Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer

The antitumor activity of IFN-alpha is well established. However, the role of the plasmacytoid dendritic cell (PDC), the major producer of IFN-alpha upon viral infection, in tumor biology is unknown. We sought to study the presence and function of PDC in a human solid tumor. Here, we demonstrate that PDCs infiltrate tumor tissue of patients with head and neck squamous cell carcinoma (HNSCC). Functional activity of PDC was examined by using CpG motif containing oligonucleotides, a defined microbial stimulus for PDCs (recognized via toll-like receptor 9). We found that HNSCC diminished the ability of PDC to produce IFN-alpha in response to CpG motif containing oligonucleotide. Tumor-induced down-regulation of toll-like receptor 9 was identified as one mechanism likely contributing to impaired PDC function within the tumor environment. In tumor-draining lymph nodes, suppression of CpG-induced IFN-alpha production was less pronounced than in single-cell suspensions of primary tumor tissue. In these lymph nodes, CpG-induced IFN-alpha production was associated with increased levels of interferon-induced protein 10 and IFN-gamma and activation of CD4 and CD8 T cells. These results show for the first time the presence of PDCs in human solid tumor tissue and that tumors suppress the capacity of PDCs to produce IFN-alpha. PDCs, which in the absence of appropriate stimulation are reported to promote regulatory CD8 T cells, may contribute to an impaired T-cell-mediated immune response in HNSCC.     

Spontaneous ex vivo apoptosis of peripheral blood mononuclear cells in patients with head and neck cancer.

Proportions of apoptotic (TUNEL+) peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry in patients with head and neck cancer and normal controls at the time of blood draws (0 time) and after 24-h incubation. PBMCs were incubated at 37 degrees C in medium (spontaneous apoptosis) and in the presence of CH-11 antibody (anti-Fas) or tumor necrosis factor (TNF)-alpha, both capable of inducing DNA fragmentation in activated T cells expressing the TNF family of receptors. PBMCs obtained from the patients had significantly higher (P < 0.0001) proportion of apoptotic cells than PBMCs of controls at 0 time as well as after 24-h incubation. Ex vivo apoptosis included all subsets of PBMCs: CD3+ T cells, CD16+ CD56+ natural killer cells, CD19+ B cells, and CD14+ monocytes, as determined by two-color flow cytometry. However, T cells represented the largest PBMC subset undergoing apoptosis, and lymphocytes rather than monocytes were the major TUNEL+ PBMC population. Among T cells, the level of spontaneous ex vivo apoptosis was nearly as high as that of CH-11 antibody-induced or TNF-alpha-induced apoptosis, indicating that activated Fas+ and TNFR1+ T cells were preprogrammed in vivo to die. Also, elevated levels of spontaneous apoptosis at time 0 in patients with head and neck cancer (P < 0.0001) indicated that a higher fraction of PBMCs was undergoing apoptosis in vivo in patients than controls. Together, the data suggest that an increased rate of turnover of lymphocytes is associated with cancer and may be responsible for functional lymphocyte imbalance, even in treated patients who have no evident disease.     

Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus, and lung

Squamous cell carcinoma of the head and neck is complicated by a second primary carcinoma of the head and neck, esophagus (the upper aerodigestive tract, or UADT), or lung in 10-40% of patients. Routine panendoscopy will identify a simultaneous second primary in 9-14% of the patients. Metachronous second cancers most often involve the esophagus or lung, whereas synchronous second cancers are more common in the head and neck as occult lesions. For the highest-risk subgroups, second primary cancers occur in 4% of patients per year. In cancer of the floor of the mouth the excess mortality rate is 5-6% per year. Risk is independent of stage of the first primary and the survival impact is the greatest in groups of patients with early-stage disease. Head and neck cancer almost always results from the heavy use of tobacco for many years, either with or without the concomitant heavy use of alcohol, and these same agents are directly responsible for the second cancers of the UADT and lung. All head and neck cancer patients should be advised to avoid these agents. The clinician must diagnose and treat second cancers to extend the survival of patients with a good prognosis for control of the initial head and neck cancer. We need further progress in eliminating the use of known carcinogens in these patients, paradigms for cost-effective diagnosis and treatment of second primary cancers, effective treatment of the head and neck primary cancer devoid of long-lasting tissue toxicities, effective chemopreventive agents to retard established processes of carcinogenesis that place the patient at continued risk after cigarette and alcohol use has been eliminated, and continued efforts to control the medical illnesses to which these patients are susceptible.     

