Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) for patients with poor performance status with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

Conclusions. Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) seems to be a promising and appropriate regimen for patients with poor performance status (PS) with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Objective. We designed a regimen based on divided low-dose administration to reduce toxicity for patients with poor PS with locally advanced SCCHN. Patients and methods. Sixty-two patients with previously untreated stage III–IV SCCHN and PS of 2 or 3 were entered into this study. They received radiotherapy: 70 Gy/35 fractions. The chemotherapy consisted of a combination of carboplatin (Calvert's formula: (GFR+25)×AUC (=5)/4 mg/week; where AUC=area under the curve and GFR=glomerular filtration rate) and UFT (300 mg/day, per os). Results. The overall clinical response rate and the pathological complete response (CR) were 90% (56/62) and 61% (38/62), respectively. Grade ≥3 mucositis occurred in only 6% of patients (4/62) and grade ≥3 leukocytopenia and neutropenia occurred in only 5% (3/62).     

Basaloid squamous cell carcinoma of the head and neck

OBJECTIVE/HYPOTHESIS: Basaloid squamous cell carcinoma (BSCC), an uncommon tumor with predilection for the upper aerodigestive tract, is a distinct variant of squamous carcinoma, because of its unique histological features and ominous clinical behavior. This study reviews the experience in treating BSCC from two institutions. STUDY DESIGN: Retrospective. METHODS: H&E-stained sections from 20 patients with BSCC of the head and neck were reviewed and clinical follow-up was obtained for all patients. RESULTS: The study group consisted of 14 male and 6 female patients. Their ages ranged from 43 to 85 years, with a mean age of 62 years. Sites of origin included the larynx (4), tongue (3), pyriform sinus (3), nose (2), floor of mouth (2), mastoid (1), tonsil (1), epiglottis (1), nasopharynx (1), trachea (1), and palate (1). Pain was the most common presenting symptom (5 cases), followed by hoarseness and bleeding (3 cases each). Tobacco and alcohol abuse was noted in 17 patients. Treatment modalities included surgery with or without chemotherapy or radiotherapy in 13 patients, chemotherapy with irradiation in 2, chemotherapy alone in 2, and radiotherapy alone in 3. Clinical follow-up revealed no evidence of disease in 11 patients. Four were alive with disease at the time of writing and five died of disease. CONCLUSION: BSCC is a highly aggressive malignant tumor that presents in elderly patients who have a history of abuse of tobacco or alcohol, or both. Greater number of patients must be studied and compared with age-matched and stage-matched controls of conventional squamous cell carcinoma to determine whether the poor clinical outcome is related more to high-stage presentation or to the tumor's high-grade malignant cytological features.     

Carnitine is associated with fatigue following chemoradiotherapy for head and neck cancer

Conclusion: Longitudinal assessments of carnitine and fatigue in patients with head and neck squamous cell carcinoma suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. Objectives: The purpose of this study was to monitor carnitine levels and fatigue in patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone. Methods: To investigate the level of carnitine, mice were administered cisplatin. Next, a prospective analysis was performed to compare plasma carnitine levels before and after cisplatin-based chemoradiotherapy and to assess the relationship between carnitine levels and fatigue. Results: The plasma levels of total carnitine (TC), free carnitine (FC), and fatty acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice. Mean total carnitine and free carnitine levels were significantly lower 2 weeks after chemoradiotherapy (total carnitine: Mean = 45.6, SD = 16.5, p = 0.01; free carnitine: Mean = 37.8, SD = 12.7, p = 0.02) than before chemoradiotherapy (total carnitine: Mean = 57.7, SD = 12.2; free carnitine: Mean = 48.1, SD = 11.6). There was a significant inverse correlation between carnitine levels and fatigue after chemoradiotherapy.     

