Guy J. Petruzzelli

Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells

Human head and neck squamous cell carcinomas (HNSCC) that produce high levels of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) have been shown to contain CD34+ natural suppressor cells that inhibit the activity of intratumoral T‐cells. The present study evaluated whether GM‐CSF production and the presence of CD34+ cells within primary HNSCC would translate into increased recurrence, metastasis or cancer‐related death during the 2 years following surgical excision. Freshly excised primary HNSCC of 20 patients that subsequently developed disease, and of 17 patients that remained with no evidence of disease were analyzed for production of GM‐CSF and for CD34+ cell content. The cancers of patients that subsequently developed recurrences or metastatic disease produced almost 4‐fold the levels of GM‐CSF and had approximately 2.5‐fold the number of CD34+ cells as did cancers of patients that remained disease‐free. In a second method of analysis, the prognostic significance of high vs. low GM‐CSF and CD34+ cell values was evaluated. These analyses showed that patients whose cancers produced high GM‐CSF levels or had a high CD34+ cell content had a disproportionately high incidence of recurrence or metastatic disease (94% and 100%, respectively), while the majority of patients whose primary cancers produced low levels of GM‐CSF or had a low CD34+ cell content remained disease‐free (16% and 19%, respectively). Our results indicate that the presence of CD34+ cells in GM‐CSF‐producing HNSCC is associated with a poorer prognosis for the cancer patients and suggest the utility of these parameters as prognostic indicators of outcome. Mechanistically, our results suggest that the presence of immune suppressive CD34+ cells in GM‐CSF‐producing HNSCC leads to increased tumor recurrence or metastasis.Int. J. Cancer 74:69–74.

Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes

It has been established that the presence or absence of cervical node metastases in patients with head and neck squamous cell carcinoma (HNSCC) is a powerful prognostic indicator. This report reviews the evolution of thinking over the past 70 years with regard to the import and detection of cervical nodal metastases which exhibit spread of tumor beyond the confines of the original encompassing nodal capsule. In the process, this discussion touches upon clinical examination, gross and microscopic pathologic examination, and radiographic imaging studies. In particular, the distinction between gross nodal extracapsular spread of tumor and microscopic nodal extracapsular spread of tumor has been drawn in recent reports; this raises the possibility that identification of microscopic breaching of the nodc capsule by tumor might provide clinically significant information which is not provided by the gross observation of an intact lymph node capsule. While it remains to be seen whether microscopic extracapsular spread alone will prove to be an important prognostic factor, it is recommended that selective neck dissection continue to be offered even in those patients with clinically negative necks; further studies should aid in defining the import of microscopic extracapsular tumor spread in patients with positive cervical nodes.

Influence of MRI on target volume delineation and IMRT planning in nasopharyngeal carcinoma.

PURPOSE To compare CT and MRI target volumes for nasopharyngeal carcinoma (NPC) and evaluate the role of intensity-modulated radiotherapy (IMRT) in treating composite CT+MRI targets. METHODS AND MATERIALS CT and T(1)/T(2)-weighted MRI scans were obtained for 8 consecutive NPC patients. Using CT, MRI, and fused CT/MRI, various target volumes (gross target volume, clinical target volume, and planning target volume [PTV]) and critical structures were outlined. For each patient, three treatment plans were developed: (1) a three-dimensional conformal RT (3D-CRT) plan using CT-based targets; (2) a 3D-CRT plan using composite CT+MRI targets; and (3) a IMRT plan using CT+MRI targets. The prescription dose was 57.6 Gy and 70.2 Gy to the initial and boost PTV, respectively. Treatment plans were compared using the PTV dose to 95% volume (D(95)), critical structure dose to 5% organ volume (D(5)), and mean dose. RESULTS Compared with CT, the MRI-based targets were 74% larger, more irregularly shaped, and did not always include the CT targets. For CT-based targets, 3D-CRT plans, in general, achieved adequate target coverage and sparing of critical structures. However, when these plans were evaluated using CT+MRI targets, the average PTV D(95) was approximately 60 Gy (14% underdosing), and critical structure doses were significantly worse. The use of IMRT for CT+MRI targets resulted in marked improvement in the PTV coverage and critical structure sparing: average PTV D(95) improved to 69.3 Gy, brainstem D(5) to <43 Gy (19% reduction), spinal cord D(5) to <37 Gy (19% reduction), and the mean dose to the parotids and cochlea reduced to below tolerance (23.7 Gy and 35.6 Gy, respectively). CONCLUSION CT/MRI fusion improved the determination of target volumes in NPC. In contrast to 3D-CRT, IMRT planning resulted in significantly improved coverage of composite CT+MRI targets and sparing of critical structures.

Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34+ progenitor cells

CD34(+) progenitor cells have previously been shown to be mobilized in patients with squamous cell carcinoma of the head and neck (HNSCC). The present study showed that these CD34(+) cells inhibit the capacity of intratumoral lymphoid cells to become activated in response to stimulation through the TCR/CD3 complex. The mechanisms that could lead to the accumulation of CD34(+) cells within the tumor tissue were assessed. This was accomplished through in vitro studies that determined if HNSCC produce soluble factors that chemoattract CD34(+) cells. The migration of cord blood CD34(+) cells, which were used as a readily available source of progenitor cells, was stimulated by products derived from HNSCC explants and primary HNSCC cultures. This stimulated migration was due to chemotaxis because it was dependent on an increasing gradient of HNSCC-derived products. CD34(+) cells that were isolated from the peripheral blood of HNSCC patients were similarly chemoattracted to the HNSCC-derived products. The majority of the chemotactic activity produced by HNSCC could be attributed to vascular endothelial cell growth factor (VEGF). These studies indicate that HNSCC can chemoattract immune inhibitory CD34(+) progenitor cells through their production of VEGF.

