Cetuximab for the treatment of metastatic and/or recurrent squamous cell carcinoma of the head and neck: appraisal consultation

Appraisal consultation document - Cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck.To take part in the 'Cetuximab for the treatment of metastatic and/or recurrent squamous cell carcinoma of the head and neck: appraisal consultation'

A New Twist on Radiation Oncology: Low-Dose Irradiation Elicits Immunostimulatory Macrophages that Unlock Barriers to Tumor Immunotherapy.

Tumor-infiltrating macrophages typically promote angiogenesis while suppressing antitumoral T cell responses. In this issue of Cancer Cell, Klug and colleagues report that clinically-feasible, low-dose irradiation redirects macrophage differentiation from a tumor-promoting/immunosuppressive state to one that enables cytotoxic T cells to infiltrate tumors and kill cancer cells, rendering immunotherapy successful in mice.

Sex-specific selective pressures on body mass in the greater white-toothed shrew, Crocidura russula.

The direction, intensity and shape of viability-, sexual- and fecundity selection on body mass were investigated in a natural population of the greater white-toothed shrew (Crocidura russula), combining parentage assignment through molecular techniques and mark-recapture data over several generations. A highly significant stabilizing viability selection was found in both sexes, presumably stemming from the constraints imposed by their insectivorous habits and high metabolic costs. Sexual selection, directional in both sexes, was twice as large in males than in females. Our results suggest that body mass matters in this context by facilitating the acquisition and defense of a breeding territory. No fecundity selection could be detected. The direction of sexual size dimorphism (SSD) was in agreement with the observed pattern of selective pressures: males were heavier than females, because of stronger sexual selection. SSD intensity, however, was low compared with other mammals, because of the low level of polygyny, the active role of females in territory defense and the intensity of stabilizing viability selection.

Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925).

INTRODUCTION: The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment. PATIENTS AND METHODS: At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by chi(2) tests and logistic regression models in all the 3,866 of 4,004 patients eligible to the trial who received the allocated treatment. RESULTS: Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities. CONCLUSIONS: IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke-induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstrutive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-beta1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.

Selective suppression of leukocyte recruitment in allergic inflammation

Allergic diseases result in a considerable socioeconomic burden. The incidence of allergic diseases, notably allergic asthma, has risen to high levels for reasons that are not entirely understood. With an increasing knowledge of underlying mechanisms, there is now more potential to target the inflammatory process rather than the overt symptoms. This focuses attention on the role of leukocytes especially Th2 lymphocytes that regulate allergic inflammation and effector cells where eosinophils have received much attention. Eosinophils are thought to be important based on the high numbers that are recruited to sites of allergic inflammation and the potential of these cells to effect both tissue injury and remodelling. It is hoped that future therapy will be directed towards specific leukocyte types, without overtly compromising essential host defence responses. One obvious target is leukocyte recruitment. This necessitates a detailed understanding of underlying mechanisms, particularly those involving soluble che-moattractants signals and cell-cell adhesion molecules.

High constant incidence rates of second primary cancers of the head and neck: a pooled analysis of 13 cancer registries.

Scanty data are available on the incidence (i.e., the absolute risk) of second cancers of the head and neck (HN) and its pattern with age. We investigated this issue using data from a multicentric study of 13 population-based cancer registries from Europe, Canada, Australia and Singapore for the years 1943-2000. A total of 99,257 patients had a first primary HN cancer (15,985 tongue, 22,378 mouth, 20,758 pharyngeal, and 40,190 laryngeal cancer), contributing to 489,855 person-years of follow-up. A total of 1,294 of the patients (1.3%) were diagnosed with second HN cancers (342 tongue, 345 mouth, 418 pharynx and 189 larynx). Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age 30-34 to 46.2/100,000 at age 70-74, and leveled off at older age; female incidence increased from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age 40-44 and age 70-74 and tended to decline at subsequent ages (150/100,000 at age 80-84); in women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and 80-84. The patterns of age-specific incidence were consistent for different subsites of second HN cancer and sexes; moreover, they were similar for age-specific incidence of first primary HN cancer in patients who subsequently developed a second HN cancer. The incidence of second HN cancers does not increase with age, but remains constant, or if anything, decreases with advancing age.