STI-571 (Gleevec) potentiates the effect of cisplatin in inhibiting the proliferation of head and neck squamous cell carcinoma in vitro

OBJECTIVE: The objective of this study was to determine whether STI-571 (Gleevec; imatinib mesylate) could sensitize established head and neck squamous cell carcinoma (HNSCC) cell lines to the effects of cisplatin. METHODS: Western blot analysis and immunofluorescence were used to examine the expression of the tyrosine kinases that are known targets of Gleevec, including c-kit, c-Abl, and platelet-derived growth factor receptor, on the cell lines, and immunohistochemistry was performed to determine the expression of these kinases in human HNSCC tissue. Once these targets were confirmed, clonogenic cell survival assays were performed to determine the effect STI-571 had on growth and proliferation when used in combination with cisplatin compared with STI-571 alone or cisplatin alone. Cells were incubated with a range of doses of STI-571 24 hours before the addition of cisplatin. Flow cytometry analysis was performed to determine cell-cycle distribution and to measure apoptosis caused by the various treatments. An annexin V assay was also used to further measure apoptosis. RESULTS: Our results indicate that STI-571 potentiates the effect of cisplatin and leads to a significant decrease in cell proliferation and colony formation compared with cisplatin alone in a dose-dependent fashion. Surprisingly, there was a slight decrease in the level of apoptosis when Gleevec was used in combination with cisplatin compared with cisplatin alone. Gleevec alone resulted in a slight increase in G1 phase of the cell cycle, whereas cisplatin alone resulted in a G2 arrest. The addition of Gleevec to cisplatin resulted in an enhanced S/G2 phase accumulation. Although we did not demonstrate an increase in cisplatin-induced cell death, we postulate that the increased S/G2 arrest resulting from the DNA damage in the presence of Gleevec results in decreased proliferation of HNSCC, resulting in a net decrease in colony formation. CONCLUSIONS: The small molecule inhibitor Gleevec, which targets specific tyrosine kinases that are expressed in HNSCC, can significantly potentiate the antiproliferative effects of cisplatin. Because Gleevec alone has minimal side effects, treatment with the combination treatment of cisplatin and Gleevec may result in increased efficacy of cisplatin in treating this cancer. Additional studies are warranted, keeping in mind that drug combinations may result in unexpected toxicities that are not frequently seen with either drug alone.     

Whole-body MRI for staging patients with head and neck squamous cell carcinoma

Conclusions. Whole-body MRI is feasible for the tumor staging of patients with malignant head and neck tumors and appears to be a quick, reliable and proven alternative in general and for patients with contraindications to CT. This examination minimizes the logistical effort required compared to multimodality strategies. Its economic impact remains to be determined. Objective. To assess the performance of whole-body MRI for staging patients with squamous cell carcinoma of the head and neck region. Material and methods. This was a randomized, prospective clinical study. For tumor staging, 21 patients (mean age 56.7 years; range 43–80 years) with advanced malignant head and neck tumors underwent whole-body MRI in addition to routinely performed imaging investigations, including sonography, chest X-ray, CT of the head, neck and thorax and endoscopy. All investigations were accomplished within a period of 10±3 days in a random order. A randomized, blinded, consensus assessment of all the whole-body MRI examinations was performed by two radiologists. The localization and extent of the primary tumor and metastases were documented for whole-body MRI and compared to the standard of reference (all other imaging modalities as well as histology). Point estimates of the diagnostic accuracy of whole-body MRI were calculated. Results. In accordance with the standard of reference, the overall TNM category was correctly determined with whole-body MRI in all 21 patients. However, four patients were classified as having carcinoma of unknown primary, as the primary tumor was not found with any imaging modality. Two patients had mediastinal, pulmonary and hepatic metastases.     

