess specific molecular characteristics that exist because of unique somatic mutations, vital growth factor or growth factor receptor overexpression, or are critically dependent on host pathways. Currently these tumors are classified on the basis of their tissue of origin and histologic appearance. Gene expression and proteomic analysis of sarcomas may enable reclassification of these tumors and help predict their biologic behavior and devise common therapeutic strategies within a class. It may not be long before cDNA/protein expression profiling and karyotyping complement the current standard pathological evaluation of a newly diagnosed sarcoma, thereby helping the clinician pick targeted agent(s) relevant to the expression profile. The spectacular success of imatinib in patients with gastrointestinal stromal tumor demonstrates how molecular targeting can fulfill the promise of low toxicity and high response rates. Finding new targets, and learning how to use the current generation of targeting drugs in sarcoma, are urgent challenges. Therapeutic clinical trials with a host of new molecular-targeting agents are underway that will drive new paradigms in sarcoma therapeutics. Patients with refractory disease who currently have no viable therapeutic options may have options that open up with the advent of newer targeted approaches, converting their disease from an acute short-lived one to a chronic process with preservation of quality of life while receiving therapy.

Objective: We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. Methods: In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly ×6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. Results: Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6-3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2-10.2 months). Conclusions: The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting. Copyright

Purpose: 9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m2/day × 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration.Experimental Design: On schedule A, 9NC was administered orally daily × 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily × 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography.Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m2/day, respectively, each providing the same dose intensity (i.e., 24 mg/m2/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of ∼4 to 1.Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m2 basis does not reduce pharmacokinetic variability.

To determine the response rate of trastuzumab and irinotecan in HER-2/neu overexpressing advanced colorectal cancer (CRC), determine the frequency of HER-2/neu expression in CRC, and evaluate the pharmacokinetics of trastuzumab in a phase II study.Patients were screened for HER-2/neu by immunohistochemistry (DAKO HercepTest). Prior chemotherapy was limited to one regimen. Trastuzumab was administered weekly (loading dose of 4 mg/kg i.v. and 2 mg/kg thereafter). Irinotecan 125 mg/m2, i.v. was administered weekly for 4 weeks with a 2-week rest period.HER-2/neu overexpression was detected in 11 of 138 (8.0%) of screened tumors (2+ in 5 and 3+ in 6 patients). Nine patients were entered in the study; 6 had received prior chemotherapy. Partial responses were seen in 5 of 7 evaluable patients. Grade 3-4 toxicities in 31 cycles of therapy included diarrhea (19%), nausea (10%), and vomiting (6%). Leukopenia occurred in 6%, and congestive heart failure and acute renal failure (secondary to diarrhea and dehydration) were seen in 3% of cycles. The study was prematurely closed due to low accrual.The low overexpression rate of HER-2/neu (8.0%) in advanced CRC limits the potential for further investigation of regimens involving trastuzumab, despite evidence suggestive of activity. Irinotecan did not alter the pharmacokinetic disposition of trastuzumab.

Purpose: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2. Experimental Design: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with “good” predictive pathologic features based on an “integrated selection” model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%–33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC. Conclusions: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation. Clin Cancer Res; 21(3); 561–8. ©2014 AACR.

Elevated expression of plasminogen activator inhibitor-1 (PAI-1) in tumors is associated with a poor prognosis in many cancers. Reduced tumor growth and angiogenesis have also been reported in mice deficient in PAI-1. These results suggest that PAI-1 may be required for efficient angiogenesis and tumor growth. In the present study, we demonstrate that PAI-1 can both enhance and inhibit the growth of M21 human melanoma tumors in nude mice and that this appears to be due to PAI-1 regulation of angiogenesis. Quantitative analysis of angiogenesis in a Matrigel implant assay indicated that in PAI-1 null mice angiogenesis was reduced approximately 60% compared with wild-type mice, while in mice overexpressing PAI-1, angiogenesis was increased nearly 3-fold. Furthermore, addition of PAI-1 to implants in wild-type mice enhanced angiogenesis up to 3-fold at low concentrations but inhibited angiogenesis nearly completely at high concentrations. Together, these data demonstrate that PAI-1 is a potent regulator of angiogenesis and hence of tumor growth and suggest that understanding the mechanism of this activity may lead to the development of important new therapeutic agents for controlling pathologic angiogenesis.

