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Biomedical subjects

J E Tomaszewski

Publications and source records attributed to J E Tomaszewski.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prostate specific antigen outcome based on the extent of extracapsular extension and margin status in patients with seminal vesicle negative prostate carcinoma of Gleason score < or = 7.

BACKGROUND: Early (< or = 2 years) prostate specific antigen (PSA) failure after radical prostatectomy (RP) has been shown to predict for distant failure. After excluding patients with the pathologic predictors of early PSA failure, an analysis of PSA failure free (bNED) survival was performed to identify patients who may benefit from the use of postprostatectomy radiation therapy (RT). METHODS: Of 1,028 patients treated with RP for clinically localized prostate carcinoma between 1989 and 1999, 862 (84%) had either organ confined (OC), specimen confined (SC), or margin positive disease with negative seminal vesicles (SV) and a prostatectomy Gleason score < or = 7. A Cox regression multivariate analysis was performed in these patients evaluating the ability of the extent of extracapsular extension (ECE) (into but not through the capsule, SC focal ECE, SC established ECE, margin positive) and prostatectomy Gleason score (2-6 vs. 7) to predict time to postoperative PSA failure. RESULTS: SC focal ECE (P = 0.0017), SC established ECE (P < 0.0001), and margin positive disease (P < 0.0001) were significant predictors of time to postoperative PSA failure, whereas prostatectomy Gleason score and disease extending into but not through the capsule were not. Five-year bNED rates were 90%, 88%, 69%, 45%, and 33% for patients with OC, into but not through capsule, SC focal ECE, SC established ECE, and margin positive prostate carcinoma, respectively. CONCLUSIONS: Patients with SC ECE or margin positive prostate carcinoma and a prostatectomy Gleason score < or = 7 with no evidence of SV invasion may benefit from adjuvant postoperative RT.

Actuarial Analysis↗
PubMed2000

Vaccination with a recombinant vaccinia vaccine containing the B7-1 co-stimulatory molecule causes no significant toxicity and enhances T cell-mediated cytotoxicity.

B7-1 is a co-stimulatory molecule that provides a second signal for T-cell activation. Several studies have demonstrated that vaccination with a vector containing genes encoding B7-1 and an antigen appears to be efficacious at promoting immune responsiveness to the antigen. To evaluate the safety of such a protocol and determine the effect of the B7-1 vector on immune responsiveness, female C57BL/6 mice were administered Wyeth wild-type vaccinia virus (V-WT) or V-WT containing the gene for B7-1 (rV-B7-1) as a single s. c. injection or 3 monthly s.c. injections. Immunologic parameters were evaluated in half of the mice and general toxicity in the other half. Immunologic end points included determination of splenic lymphocyte phenotypes, mitogen-induced T- and B-cell proliferation, T-cell proliferation in response to alloantigens, cell-mediated cytotoxicity (CMC), natural killer cell activity and serum anti-nuclear antibody (ANA) titers. No significant signs of general toxicity were noted. The primary immunologic effect was an increase in the ability of spleen cells to lyse allogeneic targets and to proliferate in response to allogeneic stimulation. Numbers of splenic CD8(+) cells were also increased. These effects were more pronounced after 3 vaccinations than after a single vaccination. Minimal differences in ANA were observed between mice immunized with V-WT and rV-B7-1. In addition, no serum antibodies against B7-1 were detected in any mice. The data suggest that vaccination with rV-B7-1 augments CMC with minimal toxicity.

Alanine Transaminase↗
PubMed2000

Identification of meiotic and postmeiotic gene expression in testicular tissue of patients histologically classified as Sertoli cell only.