头颈部鳞状细胞癌的靶向治疗研究进展

头颈部肿瘤是常见肿瘤之一,超过95%的病理类型是鳞状细胞癌,手术与放化疗结合的综合治疗方案是头颈部鳞状细胞癌(HNSCC)的主要治疗方案,但是总体生存率并不高,主要原因是肿瘤复发和/或转移;同时复发性或转移性HNSCC常无法进行手术治疗,放化疗效果也差。靶向治疗的发现为HNSCC、特别是复发性或转移性HNSCC的治疗提供了新的方法。为了进一步认识靶向治疗的临床治疗作用,就HNSCC的靶向治疗研究进展做一综述。     

The role of positron emission tomography scans in the management of the N-positive neck in head and neck squamous cell carcinoma after chemoradiotherapy

OBJECTIVE: The objective of this study was to determine the sensitivity, specificity, and predictive value of 18-fluorodeoxyglucose positron emission tomography (PET) in predicting residual cervical metastatic disease in patients with N-positive necks undergoing curative radiotherapy and chemoradiotherapy for squamous cell carcinoma (SCC) of the upper aerodigestive tract. METHODS: The authors studied a prospective case series of patients (2003-2005) of patients undergoing radiotherapy and chemoradiotherapy for advanced head and neck SSC. Study entry criteria included N-positive neck disease, a complete response to treatment at the primary tumor site, posttreatment PET scan (8-12 weeks after completion of treatment), followed by salvage neck dissection. The posttreatment PET scan neck findings were correlated to the salvage neck dissection pathology report. The sensitivity, specificity, and predictive values of the PET scan to predict residual cervical metastatic disease after curative chemoradiotherapy were calculated. RESULTS: Twenty-one neck dissections (pretreatment N1 = 5, N2a = 2, N2b = 8, N3 = 6) were entered into the protocol. Four (19.0%) of the 21 neck specimens were positive for residual cervical metastatic disease, whereas the remaining 17 (80.9%) specimens demonstrated no residual carcinoma. The overall sensitivity and specificity were 75.0% and 64.7%, respectively. The positive predictive value was 33% and the negative predictive value was 91.7%. CONCLUSIONS: Although the role of posttreatment neck dissection remains controversial, the surgeon must rely on clinical examination and imaging studies. Our practice has been to perform planned staged neck dissections on all N2 and N3 necks, as well as N1 necks with an incomplete response to treatment. Based on this small prospective study, it appears that PET imaging lacks adequate sensitivity and specificity to reliably predict the presence of residual cervical metastatic disease after completion of chemoradiotherapy. With a negative predictive value of 91.7%, however, a negative PET scan appears to be a reliable predictor of the absence of residual tumor.     

Control of neck nodes in squamous cell carcinoma of the head and neck by radiotherapy: prognostic factors

313 patients with cervical metastases from a squamous carcinoma of the head and neck treated with radiotherapy, were studied by means of a multivariant analysis in order to determine the prognostic factors for cure. These were: lymph node response to irradiation (P= 0.0000), size of node (P= 0.0000), radiotherapy dose (P= 0.0037), condition of the primary (controlled vs non-controlled) (P= 0.0015), recurrent cervical metastases post-surgery (P= 0.0286).     

Soft tissue cervical metastases of squamous carcinoma of the head and neck

Some 497 of 3085 patients with squamous cell carcinoma of the head and neck treated between 1963 and 1990 had a later radical neck dissection at some time after initial treatment. The histological slides were all reviewed, firstly to confirm the presence of squamous cell carcinoma within the neck, and secondly to ascertain whether the metastasis was to soft tissue, to a lymph node or to both. The presence of extracapsular rupture in lymph node deposits was also assessed. Of the 497 patients, 138 had soft tissue deposits only, and 359 had nodal deposits only. Of the patients with nodal deposits 165 had extracapsular rupture and 194 did not. The 5-year survival of the 138 patients with soft tissue metastases was 27% compared with 33% for patients with extracapsular rupture and 50% for patients with no extracapsular rupture. Weighted logistic regression showed that soft tissue deposits were significantly more common in patients in poor general condition, plus poorly differentiated squamous cell carcinoma plus T₄ tumours (P < 0.005), and in patients with poorly differentiated squamous cell carcinoma plus T₄ tumours (P < 0.025). Cox's multivariate analysis with backward elimination showed that gender, histological differentiation, site of primary tumour and age of patient had no statistically significant effect on survival. The number of nodes (P < 0.0001), the presence of extracapsular rupture (P < 0.0001) and the presence of soft tissue free metastases (P < 0.001) were all highly significant. The N-status at recurrence also reached statistical significance (P < 0.0001).     