The process of angiogenesis is important in both normal and pathologic physiology. However, the mechanisms whereby factors such as basic fibroblast growth factor promote the formation of new blood vessels are not known. In the present study, we demonstrate that exogenously added plasminogen activator inhibitor-1 (PAI-1) at therapeutic concentrations is a potent inhibitor of basic fibroblast growth factor-induced angiogenesis in the chicken chorioallantoic membrane. By using specific PAI-1 mutants with either their vitronectin binding or proteinase inhibitor activities ablated, we show that the inhibition of angiogenesis appears to occur via two distinct but apparently overlapping pathways. The first is dependent on PAI-1 inhibition of proteinase activity, most likely chicken plasmin, while the second is independent of PAI-1's anti-proteinase activity and instead appears to act through PAI-1 binding to vitronectin. Together, these data suggest that PAI-1 may be an important factor regulating angiogenesis in vivo.

To date the best regenerative strategies to repair peripheral nerve injuries (PNI) have used peripheral nerve grafts.[1] However, this strategy is inherently flawed, requiring that a second injury be created to harvest the tissue for the primary injury repair. A better strategy would be to prepare a synthetic graft that mimics the properties of a peripheral nerve graft. Non-nerve biologic tissue and synthetic biodegradable material as bridges for neural repair have been utilized for over a century (reviewed by Doolabh et al [2]). Although offering considerable promise, artificial conduits have had only limited success, possibly due to their simple design and the lack of multiple stimuli of regeneration. In developing a bioengineered nerve graft, we have been systematically investigating a number of strategies to optimize nerve regeneration through tubular devices. We report our initial results with the use of bioengineered nerve grafts for repair of PNI in a rat model.

Cancer therapeutics is undergoing a revolution with the advent of new drugs that can selectively target molecules responsible for carcinogenesis and tumor growth. The type and mechanism of these targeting drugs vary. Some are small molecules that specifically target a binding site on a receptor or signal transduction molecule. Antibodies have been engineered to bind to the receptors or the corresponding ligands that mediate a critical cancer activity. In almost all cases, the intent is to inhibit or shut down a specific molecular pathway. Unprecedented activity against the cancer is seen without overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias. Unfortunately, an increase in toxicity has now become evident as more experience accumulates with the use of these drugs. In some cases, unexpected cardiotoxicities have arisen when these new drugs have been added to more conventional chemotherapies. Heart failure is the unfortunate manifestation for many of these toxicities. We outline the scope of this problem and examine the mechanisms of drug-induced heart failure. The distinctive signs and symptoms specific to each drug are described, and the diagnosis and treatment of the condition are discussed. Our aim is to allow the practitioner to recognize the unusual manifestations of heart failure in this setting in order to make a timely diagnosis and begin appropriate treatment measures.

BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 μg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 μg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 μg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC. Cancer 2010. © 2010 American Cancer Society.

The migration from cytokine therapy to the use of recently approved tyrosine kinase inhibitors and targeted therapeutic strategies may deprive some patients of a chance for long-term survival, as many clinicians now see these new agents as “easy fixes’ for treating renal cell carcinoma (RCC). New developments pertaining to the mechanism, patient selection, predictive biomarkers, and administration of interleukin-2 mandate a reassessment of the clinical landscape and the clinical trial information upon which our current practices are based. Recalibration of the scales that we use to weigh the various possible therapies for advanced kidney cancer is also needed. Despite the shift away from cytokine therapy in the current treatment paradigm, new therapeutic approaches continue to build upon the undisputed fact that RCC can be cured with immunotherapy.

