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Joseph Valentino

Publications and source records attributed to Joseph Valentino.

14 recordsLinked to original sources
PubMed2006

Cigarette smoke condensate and dioxin suppress culture shock induced senescence in normal human oral keratinocytes.

The aryl hydrocarbon receptor is a ligand activated transcription factor which regulates biological responses to a variety of environmental pollutants, such as dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and cigarette smoke. The purpose of this study was to determine whether cigarette smoke condensate (CSC) is capable of activating the AHR in normal human oral keratinocytes (NHOK) and inhibiting their ability to senesce. Towards this end, NHOK were isolated from human subjects and were cultured in the presence or absence of either TCDD or CSC. While neither TCDD nor CSC treatments altered the lifespan of NHOK in culture, both were capable of suppressing a culture induced premature senescence as indicated by their ability to decrease the mRNA and protein levels of the senescence markers p16(INK4a), p53 and p15(INK4b). A role of the AHR in mediating these events is indicated by the observations that the TCDD and CSC-induced decreases in p15(INK4b), p16(INK4a) and p53 expression was accompanied by a corresponding increase in the expression levels of the AHR target gene, CYP1A1. In addition, cotreatment with the AHR antagonist, 3'-methoxy-4'-nitroflavone (MNF) blocked the effects of TCDD and CSC on p53 and CYP1A1 expression. The findings of this study indicate that in NHOK, CSC is capable of altering a key cell fate decision, i.e., commitment to premature senescence, that is in part, dependent on the AHR. These results support the idea that progression of CSC-induced tumorigenesis may include an AHR-mediated inhibition of senescence that contributes to immortalization and agents that block the actions of the AHR may be effective components of novel cancer therapeutics.

Blotting, Western↗
PubMed2006

Identification of molecular targets for immunotherapy of patients with head and neck squamous cell carcinoma.

To identify molecular targets for immunotherapy of head and neck squamous cell carcinoma (HNSCC) patients, we analyzed gene expression profile in matched tumor (HN) and normal fibroblast (FB) cell lines established from a HNSCC patient using microarray technique followed by real-time RT-PCR. Screening against a series of established normal and malignant cell lines followed by screening against a panel of normal human tissues led to the identification of 7 genes (AREG, CDH3, KLK10, NmU, SLPI, ANAX3 and MAL2), which were over-expressed at least 10-fold in tumors over any of the normal tissues. We determined the expression of mRNA encoding these genes against a panel of 15 HNSCC primary tumor samples. Relative expression of these genes was at least 20-fold. Expression of AREG, CDH3, KLK10, NmU and SLPI at the protein level was determined by immunohistochemistry in seven supraglottic laryngeal cancer specimens. All five proteins were expressed in these tumor samples with high intensity. We conclude that these molecules are potential targets for immunotherapy of HNSCC patients.

Biomarkers, Tumor↗
PubMed2006

Analysis of unknown primary carcinomas metastatic to the neck: diagnosis, treatment, and outcomes.

Metastatic squamous cell carcinoma presenting in the neck from an unknown primary site represetns 2% to 6% of head and neck cancers. Optimal management of these cases remains controversial and continues to evolve with experience. We performed a retrospective analysis involving patients treated for unknown primary squamous cell carcinomas with metastases to cervical lymph nodes who presented to either the University of Kentucky or the Veterans Affairs Hospital of Lexington, Kentucky, from 1990 to 2000. Thirty-five out of 173 patients met inclusion criteria for carcinoma of unknown primary. The following data subsets were analyzed: age, gender, smoking and alcohol use, family history, diagnostic studies performed, radiation dose, surgical intervention, number and location of pathologic nodes, presence or absence of extracapsular extension, time between surgery and radiation, disease-specific and overall survival, response to treatment, emergence of a primary tumor, and duration of follow-up. Overall and disease-specific survivals were analyzed using, the Kaplan-Meier method and the log-rank test was used to assess differences in survival curves. The actuarial 5-year overall and disease-specific survival of all patients in this study was 54% and 63%, respectively. At 10 years, the overall survival declined to 37% with a disease-specific survival rate of 49%. The 5-year survival rates stratified by nodal stage were 80% for N1 patients, 64.7% for N2, 55.6% for N3, and 0% for any M disease. These rates declined to 60% for N1, 52.9% for N2, 11.1% for N3, and 0% for any M disease at 10 years (p<.0001). The presence of extracapsular spread, increased number of positive lymph nodes, and eventual discovery of a primary tumor did not significantly decrease survival in this series. The mean follow-up period for patients in this study was 54.8 months. We continue to refine our diagnostic and treatment strategies in this group of patients in an effort to improve long-term survival and reduce patient morbidity.