A prospective study of PET-FDG imaging for the assessment of head and neck squamous cell carcinoma

The main aim of the study was to evaluate the use of positron emission tomography using fluoro-deoxyglucose (PET-FDG) imaging for the detection of squamous cell carcinoma of the head and neck. Fifty-four consecutive patients with malignancies involving the head and neck were studied prospectively. Thirty-one patients presented with primary disease and 23 were suspected of recurrent or residual disease. All patients underwent full clinical staging, PET-FDG scans and anatomical imaging, 37 underwent computed tomography (CT), 13 magnetic resonance (MR) and four had both CT and MR. Clinical assessment, CT/MR, PET-FDG and histological examination were all evaluated independently of each other. All 31 primary head and neck malignant tumours were detected by PET-FDG. Based on 16 patients who underwent neck dissections, the sensitivity and specificity of PET-FDG for detecting nodal disease was 67% and 100% respectively, compared with clinical assessment of 58% and 75% and CT/MR of 67% and 25%. In all 12 patients, PET-FDG correctly identified the presence or absence of recurrent or residual disease. PET-FDG staged 13 post-treatment necks with an accuracy of 100%, as compared to CT/MR which was accurate in 7 of 13 and clinical assessment which was accurate in eight. Three sites of abnormal tracer uptake unrelated to malignancy were recorded as incidental findings (mandibular osteomyelitis, 1; post glossectomy site, 2). PET-FDG was more accurate than CT/MR for identifying primary and recurrent tumours as well as metastatic lesions in the neck. If these diagnostic properties of PET-FDG are confirmed in further prospective studies, it could prove a valuable adjunct for the management of head and neck cancer.     

p53 expression in concurrent chemoradiotherapy with docetaxel for head and neck squamous cell carcinoma

Background

The current study aimed to evaluate the significance of an immunohistochemical assessment of tumor suppressor p53 as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) patients treated with docetaxel and radiotherapy.

Methods

The expression of tumor suppressor p53 and its phosphorylated form at the Ser392 residue was retrospectively evaluated by immunohistochemistry in 51 Stage T1-3N0-2M0 (except T1N0 glottis) HNSCC patients who were treated with 10 mg/m²/week docetaxel four to six times and received concurrent chemoradiotherapy.

Results

Kaplan–Meier univariate analysis revealed that no difference in rates for overall and disease-free survival (DFS) between patients with p53-positive and -negative tumors (p = 0.786 and p = 0.924, respectively). The prognostic significance of phosphorylated p53 at the Ser392 residue was neither observed.

Conclusions

An immunohistochemical assessment of the expression of p53 and its phosphorylated form might not be of clinical use in defining subgroups of patients with poor prognosis.     

