Screening for Distant Metastases in Patients With Head and Neck Cancer

Objectives The detection of distant metastases at initial evaluation may alter the selection of therapy in patients with head and neck squamous cell carcinoma (HNSCC). In this study the value of screening for distant metastases is evaluated. Study Design Retrospective analysis. Methods The results of screening for distant metastases were retrospectively analyzed in 101 consecutive HNSCC patients with high‐risk factors who were scheduled for major surgery. All patients had computed tomography (CT) scan of the thorax, bone scintigraphy, examination of the liver by ultrasound and/or CT scan, and blood tests. Results Distant metastases were found in 17% of the patients. Patients with four or more clinical lymph node metastases or low jugular lymph node metastases had the highest incidence of distant metastases (33%). CT scan of the thorax detected in 12 patients, lung metastases; in 4, mediastinal lymph node metastases; and in 2, primary lung tumors. Bone scintigraphy detected in four patients bone metastases; in all four patients lung or mediastinal lymph node metastases were also found. Ultrasound and/or CT scan of the liver revealed one patient with metastases. Blood tests did not show any significant difference between patients with or without bone or liver metastases. Conclusions Screening in patients with three or more lymph node metastases, bilateral lymph node metastases, lymph nodes of 6 cm or larger, low jugular lymph node metastases, locoregional tumor recurrence, and second primary tumors revealed distant metastases in 10% or more. CT scan of the thorax is currently the single most important diagnostic technique for screening of distant metastases.     

Wound Complications in Head and Neck Squamous Cell Carcinomas After Anti–PD‐1 Therapy

Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long‐term sequelae. We describe four patients who, after complete responses to anti–PD‐1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57‐year‐old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39‐year‐old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66‐year‐old male with craniofacial osteoradionecrosis. Patient 4 is a 71‐year‐old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 129:E428–E433, 2019     

Gene Therapy for Head and Neck Cancer

Objectives/Hypothesis New treatment methods are needed for head and neck cancer to improve survival without increasing morbidity. Gene therapy is a potential method of improving patient outcome. Progress in gene therapy for cancer is reviewed with emphasis on the limitations of vector technology and treatment strategies. Given the current technological vector limitations in transmitting the therapeutic genes, treatments that require the fewest number of cells to be altered by the new gene are optimal. Therefore an immune‐based gene therapy strategy was selected in which the tumors were transfected with the gene for an alloantigen, human leukocyte antigen (HLA)–B7, a class I major histocompatibility complex (MHC). This would restore an antigen presentation mechanism in the tumor to induce an antitumor response. This gene therapy strategy was tested in patients with advanced, unresectable head and neck cancer. Study Design Prospective trial. Methods Twenty patients with advanced head and neck cancer who had failed conventional therapy and did not e‐press HLA‐B7 were treated with gene therapy using a lipid vector by direct intratumoral injection. The gene therapy product contained the HLA‐B7 gene and the β2‐microglobulin gene, which permits complete e‐pression of the class I MHC at the cell surface. Patients were assessed for any adverse effects, for changes in tumor size, for time to disease progression, and for survival. Biopsy specimens were assessed for pathological response, HLA‐B7 e‐pression, apoptosis, cellular proliferation, CD‐8 cells, granzyme, and p53 status. Results There were no adverse effects from the gene therapy. At 16 weeks after beginning gene therapy, four patients had a partial response and two patients had stable disease. Two of the tumors completely responded clinically, but tumor was still seen on pathological examination. The time to disease progression in the responding patients was 20 to 80 weeks. The median survival in patients who completed gene therapy was 54 weeks, compared with 21 weeks in patients whose tumors progressed after the first cycle of treatment. One patient survived for 106 weeks without any additional therapy. HLA‐B7 was demonstrated in the treated tumors, and increased apoptosis was seen in the responding tumors. Conclusion Significant advances have been made in the field of gene therapy for cancer. Alloantigen gene therapy has had efficacy in the treatment of cancer and can induce tumor responses in head and neck tumors. Alloantigen gene therapy has significant potential as an adjunctive treatment of head and neck cancer.     