OBJECTIVE: To determine whether meiotic and postmeiotic germ cell gene products could be detected in biopsy specimen from patients with Sertoli cell only (SCO) and maturation arrest. DESIGN: Prospective clinical study. SETTING: University-based departments and laboratories. PATIENT(S): Nine patients, seven with nonobstructive azoospermia (12 biopsies) and two with obstructive azoospermia (controls) (2 biopsies). INTERVENTION(S): Specimens were divided into three parts: IVF laboratory, histology, and molecular analysis. Germ cell-specific messenger RNAs (mRNAs) were detected by extracting total RNA for Northern blotting or reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Detection of meiotic (lactate dehydrogenase C4) and postmeiotic (transition protein 1 and protamine 1 and 2) gene expression and correlation with histologic and IVF laboratory findings. RESULT(S): The IVF laboratory identified spermatozoa in 3 of 14 biopsies (controls and severe hypospermatogenesis). Histologically, 6 of 14 biopsies (43%) were diagnosed as SCO, 4 (29%) maturation arrest, 2 (14%) severe hypospermatogenesis, and 2 normal. Molecular analysis showed mRNA for meiotic and postmeiotic genes in 12 of 14 biopsies (86%) (P =. 006), of which 4 (67%) in SCO and 3 (75%) in maturation arrest. CONCLUSION(S): Differentiated germ cells are present in biopsies of men histologically diagnosed as SCO. Absence of these molecular markers strengthens the histologic diagnosis and helps the physician in counseling the infertile couple.

Adult↗
PubMed2000

Combination of the preoperative PSA level, biopsy gleason score, percentage of positive biopsies, and MRI T-stage to predict early PSA failure in men with clinically localized prostate cancer.

OBJECTIVES: Early (2 years or less) prostate-specific antigen (PSA) failure has been shown to predict for distant failure. The independent clinical predictors of time to postoperative PSA failure were used to identify prostate cancer patients at high risk for early PSA failure. METHODS: A Cox regression multivariable analysis was used to determine whether additional predictive information was provided by the endorectal coil magnetic resonance imaging (erMRI) T-stage when controlling for the established prognostic factors in predicting the time to postoperative PSA failure in 977 men with palpable (T2) or PSA-detected (T1c) prostate cancer. RESULTS: Preoperative PSA (P = 0.0001), percentage of positive prostate biopsies (P= 0.0001), erMRI T-stage (P = 0.0001), biopsy Gleason score (P = 0.0015), and clinical stage T2c disease (P = 0.004) were independent predictors of time to postoperative PSA failure. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in nomogram format stratified by the preoperative PSA, percentage of positive prostate biopsies, erMRI T-stage, and the biopsy Gleason score. CONCLUSIONS: Patients at high risk for early PSA failure and subsequent distant progression include men with erMRI T3 disease and 3 or more of 6 cores positive for a Gleason score 6 or higher disease when the PSA is more than 10 but not more than 20 ng/mL and any Gleason score when the PSA is more than 20 ng/mL. Men with erMRI T2 disease and 3 or more of 6 cores positive for a Gleason score 8 or higher disease and who have a PSA more than 20 ng/mL are also at high risk. Neoadjuvant therapy trials in these select patients may be justified.

Biomarkers, Tumor↗
PubMed2000

Early post-transplant lymphoproliferative disease following heart transplantation in the absence of lymphocytolytic induction therapy.

We report a case of post-transplant lymphoproliferative disease presenting as a disseminated polymorphous B-cell lymphoma involving the cardiac allograft 3 months following transplantation in a recipient who did not receive anti-lymphocyte induction immunosuppression. In situ hybridization for the lytic Epstein-Barr virus marker NOT I was positive within a lymphocytic infiltrate on endomyocardial biopsy. Our case is the third of early post-transplant lymphoproliferative disease (within 6 months of transplantation) involving the heart allograft in the absence of anti-lymphocyte induction immunosuppression. Post-transplant lymphoproliferative disease of the heart allograft should be considered in the presence of an atypical cardiac lymphocytic infiltrate, with possible differentiation from allograft rejection using in situ hybridization for Epstein-Barr virus.

Drug Therapy, Combination↗
PubMed2000

Investigating the clinical utility of the percent of positive prostate biopsies in predicting PSA outcome following local therapy for patients with clinically localized prostate cancer.

The clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following radical prostatectomy (RP), or external beam radiation therapy (RT), for men with PSA detected, or clinically palpable prostate cancer was investigated. After accounting for the established prognostic significance of the PSA level, biopsy Gleason score and the clinical T-stage, the percent of positive prostate biopsies added clinically significant information regarding time to PSA failure following RP. These findings were validated in the intermediate risk patients using an independent surgical and radiation data set. Prostate Cancer and Prostatic Diseases (2000) 3, 259-264

Journal Article↗
PubMed2000

Pathology residents' use of a Web-based tutorial to improve Gleason grading of prostate carcinoma on needle biopsies.