Perivascular stem cell niche in head and neck cancer

Cancers may contain a small sub-population of uniquely tumorigenic cells that exhibit self-renewal and multipotency, i.e. cancer stem cells (CSCs). These cells reside in invasive fronts in close proximity to blood vessels in many tumors, including head and neck squamous cell carcinomas (HNSCCs). Recent evidence suggests that CSC resist chemotherapy and “drive” local recurrence and metastatic spread. Notably, endothelial cell-initiated signaling is critical for the survival and self-renewal of CSC and may play a role in resistance to therapy. Therefore, patients with head and neck cancer might benefit from therapies that target the CSC directly or their supportive perivascular niche.     

Indomethacin sensitive suppressor-cell activity in head and neck cancer patients. The role of the adherent mononuclear cell

Head and neck cancer (H&N CA) patients have known depression of cell-mediated immunity. There is suggestive evidence that prostaglandin (PGE2)-secreting cells may be a major factor. The authors have sought to determine the role of PGE2-releasing monocytes-macrophages in this immune depression by determining the effects of adherent cell depletion and by measuring the effects of indomethacin, a PGE2 synthetase inhibitor, on selected tests of lymphocyte function. Lymphocyte stimulation with phytohemagglutinin (PHA) (T-cell stimulant) and Staph phage lysate (SPL) (B-cell stimulant) was done in the presence of varying concentrations of indomethacin; the effect of adherent cell depletion also was determined. The study population included 45 patients with localized or locoregional squamous CA of the H&N and 40 controls. Results included the following: (1) lymphocyte stimulation responses to PHA and SPL were generally depressed in the CA patients versus controls; (2) incubation with indomethacin produced bivalent effects in both controls and CA patients, depending on the concentration of indomethacin and lymphocyte stimulant; incubation with optimum concentrations of indomethacin generally produced augmented responses in both study groups whereas high concentrations of indomethacin were suppressive; (3) the immune potentiating effects were not observed in older patients with advanced disease; and (4) removal of adherent leukocytes (mainly monocytes) also restored depressed lymphocyte responses. Although other factors also are operative, our data suggest that PGE2-secreting monocytes-macrophages may have a major role in the immune depression of H&N CA patients. Age and host effects of the cancer and the malnutrition common to these patients probably are involved also, although their singular contribution has not been measured. This depression is largely reversible by a PGE2 synthesis inhibitor, indomethacin, which suggests the potential value of in vivo administration of indomethacin to H&N CA patients as an adjunct.     

Oxaliplatin activity in head and neck cancer cell lines

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N] [oxalato(2-)-O,O] platinum; Eloxatin) is a third-generation platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand, which has a wide spectrum of anticancer activity in vitro systems and has displayed preclinical and clinical activity in a wide variety of tumors. To investigate its in vitro activity against head and neck cancer, we exposed two head and neck cancer cell lines to the compound, created a variant resistant to cisplatin to study cross-resistance to the compound and analyzed the potential radiosensitizing effect of the drug. We report here that oxaliplatin was cytotoxic at similar doses to cisplatin in these cells. There was no cross-resistance to cisplatin, as demonstrated by different IC₅₀ values in these cell lines and the sensitivity to oxaliplatin of the cisplatin-resistant cell line. There was an effective radiosensitizer effect of the compound in either cell line. Additional in vitro and in vivo experimentation is warranted in order to support the use of oxaliplatin as a radiosensitizer in head and neck cancer patients.Magali Espinosa and Moises Martinez contributed equally to this paper.     