Plasminogen activator inhibitor-1 (PAI-1) is an important endogenous inhibitor of urokinase-type plasminogen activator. Its action in tumor angiogenesis is complicated, varying with experimental setting and its cellular origin. To further understand the mechanism of the effect of PAI-1 on tumor angiogenesis, especially newly established tumor vasculature in early tumor progression, stable transfectants (TO-PAI-1) of the human prostate adenocarcinoma, PC3, were generated in which PAI-1 expression is under the control of the tetracycline-responsive promoter (Tet-On system). The TO-PAI-1 transfectants exhibit tight inducibility of expression of biologically active PAI-1 in vitro. Induction of PAI-1 expression in nude mice resulted in significant inhibition of tumor growth. This inhibition appears to be due to the effect of PAI-1 on angiogenesis, because it is manifested by an initial wave of tumor endothelial apoptosis accompanied by induction of tumor cell apoptosis and inhibition of tumor cell proliferation. Similar endothelial apoptosis is observed in vitro when human microvascular endothelial cells are physically cocultivated with TO-PAI-1 cells on vitronectin-coated plate. Taken together, these data show for the first time that PAI-1 induces endothelial apoptosis in the newly established tumor vasculature. [Mol Cancer Ther 2008;7(5):1227–10]

The potent effects of PAI-1 on tumorigenesis and angiogenesis in various experimental models are complex, complicated and at times contradictory. We determined the therapeutic potential of PAI-1 for inhibiting bladder tumor invasion under conditions that closely mimic the clinical setting.An orthotopic rat bladder tumor model was established by implanting AY-27 rat transitional carcinoma cells into the bladder lumen of syngeneic Fischer F344 rats. Three weeks after implantation 1 microM PAI-1 was administrated directly into the bladder lumen twice weekly for 2 weeks. Two days after the final treatment tumor size, total bladder weight, tumor stage and angiogenesis were assessed. To assess the uPA axis the levels of active and total uPA, and active and total PAI-1 in tumor extracts were determined 0, 2, 24 and 48 hours after intravesical PAI-1 administration.Intravesical PAI-1 bound and inactivated its molecular target, tumor uPA. There was significant inhibition of bladder tumor progression, as manifested by 53%, 37% and 57% reductions in tumor size, total bladder weight and angiogenesis, respectively. Only 22% of PAI-1 treated tumors invaded muscle vs 79% in controls. No PAI-1 toxicity was detected.To our knowledge this study is the first to demonstrate that intravesical treatment with PAI-1 significantly inhibits tumor progression in an in vivo model of bladder cancer. Further clinical development is warranted for using PAI-1 directly or in combination with current standards, such as bacillus Calmette-Guerin or interferon.

The incidence rate of malignant melanoma has shown a rapid worldwide rise in recent years. The staging and management of head and neck melanoma presents some unique challenges. Surgery remains the cornerstone of treatment, while sentinel node biopsy is the most accurate staging modality for regional disease. The complex regional anatomy and lymphovascular drainage of this region may account for the increased biologic aggressiveness and treatment challenges of this disease. Improved understanding of the radiobiology of melanoma has resulted in new adjuvant radiotherapy approaches, yielding improved control rates. The treatment outcomes of metastatic head and neck melanoma remain disappointing but important progress has been made in the understanding of melanoma biology.

Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. Experimental Design: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly × 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot. Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content. Conclusions: 17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly × 3, repeated every 4 weeks.

This commentary raises an important issue that has not been sincerely considered in the field of dermatology, which is the vital role of hairdressers--a group that makes daily observations of the general populations' scalp and neck--in the detection of head and neck melanomas in the general population. We note several key areas of research that are needed to assess the feasibility of using hairdressers as a resource for melanoma detection and referral. If research suggests hairdressers can be trained and are willing to make appropriate referrals then implementing these efforts will likely reduce the increasing disease burden of head and neck melanomas.