The Occurrence of Sleep‐Disordered Breathing Among Patients With Head and Neck Cancer

Objective To identify the incidence of obstructive sleep apnea (OSA) in patients treated for head and neck cancer. Obstructive sleep apnea is a relatively common and highly morbid condition that affects 9.1% of male and 4% of female middle‐aged adults. ¹ Patients who have been successfully treated for head and neck cancer may often have a partially obstructed upper airway which is functional during the day, but collapses during sleep. Study Design/Methods Twenty‐four patients successfully treated for tumors of the tongue‐base, pharynx, or supraglottic larynx were enrolled. Through OSA‐related questionnaires, physical examination, and polysomnography, the incidence of OSA in this patient population was determined and compared with that of the general population. Results The incidence of OSA (91.7%) in this head and neck cancer patient population was found to be significantly (P = .001) higher than that of the general population. (In a random sampling of middle‐aged adult males between the ages of 30 and 60 years old with a respiratory disturbance index (RDI) >15, the prevalence was previously reported to be 9.1%. ¹ ) Sixteen of 24 patients (72.7%) had clinically defined symptoms of sleep apnea. Ten of 24 patients (41.7%) received radiation therapy; all had an RDI >15. Eleven of the 14 patients (78.5%) who did not receive radiation therapy also had an RDI >15. Eight patients (33.3%) continue to regularly use continuous positive airway pressure with significant improvement in symptoms. Conclusions Identification and treatment of OSA may be an important factor in improving quality of life for patients with head and neck cancer.     

Risk Factors and Survival Outcomes for Patients With Anastomotic Leakage After Surgery for Head and Neck Squamous Cell Carcinoma

Objectives

This study evaluated the risk factors for anastomotic leakage (AL) and survival outcomes in patients with head and neck squamous cell carcinoma (HNSCC).

Methods

Patients with HNSCC who underwent surgery carrying potential AL from 2003 through 2009 were included in this study. Univariate and multivariate analyses were performed and patient survival was calculated by the Kaplan-Meier method.

Results

Of 232 eligible patients, 25 (10.8%) developed AL. Univariate analyses revealed that primary tumor site, salvage surgery, perineural invasion, radiotherapy, chemotherapy, and blood transfusion were significantly associated with the occurrence of AL (P<0.05). Independent risk factors for AL were salvage surgery and blood transfusion (P<0.01). On univariate analysis, AL was significantly associated with overall (OS) and disease-free survivals (DFS; P<0.05) but not with decreased locoregional control (LRC) rate (P=0.07). The 5-year DFS rate was significantly different between the non-leakage and leakage groups (70.9% vs. 27.7%, P<0.001). Multivariate analysis showed, however, that AL was not an independent variable of LRC, DFS, or OS (P>0.1).

Conclusion

Patients who received salvage surgery and blood transfusion may require careful surveillance for development of AL, which has a tendency toward decreased survival.     

Peripheral Blood T‐Lymphocyte and Monocyte Function and Survival in Patients With Head and Neck Carcinoma

Objectives/Hypothesis To determine if the T‐lymphocyte and monocyte functions of peripheral blood mononuclear cells (PBMCs) from patients with head and neck squamous cell carcinomas (HNSCC) are predictive factors for outcome. Study Design A prospective study describing the outcome, as to total survival and death by disease after at least 40 months observation, of 81 previously untreated male HNSCC patients in relation to PBMC T‐lymphocyte and monocyte function. Methods T‐lymphocyte mitogenesis and the cytokine level in culture supernatants of PBMC as well as monocytes were analyzed. These parameters were related to survival by Cox regression and Kaplan‐Meier survival analysis. Results When patients with high versus low T‐lymphocyte mitogen–stimulated proliferations were compared, a decreased proliferation was seen to be related to worse outcome. The predictive value of T‐lymphocyte proliferation was shown to be an independent prognostic factor when adjusted for stage and stratified for anatomic location in survival analysis. The predictive value was also retained when the serum values of the major serum proteins and hormones and scores based on the smoking and alcohol history were added to the survival analysis with lymphocyte proliferation. Supernatant levels of γ‐interferon, interleukin (IL)‐2, or IL‐4 in PBMC cultures were not related to outcome. Monocyte function measured by endotoxin‐stimulated IL‐1β, IL‐6, IL‐12, and tumor necrosis factor‐α secretion did not relate to outcome of the patients. Conclusion The PBMC T‐lymphocyte–stimulated proliferation is an independent prognostic factor for male HNSCC patients.     