Progression of head and neck squamous cell cancer

Squamous cell cancer in the head and neck region (HNSC) is unique concerning its progression since it remains locoregional for long time and visceral metastases develop only in a later stage of the disease. Accordingly, molecular markers of the local invasion and the lymphatic dissemination both have critical importance. HNSC progression is associated with deregulated control of cell proliferation and apoptosis but it seems equally significant the disregulation of the proteolytic machineries. Here we outline the lymphatic metastatic cascade for HNSC to depict key molecular determinants as possible prognostic factors or therapeutic targets identifying immunological selection as a major feature. Unlike in local spreading, invasive potential of cancer cells seems to be less significant during lymphatic dissemination due to the anatomical properties of the lymphatic vessels and tissues. There is a general believe that HNSC is one disease however, data indicate that the anatomical localization of the tumor (the soil) such as oral, lingual, glottic or pharyngeal has a significant effect on the gene expression profile and corresponding biological behavior of HNSC. Furthermore, even the endocrine milieu of the host was proved to be influential in modulating the progression of HNSC. Gene expression profiling techniques combined with proteomics could help to define and select usefull genetic and biomarkers of progression of HNSC, some of them could well be potential novel therapeutic target.     

Tumor cell invasion and survival in head and neck cancer

Squamous cell carcinoma (SCC) is the primary tumor type in head and neck cancer. Typically, these tumor cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. The process of invasion involves concurrent infiltration and destruction of adjacent tissues. As with normal mucosal epithelium, SCC cells express receptors that mediate cell-extracellular matrix (ECM) adhesion (integrins) and cell-cell adhesion (cadherins). Both receptor families represent important signaling devices that are capable of promoting survival and proliferation. Recent results indicate that integrins and cadherins cooperate to regulate invasive behavior. During SCC invasion, cells actively migrate through the surrounding ECM with the simultaneous remodeling of their intercellular adhesions. During invasion, integrin receptor engagement with specific ECM ligands along with concurrent remodeling of cadherin adhesions induces changes in the cytoskeleton though modulation of the activities of Rho family members. Tumor development and progression of SCC proceeds with the generation of variant cells with potential alterations in expression of adhesion receptors, and their associated signaling pathways lead to a highly invasive and metastatic phenotype. Understanding the molecular events that define this subset of invasive cells will facilitate the development of new treatment strategies.     

Involuntary smoking and head and neck cancer risk: pooled analysis in the international head and neck cancer epidemiology consortium

Although active tobacco smoking has been identified as a major risk factor for head and neck cancer, involuntary smoking has not been adequately evaluated because of the relatively low statistical power in previous studies. We took advantage of data pooled in the International Head and Neck Cancer Epidemiology Consortium to evaluate the role of involuntary smoking in head and neck carcinogenesis. Involuntary smoking exposure data were pooled across six case-control studies in Central Europe, Latin America, and the United States. Adjusted odds ratios (OR) and 95% confidence interval (95% CI) were estimated for 542 cases and 2,197 controls who reported never using tobacco, and the heterogeneity among the study-specific ORs was assessed. In addition, stratified analyses were done by subsite. No effect of ever involuntary smoking exposure either at home or at work was observed for head and neck cancer overall. However, long duration of involuntary smoking exposure at home and at work was associated with an increased risk (OR for >15 years at home, 1.60; 95% CI, 1.12-2.28; P(trend) < 0.01; OR for >15 years at work, 1.55; 95% CI, 1.04-2.30; P(trend) = 0.13). The effect of duration of involuntary smoking exposure at home was stronger for pharyngeal and laryngeal cancers than for other subsites. An association between involuntary smoking exposure and the risk of head and neck cancer, particularly pharyngeal and laryngeal cancers, was observed for long duration of exposure. These results are consistent with those for active smoking and suggest that elimination of involuntary smoking exposure might reduce head and neck cancer risk among never smokers.     