Carcinoma, Squamous Cell↗
PubMed2005

Long-term results of hyperfractionated radiation and high-dose intraarterial cisplatin for unresectable oropharyngeal carcinoma.

BACKGROUND: In this report, the authors present the results from a study of patients with unresectable oropharyngeal squamous cell carcinomas who were treated on a protocol of hyperfractionated radiation and high-dose intraarterial cisplatin (HYPERRADPLAT) at the University of Kentucky. METHODS: The study was designed as a prospective, single-armed case series that was conducted in the setting of a single, academic, tertiary referral center. The patient cohort consisted of 24 previously untreated patients who were diagnosed with unresectable oropharyngeal carcinoma and were treated on the HYPERRADPLAT regimen, which included hyperfractionated external beam radiotherapy (1.2 grays [Gy] twice daily) was given for 5 weeks (60 Gy) followed by high-dose intraarterial cisplatin (150 mg/m2) and sodium thiosulfate. Shrinking "large-field" portals were started on Week 6 and finished on Week 7 with a cumulative dose of 76.8-81.6 Gy. The main outcome measures of the study were the primary and neck response rates, the 2-year and 5-year overall survival and disease-specific survival rates, and acute and late treatment morbidity. RESULTS: The median follow-up was 77 months. Complete response rates at the primary and regional lymph nodes were both 88%. The 2-year overall survival and disease-specific survival rates were 57% and 68%, respectively; whereas the 5-year overall survival and disease-specific survival rates were 33% and 42%, respectively. Two patients had Grade 4 mucosal toxicity, and no patient experienced neurologic or significant hematologic toxicities. Within 1 year of treatment, 58% of patients had used a feeding tube. CONCLUSIONS: The HYPERRADPLAT regimen produced excellent response rates and overall survival rates comparable to those achieved by patients who had unresectable oropharyngeal carcinomas. Tolerance of the therapy was good, and further studies using HYPERRADPLAT with induction therapy may improve outcomes further in this subset of patients with unfavorable disease.

Adult↗
PubMed2005

The acetabular reamer: a unique tool for anterior iliac crest bone graft harvesting.

Bone grafting is often required in craniofacial reconstruction. Morselized corticocancellous bone grafts are particularly useful in applications such as filling and contouring irregular bony defects. Obtaining grafts of this consistency by traditional methods is difficult. An efficient harvesting method that can produce such grafting material in clinically useful quantities is needed. We report the use of a mechanical acetabular reamer for the purpose of harvesting a bone graft from the iliac crest.

Acetabulum↗
PubMed2004

Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm.

PURPOSE: Current therapies for locally advanced squamous cell carcinoma of the head and neck (SCCHN) result in 50% long-term remission. Low-dose radiotherapy (<100 cGy) induces enhanced cell killing in vitro via the hyper-radiation sensitivity phenomenon but has not been used in the clinical setting. On the basis of the demonstrated synergy between chemotherapy and low-dose fractionated RT, a novel neoadjuvant therapy was designed using low-dose fractionated RT as a chemopotentiator for locally advanced SCCHN. METHODS AND MATERIALS: Forty patients with locally advanced SCCHN received paclitaxel (225 mg/m2), carboplatin (area under the curve of 6), and four 80-cGy fractions of radiotherapy (two each on Days 1 and 2). This sequence was repeated on Days 22 and 23. RESULTS: Of the 40 patients enrolled, 39 were assessable. Grade 3 or worse toxicities included neutropenia (50%), infection (13%), arthralgias/myalgias (3%), skin (8%), lung (3%), and allergic reaction (3%), with no Grade 5 toxicity. The response was assessed radiographically and by panendoscopy. At the primary site, 11 patients (28%) had a complete response, 24 (62%) had a partial response, and 4 (10%) had stable disease. Of those with lymph node involvement, 10 (31%) had a complete response, 12 (38%) a partial response, 9 (28%) had stable disease, and 1 (3%) had progressive disease. The overall response rate was 82%. CONCLUSION: Low-dose fractionated RT combined with paclitaxel and carboplatin is effective in SCCHN and has a similar toxicity profile to chemotherapy alone. This novel approach provided a response rate of 90% at the primary site and a nodal response rate of 69%. Additional scientific investigation of this new treatment paradigm is warranted.