Identification of Genes Overexpressed in Head and Neck Squamous Cell Carcinoma Using a Combination of Complementary DNA Subtraction and Microarray Analysis

Objectives/Hypothesis To discover unique genes specific for squamous cell carcinoma of the head and neck for eventual development as tumor markers and vaccine candidates. Study Design Molecular biological analysis of fresh‐frozen head and neck squamous cell cancer (HNSCC). Methods A subtractive library was made from two HNSCC and six normal tissues using a polymerase chain reaction (PCR)–based approach. Genes from this library were PCR amplified and placed on a microarray glass slide. RNA was prepared or obtained from 16 fresh‐frozen HNSCC and 22 normal tissue sources. Fluorescent probes were made from the polyA+ RNA derived from the tumor and normal tissues. The probes were hybridized to the glass slides and excited by a tuneable laser. One hundred seven of the genes showing the highest differential fluorescence value between tumor and normal tissue were identified by sequence analysis. Results Thirteen independent genes were found to be overexpressed in tumor tissues. Of these, nine were previously known: keratins K6 and K16, laminin‐5, plakophilin‐1, matrix metalloproteinase‐2 (MMP), vascular endothelial growth factor, connexin 26, 14–3‐3 sigma, and CaN19. The level of polyA+ RNA of these genes in the tumors was significantly different from the levels in normal tissue (P < .05). Four previously unidentified genes were also discovered to have increased expression in tumor tissue. Comparing the total tumor group (n = 16) to the normal group (n = 22), only one of these genes showed significant overexpression. Conclusion We report the identification of nine known genes that are significantly overexpressed in HNSCC as compared to normal tissue using subtractive and microarray technology. In addition, we present four previously unidentified genes that are overexpressed in a subset of tumors. These genes will be developed as tumor markers and vaccine candidates.     

High‐Dose‐Rate Brachytherapy in the Treatment of Recurrent and Residual Head and Neck Cancer

Objectives/Hypothesis Interstitial and endocavitary brachytherapy are well‐accepted kinds of radiotherapy that are commonly used in recurrent head and neck cancer. Most reports about brachytherapy in the successful treatment of head and neck tumors used low‐dose‐rate brachytherapy. There are only a few reports about high‐dose‐rate brachytherapy (HDRBT) in head and neck cancer patients. Methods After 10 years of experience with HDRBT with Ir 192, we have analyzed the results regarding response rates, survival time, and side effects. Between 1991 and 2000, 90 consecutive patients (68 men, 22 women) were treated with interstitial (68 patients) or intracavitary (22 patients) HDRBT in the head and neck area. Primary tumor locations were as follows: oropharynx (n = 26), tongue/floor of mouth (n = 22), nasopharynx (n = 10), nose/paranasal sinuses (n = 9), salivary glands (n = 5), hypopharynx (n = 5), CUP syndrome (n = 5), and others (n = 8). High‐dose‐rate brachytherapy was administered in 51 patients with recurrent disease and in 32 patients with residual tumor after primary radiochemotherapy. Seven patients were given exclusive HDRBT in a primary palliative situation. The single dose per fraction ranged from 1.5 to 7.5 Gy (median value, 5 Gy), and the total HDRBT dose ranged from 4.0 to 42.0 Gy (median value, 17.5 Gy). Results The overall remission rate was 81% with a 46% rate of complete remissions. We observed no change in or progression of tumor in 17 cases (19%). The rate of complete remissions (and median overall survival time) was different in the three therapy groups: in case of recurrent disease, 28% (6 mo); in case of residual tumor, 84% (25 mo); and in primary palliative brachytherapy, 0% (1 mo). Late toxicities III and IV (radiation treatment oncology group score) occurred in 6 of 90 (6.7%) patients. Conclusions High‐dose‐rate brachytherapy proved to be an effective treatment modality in locoregional recurrent head and neck cancer. In cases with persistent or residual tumor after primary radiochemotherapy a local boost with brachytherapy can improve the chance of cure of tumor disease.     

