Biomedical subjects

William G Hawkins

Publications and source records attributed to William G Hawkins.

12 recordsLinked to original sources

PubMed2026

Synthetic long peptide and DNA personalized cancer vaccines induce robust neoantigen-specific T cell responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to standard immunotherapies despite harboring cancer neoantigens capable of eliciting T cell responses. We completed two phase 1 clinical trials (NCT03956056 and NCT03122106) evaluating safety and immunogenicity of synthetic long peptide (SLP) and DNA personalized cancer vaccines (PCVs). PCVs were administered after resection and adjuvant chemotherapy. Tumor/normal whole-exome sequencing, RNA sequencing, and pVACtools were used to identify and prioritize candidate PCV neoantigens. PCVs were well tolerated without any grade ≥3 adverse events. Neoantigen-specific responses were demonstrated by interferon-γ enzyme-linked immunospot and intracellular cytokine staining. Expanded T cell receptor clonotypes were sequenced and transduced into autologous peripheral blood mononuclear cells to confirm neoantigen specificity. When compared with a contemporaneous institutional propensity-matched cohort, PCV patients demonstrated a trend toward prolonged median overall survival (4.4 versus 3.5 years, log-rank P = 0.23). Overall, PDAC PCVs are safe and feasible and elicit polyclonal T cell responses, linking prioritized cancer neoantigens to functional antitumor immunity.

Humans↗

PubMed2007

TAT-Bim induces extensive apoptosis in cancer cells.

BACKGROUND: Suppression of apoptosis is central to the development of cancer and is associated with resistance to modern adjuvant treatments. Therefore, molecules and pathways of apoptotic processes are critical targets for the development of anti-cancer therapeutics. Since apoptosis is executed by intracellular proteins, molecular approaches must incorporate a method to deliver the treatment into the tumor cells. METHODS: We utilized a peptide that contains two domains, a peptide transduction domain derived from the HIV-1 TAT protein and a biological effector domain, the BH3 domain from the pro-apoptotic Bcl-2 family member Bim. We examined whether this construct (TAT-Bim) induced apoptosis in several cancer cell lines (T-cell lymphoma (EL4), pancreatic cancer (Panc-02), and melanoma (B16)) and whether TAT-Bim treatment synergized with radiation. A mutant TAT-Bim peptide with no biologic activity (TAT-Bim-inactive) was used as a control. C57/BL6 mice were challenged with syngeneic cancer cell lines and the effects of intratumoral TAT-Bim injection on tumor growth and host survival were determined. RESULTS: TAT-Bim was internalized by all cancer cells within two hours. TAT-Bim resulted in apoptosis in a dose dependent fashion in all cell lines and sublethal irradiation augmented the effects of TAT-Bim induced apoptosis. TAT-Bim significantly slowed tumor growth in murine models of pancreatic cancer and melanoma. CONCLUSION: TAT-Bim exemplifies a strategy for cancer therapy that involves inducing apoptosis by antagonizing the endogenous anti-apoptotic machinery. Small peptide therapeutics, in combination with traditional adjuvant therapies such as radiation, may provide a valuable 'second hit' and drive tumor cells into programmed cell death.

Animals↗

PubMed2005

Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare variant characterized by the presence of fusiform melanocytes in a sclerotic stroma. Pathologic heterogeneity within DM may account for the controversy regarding the clinical presentation and prognosis of DM compared with conventional melanoma (CM). METHODS: We identified 131 patients with a diagnosis of DM seen between 1979 and 2002. Tumors were categorized as either pure DM (pDM; n = 92), if desmoplasia was prominent throughout the entire invasive tumor, or mixed DM (mDM; n = 39), if fibrosis was well developed in only parts of an otherwise non-DM. Differences in clinical behavior among pDM, mDM, and CM (n = 3976) were examined. RESULTS: Seventy-three percent of patients with DM had tumors >2 mm in depth, compared with 31% of patients with CM (P < .001). Regional nodal metastasis was uncommon in patients who presented with clinically localized pDM (1%) compared with those with mDM (10%) or CM (6%) (P < .05, pDM vs. CM). Five-year melanoma-specific mortality was lower for patients who presented with pDM compared with mDM (11% vs. 31%; P < .01). Patients with pDM and CM had a similar melanoma-specific mortality despite a 3-fold difference in median tumor depth (3.6 vs. 1.2 mm, respectively). CONCLUSIONS: DMs can be divided into two subtypes based on a histological quantification of desmoplasia. Tumors with prominent fibrosis (pure subtype) are unlikely to disseminate to regional lymph nodes and are associated with a favorable outcome when compared with those with mixed desmoplasia or CM.

Female↗

PubMed2005

Caudate hepatectomy for cancer: a single institution experience with 150 patients.