Frontal Sinus Obliteration With Hydroxyapatite Cement

Objective To evaluate the efficacy hydroxyapatite cement as an alternative to autologous fat in the obliteration of the frontal sinus after trauma or chronic suppuration.

Modulation of Th1 and Th2 Cytokine Profiles and Their Association with Advanced Head and Neck Squamous Cell Carcinoma

OBJECTIVE: Plasma cytokine concentrations from patients with head and neck squamous cell carcinoma (HNSCC) were measured to determine whether the potential modulation of host Th1 vs Th2 immune responses are associated with advanced clinical disease. STUDY DESIGN AND SETTING: The concentrations of IL-4, IL-6, IL-10, and IL-12 were measured in the plasma of 58 patients with histologically proven HNSCC. These data were examined with respect to the histologic size (T-stage) of the primary tumor, and presence of nodal metastasis. RESULTS: The concentrations of IL-12 were greater from patients without nodal metastasis, and with T1/T2-stage tumors. IL-10 levels were greater from patients with nodal metastasis, and with T3/T4-stage tumors. The concentrations of IL-6 were greater from patients with T3/T4-stage tumors. CONCLUSIONS: Using parameters of primary tumor size and presence of nodal metastasis, patients with advanced HNSCC have significantly less plasma IL-12 levels, and greater plasma IL-10 and IL-6 levels. SIGNIFICANCE: Patients with advanced HNSCC have a potentially diminished Th1 immune response, and a stronger potential Th2 immune response when compared to that of patients with less advanced disease. EBM rating: D-5.

Angiogenesis induced by head and neck squamous cell carcinoma xenografts in the chick embryo chorioallantoic membrane model.

The angiogenic potential of head and neck tumors compared to nonneoplastic control tissues was investigated by using the chick embryo chorioallantoic membrane (CAM) as a bioassay for angiogenesis. Eighty tumor specimens from 10 patients with squamous cell carcinoma of the head and neck were grafted onto the CAM of 7-day chick embryos. The presence of tumor in the original explant was confirmed histologically. Forty-four embryos (55%) survived and were evaluated histologically at day 17. Tumors were growing on or invading the CAM mesoderm in 30 of 44 embryos (68%). Before harvesting of the membranes, the tumors and surrounding blood vessels were photographed, and the angiogenic responses were graded by a panel of blinded observers. Tumor explants elicited a significantly greater angiogenic response than nontumor controls (p = .01). We conclude that head and neck squamous cell carcinomas can induce an angiogenic response in vivo, presumably secondary to the production of an unidentified angiogenic factor, and that the chick embryo CAM is an effective model for quantifying angiogenesis induced by head and neck tumors.

Heparin‐binding growth factor(s) derived from head and neck squamous cell carcinomas induce endothelial cell proliferation

Tumor growth is dependent on the expansion and proliferation of the host vascular system into the primary neoplasm (angiogenesis). The development of an intact vascular system requires migration and proliferation of endothelial cells and assembly into microvessels. Previous studies in our laboratory demonstrated that head and neck squamous cell carcinomas (HNSCC) are angiogenic in vivo. To clarify the mechanism of HNSCC‐induced angiogenesis, the present study sought to determine if HNSCCs produced endothelial cell mitogens in vitro.

Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma

Two‐thirds of patients with squamous cell carcinomas of the head and neck (SCCHN) at diagnosis have advanced disease with projected 5‐year survival rates of 30%. In those patients with distant metastatic or previously treated recurrent disease, response rate to the standard regimen of cisplatin and 5‐fluorouracil is approximately 30%. The authors investigated the use of paclitaxel and carboplatin in a limited Phase II study in recurrent or metastatic SCCHN to evaluate tumor response, time to progression, survival, and toxicities of this regimen.

Recurrent Pleomorphic Adenoma of the Parotid Gland

OBJECTIVES: To assess the long-term results in the management of 42 patients with recurrent pleomorphic adenoma of the parotid gland. STUDY DESIGN: A retrospective analysis of 42 patients who underwent parotidectomy for recurrent pleomorphic adenoma was performed to study presenting clinicoradiographic features, surgical technique, facial nerve management, and the long-term risk of recurrence. RESULTS: All 42 patients had multi-focal, nontender recurrent nodules following one to four prior surgical procedures and 6 patients underwent prior radiotherapy. Surgical procedures included subtotal parotidectomy in 12 patients, total parotidectomy in 18 patients, parotidectomy with facial nerve resection in 7 cases, and subtotal petrosectomy with facial nerve resection in 5 individuals. The 2 patients with malignant transformation died of disseminated lung and bone metastasis. Twenty-nine of the remaining 40 patients had no recurrent disease. Seven patients developed local parotid bed or cutaneous recurrent disease, 2 patients died of unrelated causes, and 2 patients were lost to follow-up. CONCLUSIONS: All 7 patients with recurrent disease underwent subtotal parotidectomy with “negative” surgical margins. Total parotidectomy or subtotal petrosectomy with facial nerve resection in selected cases may reduce the risk of multiple episodes of pleomorphic adenoma recurrence. Two of 42 patients were found to have carcinoma ex-pleomorphic adenoma, both of these patients underwent prior radiotherapy, and both died of metastatic disease.