Adult↗
PubMed2004

Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck.

This study evaluated the combined effect of Low Dose Fractionated Radiation (LDFRT) and Taxotere (TXT) therapy on the growth of SCCHN (squamous cell carcinoma of head and neck; SQ-20B, a p53 mutant SCCHN cell line) tumors in a nude mouse model to exploit the increased hyper radiation sensitivity (HRS) phenomenon present in G(2)/M cell cycle phase when induced by low doses of radiation that was demonstrated in in vitro settings. Seventy-eight animals were randomized into one control group and 5 treatment groups (treatments were administered weekly for six weeks). Tumor regression was observed in all the groups, however, tumor regression was not significant in 2 Gy or TXT or 2 Gy plus TXT treated groups when compared to control group. The tumor regression was significant in both the LDFRT group (p < 0.0043) and LDFRT + TXT group (p < 0.0006) when compared to other groups. A significantly prolonged tumor growth delay was observed in LDFRT group (p < 0.0081). Importantly, in combination of TXT and LDFRT, no tumor regrowth was observed in 12 out of 13 mice since LDFRT + TXT treatment caused a sustained regression of tumors for 9 weeks. Molecular analysis of resected tumor specimens demonstrated that Bax levels were elevated with concomitant increase in cytochrome c release to the cytosol of the treatment Group VI. These findings strongly suggest that LDFRT can be used in combination with TXT to potentiate the effects of drug on tumor regression through an apoptotic mode of death. Furthermore, the G(2)/M cell cycle arrest by TXT appears to be an important component of the enhanced apoptotic effect of TXT + LDFRT combined treatment.

Animals↗
PubMed2004

Biomechanical evaluation of fixation techniques for bridging segmental mandibular defects.

OBJECTIVE: To compare biomechanical properties of currently available plating systems used to reconstruct segmental mandibular defects. DESIGN: Controlled in vitro investigation. SETTING: Academic medical center laboratory. INTERVENTIONS: Thirty-two polyurethane mandibles were equally divided among 4 groups: mandibles with a 4-cm lateral segmental defect that was bridged with a (1) 3.0-mm locking-screw reconstruction plate, (2) 2.4-mm low-profile reconstruction plate, or (3) 2.4-mm reconstruction plate and (4) uncut (control) mandibles. All plates were contoured and secured to the synthetic mandibles with 4 bicortical screws on either side of the defect. Three constructs from each group were subjected to contralateral-molar single-load-to-failure testing. Mean yield displacement, yield load, and bending stiffness were quantified and compared among the 4 groups. The single-load-to-failure data were used to establish conditions for fatigue testing; such testing was then performed on the remaining 5 samples in each group. Mean cycles to failure were measured and compared among the 4 groups. RESULTS: Mean yield displacement, yield load, and bending stiffness were comparable among the plated groups. Both the 3.0-mm locking-screw and 2.4-mm low-profile reconstruction plate designs withstood 1580 and 1124 times more cycles to failure, respectively (P = .005), than did the control group. The other reconstruction plate was also superior to the unplated controls, offering an 865-fold improvement. CONCLUSIONS: All 3 mandibular fixation device systems tested produce comparable levels of single load to failure biomechanical integrity; however, the higher-profile plating system design offered slightly superior fatigue performance. No differences in performance were observed between the locking and nonlocking designs; neither failed at the screw-substrate interface.

Biomechanical Phenomena↗
PubMed2003

Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines.