Little is known about pathology residents' ability to Gleason grade or their ability to learn surgical pathology using Internet-based technology. A free Web-based program (available at www.pathology. jhu.edu/prostate) was developed that consisted of 20 pretutorial images for grading, 24 tutorial images, and the same 20 posttutorial images for Gleason grading. The grading images were selected from cases that had a consensus Gleason grade from 10 uropathology experts. In 2.5 months, 255 residents visited the website, and 151 (59%) completed it. Of those who completed the website, their year in training was known in 85 (56%): 1st year, 25.8%; 2nd year, 20%; 3rd year, 22.3%; 4th year, 14.1%; 5th year, 15.3%; and 6th year, 2.4%. Eighty percent learned Gleason grading in residency versus being self-taught, and 66% were male. In a multivariate analysis, higher pretutorial scores were associated with both their year in training (P = .001) and their hospital size (P = .003). Improvements in grading posttutorial were not related to the residents' year in training. Overall, the website significantly improved grading in 11 of 20 images and had no effect in 9 of 20 images. Improvements were noted in 1 of 1 Gleason score 4; 2 of 7 Gleason score 5 to 6; 2 of 6 Gleason score 7; and 6 of 6 Gleason score above 7 tumors. In summary, a Web-based tutorial improved Gleason grading accuracy by pathology residents to an equal extent regardless of their year in training. It is more difficult to teach residents to grade Gleason scores 5 to 7 tumors, and additional training should be concentrated in this area.

Biopsy, Needle↗
PubMed2000

Cellular repopulation of human vein allograft bypass grafts.

PURPOSE: Vein allografts are an alternative conduit for patients lacking available autogenous vein. The ability to develop a neoendothelium is a potential advantage of allografts over other nonautogenous grafts, because endothelial cells have been shown to play numerous essential roles in vessel survival. However, repopulation by endothelial cells has not previously been demonstrated or characterized in human subjects. METHODS: In our prospective trial, 40 patients (20 men, 20 women) underwent cryo- preserved saphenous vein bypass grafting procedures for limb salvage. Several patients underwent multiple grafting procedures. All grafts were sampled at implantation. During the 31 month follow-up interval, 22 allografts were explanted at the time of revision or subsequent surgical procedure. All grafts (22 of 22) demonstrated intact endothelium at implantation and explantation. Seventeen explantation biopsy samples (seven from men, 10 from women) from 16 patients (seven men, nine women) were adequate for further histologic and immunofluorescent analysis. Explants were stained with hematoxylin-eosin and immunohistochemical markers to quantitate rejection and also underwent fluorescence in-situ hybridization, with probes for X and Y chromosomes and counterstain for nuclear envelope. Cells were counted as XX, XY, XO, YO, or unstained. The endothelium and vessel walls were analyzed for origin of cells based on sex-mismatched transplants, with sex-matched transplants serving as controls. RESULTS: Evidence of cellular damage was noted in all explanted allografts, and moderate or severe rejection (lymphocyte infiltrate, +CD3, +CD8, +CR3, cytotoxic granules) was noted in six explanted allografts (29%). All allografts demonstrated intact endothelium (complete or partial), at the time of both implantation and explantation. Sex-matched (male to male) control explants showed only male cells, as expected. Male donor-female recipient transplants showed complete repopulation by recipient (female) cells in nine of 10 cases (90%), whereas one case (10%) demonstrated partial repopulation (a mosaic of male and female cells). One patient's slides were unreadable. Findings in cells of the allograft wall were identical to those of the endothelium (nine recipient-only cells and one mosaic). Complete absence of donor cells was noted as early as 1 week after implantation, but mosaicism was demonstrated in one patient 3 months after grafting. No relationship could be demonstrated between repopulation and time (P >.05), quantity of rejection (P >.05), or donor age (P >.05). CONCLUSION: Both the endothelial lining and vessel wall of venous allografts repopulate with cells of recipient origin, resulting in either a completely novel cellular constituency or a mosaic of host and donor cells. The loss of donor cells may be mediated by apoptosis or rejection, and the rate of migration of repopulating host cells is, at this point, unclear. Although the development of a completely endothelial-lined conduit offers a potential advantage over other alternative conduits, the functional status of the neoendothelium and repopulated vessel wall and their role in maintenance of allograft patency require further investigation.