Spectral karyotyping analysis of head and neck squamous cell carcinoma

Objectives/Hypothesis The genetic content of head and neck squamous cell carcinomas is ill defined. Spectral karyotyping (SKY) is a new technique that allows the simultaneous detection of all chromosomal translocations by labeling each individual chromosome with different fluorescent agents. In the current study we used SKY to analyze cell lines and a primary tumor derived from head and neck squamous cell carcinomas (HNSCC) to delineate recurrent translocations and breakpoints. Study Design Spectral karyotyping analysis of head and neck cancer. Methods Two cell lines (MDA886 and MSK922) and one primary tumor in short-term culture were subjected to metaphase growth arrest with colcemide in their exponential growth phase and fixed onto glass slides. Painting probes for each of the autosomes and the sex chromosomes were generated from flow-sorted human chromosomes using sequence-independent DNA amplification. The probes were labeled using a polymerase chain reaction–based reaction and hybridized to metaphase preparations for 2 days at 37°C. Biotinylated probes were detected using avidin Cy5 and digoxigenin-labeled probes with an anti-mouse digoxigenin antibody followed by goat anti-mouse antibody conjugated to Cy5.5. Chromosomes were counterstained with 4,6-diamino-2-phenyliodole (DAPI), and a minimum of five metaphases were captured and analyzed for each case. Breakpoints on the SKY-painted chromosomes were determined by comparison of corresponding DAPI banding. Results Spectral karyotyping analysis revealed a complex pattern of chromosomal abnormalities. A total of 66 translocations were identified in the three cases, with one new recurrent translocation at (der(4)t(4;20)(q35;?)). Nine complex translocations, involving three or more chromosomes, were identified in these cases. Overall, 96 breakpoints were assigned to metaphase chromosomes and another 74 breakpoints could not be assigned. Breakpoints most commonly involved chromosomes in genetic rearrangements were 1, 3, 5, 8, 13, 16, and 17. Conclusions Spectral karyotyping analysis reveals the true complexity of chromosomal aberrations in cell lines derived from head and neck squamous cell carcinomas. The use of SKY, in combination with other techniques, may allow for a more complete assessment of the genetic abnormalities of head and neck cancers and serve as a starting point for gene identification.     

Sentinel lymph node biopsy in head and neck squamous cell carcinoma

OBJECTIVES/HYPOTHESIS: Sentinel lymph node biopsy is a minimally invasive method to stage the regional lymphatics that has revolutionized the management of patients with intermediate-thickness cutaneous melanoma. Head and neck surgeons have been encouraged by the accuracy of sentinel lymph node biopsy in cutaneous melanoma and have applied the technique to patients with head and neck squamous cell carcinoma (HNSCC). The objectives of the study were 1) to study the feasibility and accuracy of sentinel lymph node biopsy as a method to stage the regional lymphatics in HNSCC and 2) to determine whether there are qualitative differences between the cutaneous and mucosal lymphatics that would affect the technique used in HNSCC. STUDY DESIGN: Two methods of investigation were employed: a prospective laboratory study using a feline model for sentinel lymph node biopsy and a retrospective review of patients who received lymphoscintigraphy before neck dissection and intraoperative identification of the sentinel lymph node. METHODS: Lymphoscintigraphy and a gamma probe were used in four felines to study the kinetics of technetium-labeled sulfa colloid (Tc-SC) in the mucosal lymphatics. In the second part of the feline study, eight subjects were studied intraoperatively. Tc-SC and isosulfan blue dye were used to study the injection technique for the mucosal lymphatics and to determine the time course of the dye and Tc-SC to the sentinel lymph node. In Part II of the present study, a retrospective review of 33 patients with HNSCC was conducted. Twenty patients (stage N0) whose treatment included elective neck dissection were studied with preoperative lymphoscintigraphy and underwent intraoperative identification of the sentinel lymph node to determine the accuracy and feasibility of sentinel lymph node biopsy. Eight patients with palpable neck disease and five patients with recurrent or second primary disease whose previous treatment included neck dissection were also studied with lymphoscintigraphy before neck dissection. RESULTS: In the feline study, both Tc-SC and isosulfan blue dye traversed the lymphatics rapidly, appearing in the sentinel lymph node in less than 5 minutes. Modification of the injection technique used for cutaneous melanoma was required to depict the sentinel lymph node of the base of tongue. In the human study, the sentinel lymph node was accurately identified in 19 of 20 (95%) N0 patients. On average, 2.9 sentinel lymph nodes (range, 1-5) were identified in 2.2 (range, 1-4) levels of the neck. Sentinel lymph nodes were bilateral in 4 of 19 patients. When the sentinel lymph node was identified, it accurately predicted the pathological nodal status of the regional lymphatics. Three of 20 patients had cervical metastases, and the sentinel lymph node was identified in 2 of 3 patients with pathologic nodes (pN+). Focal areas of radiotracer uptake were identified in seven of eight patients with palpable disease. These areas corresponded to the level with palpable disease in four patients. The lymphatics delineated by lymphoscintigraphy in the five patients with previous neck dissection were outside the levels that had been dissected. Lymphoscintigraphy depicted collateral patterns of lymphatic drainage. CONCLUSIONS: Sentinel lymph node biopsy is technically feasible and is a promising, minimally invasive method for staging the regional lymphatics in patients with stage N0 HNSCC. Lymphoscintigraphy alone may determine the levels that require treatment in patients with disrupted or previously operated cervical lymphatics.     