This study was designed to: (a) evaluate the induction of hyper-radiation sensitivity (HRS), a phenomenon observed at low doses of radiation (<1 Gy); (b) compare the potentiating effects of single dose radiation (2 Gy) versus the effect of low-dose fractionated radiation (LDFRT; <1 Gy) on Paclitaxel; and (c) understand the molecular mechanism of LDFRT-mediated chemo-potentiating effects, in wild-type p53 SCC-61 and p53 mutant SQ-20B head and neck squamous cell carcinoma cell lines. Both cell lines exhibited the HRS phenomenon at low radiation doses. Compared with SCC-61 cells, SQ-20B cells were resistant to radiation and Paclitaxel alone. A significant enhancement of radiation sensitization by Paclitaxel (0.5 or 1 nM) was observed in both cell lines. Chemo-potentiation of Paclitaxel by single 2-Gy radiation was observed in SCC-61 cells but not in SQ-20B cells. However, LDFRT (0.5 Gy in four fractions) significantly chemo-potentiated the effect of Paclitaxel in both cell lines. The cell cycle regulator p53 and its target genes p21(waf1/cip1) and BAX were induced in SCC-61 cells treated with 2 Gy, Paclitaxel, or in combination, but not in SQ-20B cells. These treatments elevated the antiapoptotic BCL-2 protein in SQ-20B cells but not in SCC-61 cells. Interestingly, LDFRT treatment in both cell lines with or without Paclitaxel down-regulated nuclear factor kappa B activity and BCL-2 protein expression and simultaneously up-regulated BAX protein. These findings strongly suggest that LDFRT (at these doses, HRS phenomenon is observed) can be used in combination with Paclitaxel to overcome the antiapoptotic effects of BCL-2 and nuclear factor kappa B.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Interval pathologic assessments in patients treated with concurrent hyperfractionated radiation and intraarterial cisplatin (HYPERRADPLAT).

BACKGROUND: To minimize surgical morbidity, surgery should be performed within 2 to 3 months of completion of radiation therapy with or without chemotherapy. Pathologic demonstration of cancer at this interval is commonly used to justify early surgical salvage of residual primary head and neck cancer. These assumptions regarding head and neck cancer in patients treated with concurrent hyperfractionated radiation therapy and intraarterial supradose cisplatin (HYPERRADPLAT) have never been evaluated. METHODS: Post-HYPERRADPLAT clinical and pathologic findings in 42 patients with stage III and IV head and neck cancer were compared with their disease outcomes. All patients underwent an interval analysis of response at 6 to 10 weeks after completion of therapy, 28 of these patients had biopsies of the primary tumor site performed. RESULTS: Clinical findings of cancer with pathologic confirmation up to 4 months after therapy can be associated with eventual complete response (CR). Pathologic CR's from deep incisional biopsies can be associated with recurrent disease within 2 months. Six HYPERRADPLAT-treated patients underwent interval surgical resection of primary disease, and only the four patients with cancer identified in the resection specimen died of recurrent disease. CONCLUSION: In patients treated with HYPERRADPLAT, interval clinical and pathologic assessments may be misleading. Only observation of progressive disease is an accurate predictor of local failure. New evaluation techniques such as metabolic imaging and molecular analysis warrant exploration as tools for interval cancer evaluations.

Antineoplastic Agents↗
PubMed2002

A phase II study of concomitant hyperfractionated radiation therapy and double dose intra-arterial cisplatin for squamous cell carcinoma of the head and neck.

This successor phase II study evaluates the tolerability and efficacy of concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In doing so, this study represents further resurgence of the potential use of IA chemotherapy in the management of SCCHN. This has been enabled by the evolution of angiographic catheter/microcatherter technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%) N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3 (79%) mucosal events; and single grade 3 hematologic, infectious and skin events. Eight patients (33%) were unable to receive the second planned dose of IA cisplatin. Twenty-two patients had complete response (92%) at the primary site. Among 17 patients with positive neck disease 12 (71%) achieved complete response in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14 patients alive without disease, 2 alive with disease, 7 dead of disease and 1 dead of intercurrent disease. While concomitant HFX-RT and double dose IA cisplatin as used in this study is associated with encouraging response rates in this highly unfavorable subset of patients with locally advanced SCCHN it was not feasible. Future investigation of this novel treatment strategy utilizing modern angiographic catheter/microcatherter technology will involve a single dose of IA cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.

Adult↗
PubMedDate not supplied

Carotid blowout with infection: management with endovascular and open vascular approaches--a case report.

The management of patients with head and neck cancer can be complicated by massive carotid artery hemorrhage, often requiring ligation owing to the emergent conditions and scarring from previous surgery and radiation. A case of emergent endovascular management of carotid artery hemorrhage in a patient treated for pharyngeal carcinoma is described. Hemorrhage was controlled, but on follow-up the patient developed a carotid-cutaneous fistula with exposure of the coils. Further management required the use of autogenous vein to replace the involved vessels. This case demonstrates that endovascular control of carotid hemorrhage can be successful, but close follow-up is necessary to identify potential subsequent complications.

Aged↗