Harold Yamase

Immunization with a tumor-cell-lysate-loaded autologous-antigen-presenting-cell-based vaccine in melanoma

Abstract The discoveries of human melanoma-associated antigens in molecular terms have renewed interest in peptide- or peptide- and antigen-presenting-cell (APC)-based cancer vaccines. Considering the limited scope of immunization using defined peptides, we have studied an alternative approach of specific immunization with tumor-lysate-loaded autologous APC (adherent peripheral mononuclear cells cultured in 1000 U granulocyte/macrophage-colony-stimulating factor for 14 days) as a surrogate vaccine. Seventeen patients (11 with active metastatic disease) were intradermally immunized with the vaccine in a phased dose escalation (105–107 cells/injection) monthly for 4 months. Thirteen patients completed all four immunizations showing no toxicity (3 patients had to be taken off study because of progressive disease and 1 patient went off study as a result of myocardial infarction due to multi-vessel coronary artery disease). None has shown any immediate or delayed toxicity attributable to the immunization and none has shown any evidence of autoimmunity. One patient showed a partial regression of a subcutaneous nodule. Thirteen patients are alive after 4+ months to 30+ months (17-month median survival for the group). Nine patients showed evidence of delayed-type hypersensitivity at the vaccine sites. Monitoring of biological response in conventional natural killer or cytolytic T lymphocyte assays with pre- and post-immune peripheral blood lymphocytes revealed no consistent differences. The vaccine-infiltrating lymphocytes (VIL) from nine specimens were adequately expanded following in vitro stimulation with the respective autologous-lysate-loaded APC for phenotypic and functional analyses. Five of the nine ex vivo expanded VIL were predominantly CD8+. Evidence of an antigen-specific CD8+ T cell response (cytotoxicity and/or tumor necrosis factor production) was detected in three of the five CD8+ VIL. These observations suggest that this type of vaccine is feasible, that it has biological activity, and that the approach may be improved through additional strategic manipulations.

Incidental oral hairy leukoplakia in immunocompetent persons: A report of two cases

In this brief article we report on two HIV-negative patients with documented oral hairy leukoplakia who had no known risk factors for HIV infection nor any evidence of other forms of immune suppression. Therefore we conclude that in some instances hairy leukoplakia can represent an isolated and innocuous Epstein-Barr virus infection.

Omental infarction : report of three cases and review of the literature

Omental Infarction, the end result of impaired perfusion to the greater omentum, is a rare entity (JBCM Puylaert, Radiology 1992;185:169–172). We recently encountered three patients in whom computed tomography (CT) showed the characteristic findings of omental infarction. The diagnosis was subsequently confirmed intraoperatively and pathologically in two of the cases. The third case showed partial resolution on follow-up computed tomography. All three cases are presented with a brief review of the literature.

S1P/S1P1 signaling stimulates cell migration and invasion in Wilms tumor.

Sphingosine-1-phosphate (S1P) is an important regulator of cellular functions via interaction with its receptors S1P(1-5). To date, nothing is known about the S1P receptor expression and the effects of S1P signaling in Wilms tumor. In this study, we found ubiquitous expression of S1P receptors in Wilms tumor specimens and cell lines. We demonstrated that S1P(1) acted as a promigratory modulator by employing S1P(1) antagonist VPC44116, S1P(1) siRNA and adenoviral transduction in Wilms tumor cells. Further, we clarified that S1P(1)-mediated migration occurred via Gi coupling and activation of PI3K and Rac1. In addition, S1P stimulated WiT49 cell invasion through S1P(1)/Gi signaling pathway. We consider that targeting S1P(1) may be a point of therapeutic intervention in Wilms tumor.

Urinary Neutrophil Chemotactic Factors in Interstitial Cystitis Patients and a Rabbit Model of Bladder Inflammation

The present study investigates a possible source of inflammatory mediators involved in the pathogenesis of bladder inflammation characteristics of interstitial cystitis disease. Our tested hypothesis is that in response to injury, tissues of the urinary bladder participate in the initiation of bladder inflammation by releasing inflammatory mediators such as neutrophil chemotactic factors. Bladders of anesthetized rabbits (n = 7) were instilled with an acidic solution (pH 4.5) for 15 minutes, then washed with saline and instilled with sterile phosphate buffered saline (PBS) (pH 7.2) for an additional 45 minutes prior to sacrificing the rabbits. Control rabbits (n = 7) were instilled with sterile PBS (pH 7.2) for 15 minutes, then 45 minutes. The levels of neutrophil chemotactic factors were measured using modified Boyden chambers and rabbit peritoneal neutrophils as indicator cells. Results indicated the release of high levels of neutrophil chemotactic factors (via a checkerboard analysis) from acid-treated bladders after 15 minutes (70 +/- 4% of standard) and 45 minutes (80 +/- 7%). Electron microscopy analysis of these acid-treated bladders revealed the infiltration of a large number of neutrophils, which correlates with the recovery of neutrophil chemotactic factors. Control rabbits, on the other hand, showed low levels of chemotactic activity (less than 10 percent) and exhibited normal bladder morphology with absence of neutrophils. The glycosaminoglycan (GAG) layer was intact in both acid-treated and control bladders. High levels of neutrophil chemotactic factors were also detected in urine samples from eleven patients with interstitial cystitis (113 +/- 25%) (not due to interleukin-1 or leukotriene B4) which were not detected in urine samples from healthy volunteers (n = 9) or from thirteen control patients with bladder diseases other than interstitial cystitis. These preliminary studies indicate the capability of injured bladder tissues to release neutrophil chemotactic factors which contribute to the initiation of bladder inflammation. The presence of neutrophil chemotactic factors in urine samples of interstitial cystitis patients suggests a possible role of these mediators in the pathogenesis of the disease.