头颈部鳞癌的术后放疗

头颈部鳞癌术后放疗的临床研究表明术后病理检查结果可作为术后放疗的主要依据；术后放疗与手术的时间间隔是否影响肿瘤的局部控制没有明确证据，但根据放射生物学理论，术后放疗仍宜尽早进行，尤其是具有高危因素的患者；术后放化疗的综合治疗推荐采用同步放化疗，可提高局部控制率、总的生存率和无病生存率，尽管同步放化疗明显增加了急性毒副反应，但远期损伤没有增加，包括第二原发肿瘤：调强收疗（IMRT）和靶向治疗如单克隆抗体C225在头颈部肿瘤术后治疗中的地位和作用有待研究。     

Peripheral blood stem cell autografts in pediatric cancer

Harvest of peripheral blood stem cells (PBSC) for autografts is a safe, reliable procedure with low morbidity in children with cancer, and cryopreserved PBSC are useful in reducing cytopenia following marrow-ablative chemotherapy. The colony forming unit granulocyte/macrophage (CFU-GM) content of the thawed grafts is an important determinant of hematopoietic recovery after PBSC autografts. The possible value of high-dose chemotherapy without total body irradiation and PBSCT compared to intensified chemotherapy in the treatment of children with very high-risk lymphoid malignant disorders was reported.     

Comparison of cervical esophagus dose-volumes for three radiotherapy techniques for head and neck cancer

PURPOSE: This study compares the radiation dose-volume of the cervical esophagus during head and neck radiotherapy using three different techniques. METHODS: Treatment plans of 58 patients from 3/04 to 1/06 treated with bilateral head and neck radiotherapy were analyzed retrospectively. A comparison of the cervical esophagus dose with three-field 3D conformal RT (3DRT, n=34), whole-field IMRT (WF-IMRT, n=12), and half-beam IMRT (HB-IMRT, n=12) was performed. The volumes of esophagus receiving > or =50Gy (V50), > or =54Gy (V54) and > or = 60Gy (V60) and lengths receiving circumferential dose > or = 50Gy (L50) and > or = 54Gy (L54) were evaluated. RESULTS: Maximum dose, V54 and L54 were greater for the first 2cm and entire cervical esophagus with WF-IMRT than HB-IMRT or 3DRT. In patients requiring a high match, WF-IMRT was associated with a greater maximum dose, V54 and L54 than HB-IMRT and 3DRT (p<0.05). In the low match group, WF-IMRT was associated with a greater V54 and L54 (p<0.05). Low neck disease, low primary site, and definitive radiotherapy were associated with increased irradiation of the esophagus. CONCLUSION: Treatment of the lower neck with IMRT is associated with increased irradiation to the cervical esophagus, and dose constraints should be included to reduce toxicity.     

Peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity in volunteers with and without diabetes mellitus

 It has been reported that cancer patients with diabetes mellitus receiving a continuous infusion of 5-fluorouracil (5-FU) have more toxicity and higher plasma 5-FU levels than patients without diabetes mellitus. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU plasma levels in patients. We therefore undertook a study to compare the activity of DPD in peripheral blood mononuclear cells of human subjects with and without diabetes mellitus. The study groups comprised 43 volunteers with and 39 without diabetes mellitus, and peripheral blood mononuclear cell DPD activity was assayed on samples obtained between 8 a.m. and 11 a.m. DPD activity was not decreased in diabetic subjects. There was no relationship between DPD activity and gender, body mass index, or race. There was a modest correlation between DPD activity and age (r=0.19, P=0.08). We conclude that increases in 5-FU-related toxicities in diabetics must be related to factors other than peripheral blood mononuclear cell DPD activity. Received: 24 March 1995/Accepted: 21 July 1995     

Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region

While multiple squamous cell carcinomas are often observed in the esophagus and the head and neck region and confound us about the favorable treatments, the reason why some patients are more likely to develop multiple cancers remains obscure. We statistically analyzed clinical factors in 203 patients with newly diagnosed squamous cell carcinoma, to assess the risk of multiple cancers for the establishment of an effective prevention and screening programs. Widespread epithelial oncogenic alterations were assessed as multiple lugol-voiding lesions (multiple LVL) using lugol chromoendoscopy. Genetic polymorphisms of alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2) were identified by PCR-restriction fragment length polymorphism analysis. Forty patients had synchronous multiple cancers and the remaining 163 had solitary cancer. Presence of multiple LVL was the only independent risk factor for multiple cancers [relative risk (RR) = 67; 95%CI, 15-310]. Multiple LVL was observed in only smoking drinkers. Among them, a multivariate analysis demonstrated that the ALDH2 deficiency allele (RR = 5.7; 95%CI, 2.8-11.6) and the slow metabolizing ADH3 allele (RR = 1.9; 95%CI, 1.1-7.9) were the independent risk factors for multiple LVL. Combination of these alleles lead to increase the risk of multiple LVL. In conclusion, an episode of multiple LVL is a remarkable high risk for multiple cancers both at the esophagus and the head and neck region. The interaction between drinking and the ALDH2 deficiency allele increases the risk. In addition, the slow metabolizing ADH3 allele enhances the risk. Prohibiting the use of alcohol and early detection of cancer are strongly recommended for such individuals.     

Radiotherapy or surgery for head and neck squamous cell cancer

BACKGROUND:

The authors compared the survival outcomes of radiotherapy +/? salvage surgery to surgery +/? postoperative radiotherapy for patients with squamous cell cancer of the hypopharynx. There was no evidence beyond observational studies and no consensus on the which treatment is most effective for this patient group.

METHODS:

The authors conducted a retrospective population‐based study of 595 patients from Ontario Canada diagnosed between January 1, 1990 and December 31, 1999. Three different methodological approaches were used for the survival analysis including a restricted cohort study, a matched case‐control study, and a natural experiment study across defined geographic regions.

RESULTS:

The authors found no survival advantage for either radiotherapy +/? salvage surgery or surgery +/? postoperative radiotherapy.

CONCLUSIONS:

This study set the baseline for clinical decisions that was not previously established there is no difference in survival for patients with hypopharynx comparing primary surgery to primary radiotherapy. This information is essential for the interpretation of current treatment results, the planning of future clinical studies and the treatment of patients who are not having chemoradiotherapy. Cancer 2009. © 2009 American Cancer Society.     

Imaging in head and neck cancer

Opinion statement The goals of imaging in head and neck cancer are to establish tumor extent and size, to assess nodal disease, to evaluate for perineural tumor spread, and to distinguish recurrent tumor from post-treatment changes. MRI is the preferred modality for assessment of nasopharyngeal, sinonasal, and parotid tumors, because of better contrast resolution, high frequency of perineural spread, and less prominent motion artifacts. MRI is the best modality to delineate the extent of intraorbital and intracranial extension of malignant tumors. Tumors of the oropharynx, larynx, and hypopharynx are frequently primarily imaged with CT, which is less affected by breathing and swallowing artifacts. MRI is also the initial study of choice for tumors confined to the oral tongue, and possibly also for other oral cavity locations because MRI is superior in detection of tumor spread into the bone marrow. There is no clear advantage of CT or MRI for evaluation of nodal disease. Positron emission tomography (PET) is very sensitive for metastatic lymph nodes that are at least 8 mm in size and is the technique of choice in dubious cases. Imaging-guided biopsies are performed whenever needed. For imaging of treated head and neck cancer, PET scans have been found to generally offer higher sensitivity than MRI or CT. Combined PET/CT may be the modality of choice because it almost completely eliminates the false-positive and false-negative PET findings. Patients with head and neck cancer who are referred to tertiary care centers commonly arrive with cross-sectional images obtained at other institutions. Reinterpretation of these studies by dedicated radiologists frequently leads to changes in findings, which alter treatment and affect prognosis.