Lung carcinoma is one of the most frequent causes of malignancy-related mortality in the world. Paclitaxel (PA) is an antineoplastic agent used in the treatment of non-small-cell lung cancer (NSCLC) and possesses a single-agent response rate approaching 25%. PA kills tumor cells by inducing both cellular necrosis and apoptosis. Fas and Trail receptors (DR4 and DR5) are TNF family members and act as death signal transduction proteins in the apoptosis cascade. Despite the importance of PA in lung cancer treatment, the function of Fas, DR4 and DR5 in PA-induced apoptosis, as well as the effect of their respective ligands FasL and TRAIL alone or in combination with PA, remains poorly understood. We show here that 10 microM PA induces a significant 10- to 57-fold increase in primary lung cancer cell apoptosis and is associated with 20-215% increases in caspase-3 activity in various NSCLC cell types. All the lung cancer cells express Fas, FasL, DR4 and DR5; however PA did not significantly modify their levels. We provide here the first time evidence that TRAIL is a potent inducer of apoptosis in multiple NSCLC cell lines. Noticeably, CH11, the Fas receptor cross-linking and the antagonistic anti-DR5 antibody enhance considerably the spontaneous apoptotic rate in 3 out of 5 cell types. The combination treatments, FasL+PA, TRAIL+PA or PA+anti-DR5 antibody, greatly enhance PA-apoptotic effect in most cell lines. These data suggest that the use of new combination treatment with PA and ligands targeting Fas or TRAIL receptors would be particularly efficacious.

Jagged-Notch interactions regulate a transmembrane ligand-receptor signaling pathway involved in the regulation of cell fate determination as well as myoblast and endothelial cell differentiation. To further examine the role of the transmembrane ligand, Jagged-1, in the regulation of cell differentiation, we stably transfected NIH 3T3 cells with a truncated form of Jagged(J)-1, which results in the secretion of a soluble(s) form of the protein. Comparison of gene expression by serial analysis demonstrated that among the 227 transcripts differentially regulated in the sJ-1 transfectants, the expression of the pro-alpha-2(I) collagen transcript and pro-alpha-1(I) collagen translation product was predominantly repressed in sJ-1 transfectants. When plated on extracellular matrices, sJ-1 transfectants formed prominent chord-like structures on type I collagen but not on fibrin, fibronectin, or vitronectin. While the sJ-1 transfectants exhibited growth kinetics similar to control cells and were unable to grow in soft agar, the cells were less sensitive to contact inhibition of growth in vitro and sJ-1 allografts formed tissue masses in nude mice after a prolonged latency period and exhibited an abundance of host-derived microvascular endothelial cells. These data suggest that J-1 may be able to modulate, in a matrix-dependent manner, the organization of cell to cell interactions including its ability to promote the development of chord-like structures.

The available data on F-actin microfilament distribution in vascular endothelial cells in vivo is limited. In this study, the appearance and distribution of endothelial cell microfilaments in the rabbit thoracic aorta, the abdominal aorta and its major arterial branch points, and the aortic bifurcation were examined. Perfusion fixed rabbit aortas were stained in situ for F-actin by infusing rhodamine phalloidin via a peristaltic pump into the aortas at a slow flow rate. This new technique resulted in excellent visualization of branch points and allowed for a precise description of the actin microfilament bundles in endothelial cells along flow dividers. In the thoracic and abdominal aorta, away from branch ostia, actin microfilaments were localized in two regions of the endothelial cells, as a prominent band that completely outlined the cell periphery, and also as short central stress fibers. The central stress fibers were more frequent and prominent in cells of the abdominal aorta. At branch sites and at the aortic bifurcation, long, thick microfilament bundles were present in endothelial cells extending from the tip of the flow divider to a few millimeters along the branch arteries, the aorta, and the iliac arteries. Peripheral actin, however, no longer completely surrounded the cells. The thick bundles were not prominent in endothelial cells located adjacent to the proximal lip of branches or at the iliac arteries opposite the flow divider. This study shows that endothelial cell F-actin microfilament distribution in vivo is well defined along the aortic-arterial system. The prominent central microfilament bundles and the reduced peripheral microfilaments seen at localized regions may reflect an adaptive response to elevated shear stress at these sites.