BACKGROUND: Resection of the caudate lobe of the liver is technically demanding, with the disparate goals of preserving major vascular and biliary structures without compromising tumor clearance. Our objective was to assess our results with resection of the caudate lobe of the liver for malignant disease. STUDY DESIGN: From 1992 to 2004, we performed caudate resection for malignancy in 150 patients. Clinicopathologic correlates, surgical methods, patterns of recurrence, and survival were analyzed. RESULTS: Of the 150 patients identified, 21 (14%) underwent an isolated caudate lobe resection and 129 (86%) underwent caudate lobe resection as part of a more extensive hepatectomy. The most common indication was for metastatic colorectal cancer (48%), followed by cholangiocarcinoma (30%) and hepatocellular cancer (10%). Thirty patients required resection and reconstruction of the portal vein (n = 16), vena cava (n = 15), or both. Pathologic microscopic margins were positive in 30 patients (20%). At least one postoperative complication was reported in the majority of patients (55%), and nine patients (6%) died as a result of these complications. Postoperative mortality was significantly higher in patients who underwent a major vascular reconstruction (20% versus 2.5%, p < 0.002). Median survivals for patients with colorectal metastasis, cholangiocarcinoma, and hepatocellular carcinoma were 37, 28, and 32 months, respectively. CONCLUSIONS: Performing caudate hepatectomy with negative microscopic margins remains a technical challenge because of the proximity of major biliary and vascular structures. Although caudate resection of the liver can be performed safely, concomitant major vascular reconstruction substantially increases the mortality of the procedure.

Adolescent↗

PubMed2005

Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases.

BACKGROUND: The objective was to evaluate the effect of preoperative administration of newer chemotherapeutic agents (irinotecan and oxaliplatin) on development of steatohepatitis, which could limit surgical options. STUDY DESIGN: Thirty-seven patients were referred for resection of hepatic colorectal metastases. Thirteen patients received no neoadjuvant therapy (NO CHEMO group); 10 received neoadjuvant 5-fluorouracil only (5-FU group), and 14 received neoadjuvant irinotecan (n = 12), or oxaliplatin, or both (n = 4), in conjunction with 5-FU (IRI-OXALI group). Specimens were graded for the presence of nonalcoholic steatohepatitis (NASH) according to established criteria. Specimens were also evaluated by a nine-criteria liver injury score (LIS). RESULTS: Mean biopsy scores were: NO CHEMO: NASH, 1.2, LIS, 5.2; 5-FU only: NASH, 1.1, LIS 5.7; and IRI-OXALI: NASH, 1.9, LIS, 9.4. Biopsy scores were significantly worse for IRI-OXALI compared with NO CHEMO or 5-FU only for NASH score, p = 0.003, and close to significantly worse for LIS score, p = 0.057. A multivariate analysis showed that both being in the IRI-OXALI group and body mass index were independent risk factors for developing this type of steatohepatitis. CONCLUSIONS: Severe steatohepatitis can be associated with preoperative administration of irinotecan or oxaliplatin, especially in the obese. It can affect the ability to perform large liver resections. Consideration should be given to performing resections before commencing these agents and to obtaining preoperative biopsy in those who have received these agents.

Aged↗

PubMed2005

Hepatic follicular dendritic cell sarcoma without Epstein-Barr virus expression.

Follicular dendritic cell sarcoma of the liver is an uncommon pathologic entity, and only 5 cases have been reported previously. Herein, we report the first case, to our knowledge, of hepatic follicular dendritic cell sarcoma without evidence of Epstein-Barr virus infection. The patient is an elderly man who was found to have an incidental liver mass and then developed weight loss and fever. The diagnosis was based on the typical morphologic appearance of spindle cell proliferation associated with a brisk lymphoplasmacytic infiltrate and strong immunoreactivity to CD21 and CD35. Based on our experience and a review of the published reports, we summarize the clinical and pathologic features of hepatic follicular dendritic cell sarcoma and its surgical management.

Aged, 80 and over↗

PubMed2004

Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors.

Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM). We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1-4, >4 mitoses/mm; P = 0.01), and tumor thickness (<1 mm, 1-4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis. Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.

Adolescent↗

PubMed2004

Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer.

BACKGROUND: In patients with gallbladder cancer, jaundice suggests tumor involvement of the porta hepatis. This study reports on the prevalence, etiology, and clinical significance of jaundice in patients with gallbladder cancer. METHODS: Patients who presented with gallbladder cancer from 1995 to 2002 were entered into a prospective database. Disease-specific survival and clinicopathologic correlates were analyzed. RESULTS: Eighty-two (34%) of 240 patients with gallbladder cancer presented with jaundice. Jaundiced patients (96%) were more likely (P <.001) to have advanced-stage disease than nonjaundiced patients (60%). Only six (7%) jaundiced patients were resected with curative intent, and only four (5%) had negative surgical margins. This was significantly different from the nonjaundiced group, in which 62 patients (39%) had negative margins (P <.001). The median disease-specific survival in patients presenting with jaundice was 6 months and was significantly lower compared with 16 months in patients without jaundice (P <.0001). In the group presenting with jaundice, there were no disease-free survivors at 2 years, compared with 21% in the group without jaundice. CONCLUSIONS: Jaundice is common (34%) in patients who present with gallbladder cancer and is an indicator of advanced malignancy. These data do not support routine operative exploration of patients with jaundice secondary to gallbladder cancer.