Mesangial proliferative glomerulonephritis with IgM deposits

To determine the natural history of mesangial proliferative glomerulonephritis (MesPGN) with IgM deposits and its relationship to minimal change disease (MC) and focal segmental glomerulosclerosis (FGS), we studied the clinical characteristics and outcome in 20 patients with MesPGN, 8 with MC, and 10 with FGS. IgM deposits were present in glomeruli of all MesPGN patients. Progression to FGS was documented in 2 patients with MesPGN, 1 of whom developed renal failure. Transition from MC to MesPGN occurred in 1 patient. 2 MC patients developed FGS, with decline in renal function in 1 of them. These data suggest the possibility of histologic transition from MC to FGS directly or through the stage of MesPGN.

Ectopic production of human chorionic gonadotropin by poorly differentiated transitional cell tumors of the urinary tract.

We performed a 5-year histopathological review of 41 consecutive cases of transitional cell carcinoma. Of these cases 8 were positive for human chorionic gonadotropin immunoperoxidase tissue staining. All tumors were grade III and stages ranged from A to D. Three patients presented with gynecomastia as the clinical manifestation of elevated serum levels of beta-human chorionic gonadotropin. These findings document the association of this phenomenon with lesions of an aggressive nature. As with the loss of cell surface antigens, the appearance of human chorionic gonadotropin within the tumor cells may be further evidence of dedifferentiation. Human chorionic gonadotropin production may be a potential marker to gauge tumor response to chemotherapy and, perhaps, a predictor of future aggressiveness and over-all progression.

Renal Malacoplakia With Papillary Necrosis and Renal Failure

Renal parenchymal malacoplakia is a rare cause of renal failure. Patients presenting with renal failure carry a poor prognosis, the majority either dying or requiring chronic dialysis. In this report, we describe an alcoholic man who presented with renal failure due to bilateral renal parenchymal malacoplakia and papillary necrosis. The patient, who initially required dialysis, partially recovered renal function following prolonged antibiotic treatment with a fluoroquinolone antibiotic.

Accelerated Hypertension With Encephalopathy Due to an Isolated Dissection of a Renal Artery Branch Vessel

Typical causes of renovascular hypertension include intramural atherosclerotic lesions of the main renal arteries or their branches and fibromuscular dysplasia of the renal arterial wall with luminal narrowing. We report a patient with new-onset, accelerated hypertension (blood pressure 220/140 mm Hg, status epilepticus, retinal hemorrhages) secondary to a dissection of the anterior division of the right renal artery that was accompanied by hyperreninemia, hyperaldosteronism, and hypokalemia. At presentation in the untreated state, unstimulated plasma renin activity and the serum aldosterone level were markedly elevated. Following right nephrectomy, blood pressure levels normalized without antihypertensive therapy, and plasma renin activity, serum aldosterone and potassium levels normalized. Histologic study of the right renal artery showed an isolated dissection of the anterior branch of the vessel between the muscularis and adventitia that created marked reduction in luminal diameter and renal ischemia. There was no evidence of any other vascular abnormalities, atherosclerosis, or fibromuscular dysplasia. These findings demonstrate that an isolated dissection of a branch of the renal artery may induce profound hyperreninemia and represents a rare, reversible etiology for accelerated hypertension associated with acute encephalopathy.

Treatment with the Immunomodulator FTY720 (Fingolimod) Significantly Reduces Renal Inflammation in Murine Unilateral Ureteral Obstruction

PURPOSE The S1P signaling pathway represents an important potential target for the modulation of tissue inflammation/injury. The immunomodulator FTY720, also known as fingolimod, is a potent agonist for multiple S1P receptors that was approved by the Food and Drug Administration to treat multiple sclerosis. We examined the therapeutic role of FTY720 for renal injury secondary to unilateral ureteral obstruction. MATERIALS AND METHODS CB57BL/6 mice underwent a sham procedure or unilateral ureteral obstruction and were treated with FTY720 by gavage for 1, 3 and 5 days. Control groups received vehicle. Ligated and unligated renal tissue was examined for histopathological changes, inflammatory and fibrotic markers, TGF-β1, α-SMA, and macrophage infiltration by Western blot and immunohistochemistry. Proinflammatory and profibrotic cytokines were profiled by quantitative reverse transcriptase-polymerase chain reaction. RESULTS Pathological evaluation revealed that FTY720 treatment resulted in a significant reduction in inflammatory infiltration in obstructed kidneys compared to controls. Immunohistochemical and Western blot showed that TGF-β1 and α-SMA protein levels were similarly decreased, as was macrophage infiltration into the renal interstitial space, compared to untreated mice. In agreement with these observations quantitative reverse transcriptase-polymerase chain reaction revealed that inflammatory and fibrotic cytokines (MCP-1, IL-1β, CXCL1, TNF-α and TGF-β1) were also significantly decreased in the FTY720 group. CONCLUSIONS This study suggests that in a murine ureteral obstruction model FTY720 significantly inhibited the production of inflammatory cytokines and factors regulating interstitial fibrosis and extracellular matrix accumulation. These findings were associated with decreased evidence of renal injury on pathological examination, suggesting that FTY720 or related compounds may be valuable modulators of obstruction induced renal injury.