Cell Division↗
PubMed2000

Endorectal magnetic resonance imaging as a predictor of biochemical outcome after radical prostatectomy in men with clinically localized prostate cancer.

PURPOSE: Endorectal magnetic resonance imaging (MRI) of the prostate is sometimes performed before radical prostatectomy but to our knowledge its role for predicting outcome after radical prostatectomy is not yet established. We evaluated the clinical usefulness of endorectal MRI for predicting time to prostate specific antigen (PSA) failure after radical prostatectomy in 1,025 consecutive men with clinically localized or PSA detected prostate cancer. Our analysis controlled for PSA level, biopsy Gleason score, clinical T stage and percent of positive biopsies. MATERIALS AND METHODS: Using Cox regression analysis we prospectively assessed time to PSA failure to determine the role of endorectal MRI in predicting PSA outcome after radical prostatectomy at our institution, where an expert prostate magnetic resonance radiologist is available. The main outcome measure was actuarial freedom from PSA failure. RESULTS: Endorectal MRI did not add clinically meaningful information in 834 of our 1,025 cases (81%) after accounting for the prognostic value of PSA, biopsy Gleason score, clinical T stage and percent of positive biopsies. However, this modality provided a clinically and statistically relevant stratification of 5-year PSA outcome in the remaining 191 patients at intermediate risk based on established prognostic factors. Specifically when endorectal MRI was interpreted as indicating extracapsular versus organ confined disease the relative risk of PSA failure was 3.6 (95% confidence interval 2.0 to 6.3), and 5-year actuarial freedom from PSA failure was 33% versus 72% (p <0.0001). CONCLUSIONS: Despite expert radiological interpretation endorectal MRI had potential clinical value in less than 20% of the cases in our study after accounting for established prognostic factors. While further study of the value of this modality for predicting clinical outcome after radical prostatectomy should be performed in this select cohort, routine use of endorectal MRI cannot be justified based on these data.

Actuarial Analysis↗
PubMed2000

Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer.

PURPOSE: To determine the clinical utility of the percentage of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for men with PSA-detected or clinically palpable prostate cancer. METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men while accounting for the previously established risk groups that are defined according to pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Committee on Cancer (AJCC) clinical T stage. The findings were then tested using an independent surgical database that included data for 823 men. RESULTS: Controlling for the known prognostic factors, the percentage of positive prostate biopsies added clinically significant information (P <.0001) regarding time to PSA failure after RP. Specifically, 80% of the patients in the intermediate-risk group (1992 AJCC T2b, or biopsy Gleason 7 or PSA > 10 ng/mL and </= 20 ng/mL) could be classified into either an 11% or 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated in the intermediate-risk patients using an independent surgical data set. CONCLUSION: The validated stratification of PSA outcome after RP using the percentage of positive prostate biopsies in intermediate-risk patients is clinically significant. This information can be used to identify men with newly diagnosed and clinically localized prostate cancer who are at high risk for early (</= 2 years) PSA failure and, therefore, may benefit from the use of adjuvant therapy.

Biopsy↗
PubMed2000

Hepatosplenic gamma-delta T-cell lymphoma as a late-onset posttransplant lymphoproliferative disorder in renal transplant recipients.