Adult↗

PubMed2003

A single heteroclitic epitope determines cancer immunity after xenogeneic DNA immunization against a tumor differentiation antigen.

Successful active immunization against cancer requires induction of immunity against self or mutated self Ags. However, immunization against self Ags is difficult. Xenogeneic immunization with orthologous Ags induces cancer immunity. The present study evaluated the basis for immunity induced by active immunization against a melanoma differentiation Ag, gp100. Tumor rejection of melanoma was assessed after immunization with human gp100 (hgp100) DNA compared with mouse gp100 (mgp100). C57BL/6 mice immunized with xenogeneic full-length hgp100 DNA were protected against syngeneic melanoma challenge. In contrast, mice immunized with hgp100 DNA and given i.p. tolerizing doses of the hgp100 D(b)-restricted peptide, hgp100(25-33), were incapable of rejecting tumors. Furthermore, mice immunized with DNA constructs of hgp100 in which the hgp100(25-27) epitope was substituted with the weaker D(b)-binding epitope from mgp100 (mgp100(25-27)) or a mutated epitope unable to bind D(b) did not reject B16 melanoma. Mice immunized with a minigene construct of hgp100(25-33) rejected B16 melanoma, whereas mice immunized with the mgp100(25-33) minigene did not develop protective tumor immunity. In this model of xenogeneic DNA immunization, the presence of an hgp100 heteroclitic epitope with a higher affinity for MHC created by three amino acid (25 to 27) substitutions at predicted minor anchor residues was necessary and sufficient to induce protective tumor immunity in H-2(b) mice with melanoma.

Amino Acid Sequence↗

PubMed2003

The role of lipopolysaccharide in T-cell responses following DNA vaccination.

Bacterial products, including lipopolysaccharide (LPS), are potential impurities in plasmid DNA vaccines. LPS has immunostimulatory properties even at exceedingly low concentrations through activation of Toll-like receptor 4 (TLR4). The potency of T-cell responses after vaccination was tested with DNA containing high LPS or depleted of LPS in TLR4-competent and TLR4-deficient mice. CD8(+) T-cell responses were readily induced in TLR4-deficient mice immunized with DNA depleted of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses.

Animals↗

PubMed2002

Xenogeneic DNA immunization in melanoma models for minimal residual disease.

INTRODUCTION: DNA immunization with xenogeneic genes encoding homologous antigens protects mice against tumor challenge with syngeneic melanoma in a lung metastasis model. The effect of xenogeneic human TRP-2 (hTRP2) DNA immunization on disease confined to an orthotopic site, the skin, and in a model of minimal residual disease that is relevant to a setting of adjuvant therapy for micrometastatic cancer is reported. METHODS: Immunization and tumor challenge with B16F10LM3 melanoma were performed in C57BL/6 mice and in mice genetically deficient in MHC class I or II molecules. A melanoma variant of B16 with a predilection for lung metastasis was selected and used to challenge C57BL/6 mice. Tumor challenge in the footpad with the B16 variant was followed by local tumor growth and lung metastasis. The tumor-bearing distal extremities were surgically resected and mice were randomized to receive hTRP2 DNA immunization or no treatment. Approximately 3-5 weeks after surgical resection, lungs were harvested and metastases counted. RESULTS: Xenogeneic DNA immunization with hTRP2 prevented tumor growth in the skin by a mechanism requiring CD4(+) and CD8(+) T cells but did not inhibit the growth of established tumors. Adjuvant immunization with hTRP2 DNA after resection significantly reduced lung metastases and decreased local recurrence rates after surgical resection. CONCLUSIONS: Xenogeneic DNA immunization with hTRP2 was effective in protecting mice from intradermal tumor challenge. Immunization prevented local recurrence and the development of metastases in a mouse model of minimal residual disease, supporting a role for DNA immunization against melanosomal antigens as an adjuvant to surgery in high-risk primary melanomas.

Animals↗

PubMed2002

Image reconstruction algorithm for a rotating slat collimator.

A slat collimator in single photon emission computed tomography consists of a set of parallel slats. As the collimator spins, the detector measures a one-dimensional projection data set. A complete data set can be obtained by rotating the detector/collimator assembly around the object (patient) while the collimator spins continuously. The measured projection data are assumed to be weighted planar integrals of the object. This paper describes the development of an approximate three-dimensional image reconstruction algorithm for a rotating/spinning slat collimator. This algorithm is in filtered backprojection form. Computer simulations were performed to verify the effectiveness of the algorithm.

Algorithms↗