End‐to‐Side Venous Anastomosis With an Anastomotic Coupling Device for Microvascular Free‐Tissue Transfer in Head and Neck Reconstruction

Objective: The purpose of this study is to demonstrate the success rate of using a coupling device for end‐to‐side venous anastomosis in patients undergoing free‐tissue transfer (FTT) in head and neck reconstruction. Methods and Measures: Retrospective data were collected in consecutive series of 134 patients undergoing surgical resection of head and neck tumors followed by FTT. All microvascular FTTs were performed at Yale‐New Haven Hospital between November 2001 and August 2007. The Unilink coupling device was used to perform arterial and venous anastomosis in this case series. Flap survival and thrombosis of the venous anastomoses were determined. Results: One hundred thirty‐four consecutive patients underwent a total of 137 microvascular FTTs using a coupling device. In our series, a total of 173 end‐to‐side anastomoses were completed in 96 patients. Of these, 77 patients had both venous anastomoses, 17 underwent one end‐to‐side and one end‐to‐end anastomoses, and two patients had one venous anastomosis per patient performed in end‐to‐side fashion. Reconstruction included 76 radial forearm, 17 fibula, and three rectus abdominis free flaps. There were three vascular insufficiency related complications of which two were salvageable. There was one case of flap failure (1%), resulting in a free flap survival rate of 99%. Conclusion: This largest reported series of end‐to‐side venous anastomoses with an anastomotic coupling device demonstrates feasibility and efficacy of this technique in head and neck reconstruction.     

头颈鳞状细胞癌乏氧微环境与放疗抵抗相关性的研究进展

头颈鳞状细胞癌(HNSCC)的治疗方式有手术和放化疗.治疗后HSNCC的高复发率及其显著的转移能力是影响HNSCC患者预后的主要因素,且放化疗存在各种并发症,包括放射性口腔黏膜炎、局部软组织损伤等,严重影响患者生活质量.而肿瘤局部组织内乏氧造成的乏氧微环境与肿瘤治疗抵抗和复发的关系密切相关,如果能采取措施改善肿瘤微环境...     

Targeting of a Head and Neck Squamous Cell Carcinoma Xenograft Model Using the Chimeric Monoclonal Antibody U36 Radioiodinated with a closo-Dodecaborate-containing Linker

Objective —High rates of local recurrence and distant metastases following surgery of high-grade head and neck squamous cell carcinoma (HNSCC) necessitate the use of adjuvant systemic treatment. Radioimmunotargeting might be a possible treatment modality in this case. The nuclear properties of ¹³¹I make it a suitable isotope for treatment of minimal residual disease and small metastases, but the conventional radioiodine label has poor cellular retention and its radiocatabolites accumulate in the thyroid. We attempted to overcome these problems by using closo-dodecaborate derivatives for attachment of radioiodine.

Material and Methods —We investigated the feasibility of targeting an SCC25 HNSCC xenograft in vivo using a benzylisothiocyanate derivative of closo-dodecaborate (DABI) as radioiodine linker and the chimeric anti-CD44v6 antibody U36. ¹²⁵I was used in biodistribution studies.

Results —The use of DABI enabled tumor targeting and decreased the radioactivity uptake of the thyroid.

Conclusion —Tumor localization of DABI-labeled U36 was similar to its para-iodobenzoate-labeled counterpart, presumably due to the strong dependence of targeting efficiency on tumor size.