鉴定头颈部鳞癌中异常甲基化的差异表达基因及其通路

目的 基于头颈部鳞癌(HNSCC)的生物标记物及其通路尚不明确的现状,研究旨在分析和鉴定HNSCC中异常甲基化的差异表达基因,探讨其关键基因和潜在通路。 方法 从GEO数据库下载基因表达的数据集GSE107591和甲基化数据集GSE33202。通过R软件筛选异常甲基化基因和差异表达基因,两者取交集后获得低甲基化高表达基因(Hypo-HGs)和高甲基化低表达基因(Hyper-LGs)。利用Enrichr对两组基因进行功能富集分析。蛋白互作(PPI)网络由STRING构建并在Cytoscape中可视化,最后利用生存分析来鉴定出关键基因。此外,还进行了免疫组化分析,利用CMap寻找可能逆转HNSCC基因表达的候选小分子。 结果 共鉴定出28个低甲基化高表达基因,GO富集分析显示其主要参与T细胞趋化性的正调节,表皮发育、细胞-基底连接组件及调节T细胞趋化性等方面。Wiki通路分析的结果表明,其主要参与典型和非典型TGF-β信号传导、血液凝结级联反应、α6β4信号通路、补体和凝血级联反应及癌症中的衰老和自噬途径。同时,发现了24个高甲基化低表达基因,主要富集于血管生成及发育的调节,对干扰素-γ反应的负调节,对干扰素-γ介导的信号通路的负调节和上皮发育的生物学过程。Wiki通路分析显示其主要参与哺乳动物含黄素单加氧酶(FMOs)的催化循环,HIF1A和PPARG调节糖酵解以及苯和黄曲霉毒素B1的代谢。此外,鉴定出与HNSCC预后相关的关键基因,分别是SERPINE1、PLAU、MMRN1、LAMB3、LAMC2、PDPN和CXCL13。 结论 通过生物信息学分析并鉴定出HNSCC中异常甲基化差异表达的基因和作用途径,为揭示HNSCC发病机制提供了重要的分子学基础。包括SERPINE1、PLAU、MMRN1、LAMB3、LAMC2、PDPN和CXCL13在内的关键基因可能作为基于甲基化的异常生物标志物,为未来寻找HNSCC诊断和治疗靶点提供了新的思路。     

Implications of tumour in resection margins following surgical treatment of squamous cell carcinoma of the head and neck

Presence of tumour at the resection margin following primary surgical treatment for squamous cell carcinoma of the head and neck is thought to adversely affect prognosis. To confirm this we performed a review of 478 patients treated by primary surgery for squamous cell carcinoma of the head and neck and sub-divided them into those exhibiting postive margins and those with negative margins following resection. Uni-variate and multi-variate statistical methods were used to analyse survival figures and a variety of parameters associated with the presence of positive resection margins. We found 5-year survival was decreased if resection margins were found to be positive (P < 0.025). The presence of positive resection margins was also significantly associated with time to tumour recurrence (P < 0.001) and survival with nodal recurrence (P < 0.001). Other factors which were significantly associated with survival using Cox's multi-variate analysis were site of tumour (P < 0.005), nodal extracapsular rupture (P < 0.05) and pathological T-stage (P < 0.05). Uni-variate analysis revealed no significant associations betweent the presence of positive margins and the patient's age, sex, tumour site, degree of tumour differentiation, and nodal status, though using multiple logistic regression, the general condition of the patient (P < 0.01) and the tumour site P < 0.05) were significantly related. The results support the concept that every effort should be made to obtain negative resection margins when undertaking primary ablative surgery for squamous cell carcinoma of the head and neck.