We report 2 cases of renal transplant recipients in whom hepatosplenic gamma-delta T-cell lymphoma (gamma-delta HSTCL) developed 5 and 10 years after transplantation. Both patients had marked hepatosplenomegaly, B symptoms (weight loss, fever, and night sweats), and abnormal peripheral blood findings, including anemia in both, thrombocytopenia and leukoerythroblastic changes in 1, and leukocytosis in the other. Markedly atypical lymphoid infiltrate of intermediate to large cells was observed in the spleen, liver, and bone marrow. The malignant cells showed typical immunophenotype of gamma-delta T cells (CD2+, CD3+, CD4-, CD8-, CD7+, gamma-delta T-cell receptor-positive, and alpha-beta T-cell receptor-negative) with clonal T-cell receptor gene rearrangement and were of the V-delta-1 subset. In addition, the cells contained a cytolytic granule-associated protein, TIA-1, and Fas ligand, indicating cytotoxic T-cell differentiation. The malignant T cells in both cases were of host tissue origin. Both cases were negative for Epstein-Barr virus genome using Southern blot analysis. The patients did not respond to reduction of immunosuppression. Despite initial response to chemotherapy, both patients died within 6 months of diagnosis. Our findings indicate that gamma-delta HSTCL can occur as a late complication in transplant recipients.

Adult↗
PubMed2000

Worrisome histologic alterations following fine-needle aspiration of benign parotid lesions.

OBJECTIVE: To describe the histologic changes associated with preoperative fine-needle aspiration biopsies of benign parotid lesions and the features that distinguish these changes from malignant neoplasms. MATERIALS AND METHODS: Ten benign parotid lesions with a recent history of preoperative fine-needle aspiration were selected, including pleomorphic adenoma (4 cases), oncocytic adenoma (3 cases), myoepithelioma (1 case), Warthin tumor (1 case), and lymphoepithelial cyst (1 case). RESULTS: A spectrum of histologic alterations were observed. Alterations included squamous cell metaplasia (8 cases), infarction and necrosis (4 cases), subepithelial stromal hyalinization (3 cases), acute and chronic hemorrhage and inflammation with multinucleated giant cells (all cases), granulation tissue with subsequent fibrosis (all cases), cholesterol cleft formation (1 case), pseudoxanthomatous reaction (1 case), pseudocapsular invasion (1 case), and microcystic degeneration (2 cases). In cases with exuberant squamous metaplasia, necrosis, or subepithelial stromal hyalinization, a diagnosis of squamous cell carcinoma or low-grade mucoepidermoid carcinoma was seriously considered. CONCLUSIONS: Knowledge of a previous fine-needle aspiration procedure and awareness of its effects on histology of the subsequent parotidectomy specimens are necessary to avoid potential misdiagnosis.

Adolescent↗
PubMed2000

Clinical utility of percent-positive prostate biopsies in predicting biochemical outcome after radical prostatectomy or external-beam radiation therapy for patients with clinically localized prostate cancer.

BACKGROUND AND PURPOSE: The clinical utility of the percentage of positive prostate biopsies in predicting prostate specific antigen (PSA) outcome after radical prostatectomy (RP) or external-beam radiation therapy (EBRT) for men with PSA-detected or palpable prostate cancer is not established. METHODS: A Cox regression multivariable analysis was used to determine whether percent-positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men, while accounting for the previously established risk groups based on the pretreatment PSA concentration biopsy Gleason score, and the 1992 American Joint Commission on Cancer clinical T stage. RESULTS: In the intermediate-risk group, 80% of the patients (stage T(2b) or biopsy Gleason 7 or PSA 10-20 ng/mL) could be classified into either an 11% or an 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated using an independent surgical (N = 823) and radiation (N = 473) data set. Percent-positive prostate biopsies added clinically significant information regarding time to PSA failure after RP. CONCLUSIONS: The percentage of positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome after RP or EBRT.

Biopsy↗
PubMed1999

Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage.

PURPOSE: Ideal candidates for 3D dose escalation conformal radiation or external beam + implant therapy are identified on the basis of the prostate-specific antigen (PSA) level, biopsy Gleason score, and the 1992 American Joint Commission Cancer (AJCC) clinical T-stage. METHODS AND MATERIALS: The pathologic findings of 1742 men with clinical stage T1c,2 prostate cancer managed with a radical prostatectomy (RP) between 1990 and 1998 were subjected to a logistic regression multivariable analysis. The endpoints examined included pathologic organ-confined (OC), specimen-confined (SC), and margin (M) or seminal vesicle (SV) positive disease. SC disease was defined as extracapsular extension (ECE) with a negative surgical margin. The clinical factors tested included PSA level, biopsy Gleason score, and the 1992 AJCC clinical T-stage. PSA failure-free (bNED) survival was calculated according to the method of Kaplan and Meier. RESULTS: Significant negative predictors of pathologic OC-disease or positive predictors of M+ or SV+ disease included a PSA > 10 ng/ml (p<0.0001), biopsy Gleason score < or =7 (p< or =0.0004), and > or =T2b disease (p< or =0.03). Only biopsy Gleason score 7 (p = 0.0006) and PSA 10-15 ng/ml (p = 0.04) were significant predictors of SC disease. The estimates of 5-year bNED survival were 80%, 62%, and 35% (p<0.0001) for patients having a low, intermediate, or high likelihood of having M+ or SV+ disease respectively. CONCLUSIONS: Patients most likely to derive a survival benefit from the improved local control possible using dose escalation techniques were those who had both a low risk of having occult micrometastatic disease (<25% M+ or SV+) and a reasonable likelihood of remaining disease-free after RP (>50% 5-year bNED). These patients included those having T1c, 2a, PSA > 10-15 ng/ml, and biopsy Gleason < or =6 or T1c, 2a, 2b, PSA < or =10 ng/ml, and biopsy Gleason < or =7 prostate cancer.

Biopsy↗
PubMed1999

Toxicity of dolastatin 10 in mice, rats and dogs and its clinical relevance.

PURPOSE: Dolastatin 10 (DOL 10), an oligopeptide isolated from the sea hare Dolabella auricularia, has been shown to be a highly potent cytotoxic agent in a variety of human tumor cell lines. The purpose of this study was to conduct preclinical toxicity evaluations to determine the target organ(s) of toxicity and its reversibility, the dose-limiting toxicity and the maximum tolerated dose (MTD), and to use this information for arriving at a safe starting dose and dose schedule for phase I clinical trails. METHODS: DOL10 was administered as a single intravenous bolus dose to CD2F1 mice, Fischer-344 rats and beagle dogs. Endpoints evaluated included clinical observations, body weights, hematology, serum clinical chemistry, and microscopic pathology of tissues. RESULTS: The MTD (i. e. the highest dose that did not cause lethality but produced substantial toxicity) was approximately 1350 microg/m(2) body surface area (450 microg/kg) in mice, 450 microg/m(2) (75 microg/kg) in rats and </=400 microg/m(2) (</=20 microg/kg) in dogs. Adverse signs were observed at doses >/=1350 microg/m(2) in mice, >/=150 microg/m(2) in rats and >/=400 microg/m(2) in dogs. Decreased weight gain or actual weight loss was observed at doses >/=1350 microg/m(2) in mice, >/=600 microg/m(2) in rats and >/=450 microg/m(2) in dogs. In all three species, the primary target organ of toxicity was the bone marrow, as indicated by decreases in the numbers of erythroid cells, myeloid cells, and megakaryocytes in the femoral bone marrow and by decreased white blood cell (WBC) and reticulocyte counts in peripheral blood. Marked neutropenia (i.e. >50% decrease compared to control animal or baseline values) was the principal effect on WBCs and occurred within a week of dosing. A mild anemia was evident 1 week after administering the drug to rats and dogs. The hematologic effects were transient and reversed by study termination. Other lesions at the MTD levels were cellular depletion and necrosis in lymphoid organs (rats and dogs), marked depletion of extramedullary hematopoietic cellular elements in the spleen (rats), thymic atrophy (mice and dogs), and minimal cellular necrosis in the ileum (rats). More extensive and severe pathology was observed in animals sacrificed in a moribund condition or found dead. CONCLUSIONS: Myelotoxicity was dose-limiting in all three species with mice being the least sensitive. In a phase I clinical trial, granulocytopenia was dose-limiting. Moreover, the MTD of DOL10 for rats and dogs is comparable to the human MTD. Therefore, the results from the preclinical toxicology studies correctly predicted a safe starting dose, the dose-limiting toxicity, and the MTD in humans.

Anemia↗