Efficacy And Safety Of Baerveldt Aqueous Shunts In Glaucoma Secondary To Anterior Segment Irradiation, For Uveal Melanoma

Purpose: Elevated IOP is commonly associated with iris and ciliary body melanoma. Traditional management requires the majority of eyes to undergo enucleation. The authors describe the first series of Baerveldt aqueous shunts in eyes with uveal melanoma, treated by total anterior segment irradiation.Methods: 25 consecutive patients with unilateral iris melanoma were prospectively recruited after obtaining informed consent. All patients underwent anterior segment proton beam irradiation, corneal limbal autografts and Baerveldt tube implantation at Jules Gonin Eye Hospital, Lausanne. Postoperative examinations were performed on day 1, weeks 1,3,6,9 and months 3,6,12 and annually thereafter. Success was defined as: IOP </=18mmHg (definition A); IOP </= 21mmHg and 20% reduction in IOP (definition B). All complications were recorded.Results: Mean age was 53; mean follow up, 10.3 months; mean interval to treatment following irradiation, 2.4 years; mean pre-op IOP was 29.9 mmHg; mean post-op IOP 14.1 mmHg; mean pre-op medications 3.0; post-op medications 1.3. Success rates were, definition A: 95%; definition B: 90%. Only11% had minor complications and there were no sight-threatening complications. Aggressive ocular hypertension was observed in the several eyes prior to shunt implantation. Two eyes were enucleated for non-glaucoma related sequelae.Conclusions: Baerveldt aqueous shunts are safe and efficacious following total anterior segment irradiation for uveal melanoma. The novel interdisciplinary approach improved ocular retention rates, offering a promising alternative to current management algorithms.

Selective three-dimensional visualization of the coronary arterial lumen using arterial spin tagging.

Conventional coronary magnetic resonance angiography (MRA) techniques display the coronary blood-pool along with the surrounding structures, including the myocardium, the ventricular and atrial blood-pool, and the great vessels. This representation of the coronary lumen is not directly analogous to the information provided by x-ray coronary angiography, in which the coronary lumen displayed by iodinated contrast agent is seen. Analogous "luminographic" data may be obtained using MR arterial spin tagging (projection coronary MRA) techniques. Such an approach was implemented using a 2D selective "pencil" excitation for aortic spin tagging in concert with a 3D interleaved segmented spiral imaging sequence with free-breathing, and real-time navigator technology. This technique allows for selective 3D visualization of the coronary lumen blood-pool, while signal from the surrounding structures is suppressed.

Oral mucosal melanoma: conservative treatment including laser surgery.

Objective: To discuss the convenience of laser surgery as optimal treatment for melanoma of the oral mucosa.Patients and methods: A retrospective evaluation of four patients with primary oral melanomas treated at a single Cancer Institution in Mexico City.Results: Two patients were treated with resection of the melanoma with CO2 laser together with extraction of the involved dental organs and curettage of the alveolar walls. These two cases had melanoma in situ with multiple isolated foci. The third patient had a lesion with vertical growth, who was submitted to partial maxillectomy along with selective dissection of bilateral neck levels I-V with a negative report and the fourth patient had a history of oral nodular melanoma and presented with lymph node metastasis. According to follow-up status, there was no distant metastasis in any of the patients reported here.Conclusion: In our experience, conservative management with CO2 laser is adequate for melanomas of the oral mucosa with extraction of the dental organs and curettage of the alveoli to achieve complete surgical resection microscopically without sacrifice of the quality of life. Management of the neck is controversial. We recommend selective therapeutic resection of the neck only if it is found to be clinically positive. Elective dissection has not shown to have an impact in overall survival.

Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk.

BACKGROUND: Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. METHODS: We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. RESULTS: Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after >/=20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after >/=20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. CONCLUSIONS: Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer.

Selective acquired long QT syndrome (saLQTS) upon risperidone treatment.

ABSTRACT: BACKGROUND: Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially. CASE PRESENTATION: We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes. CONCLUSIONS: Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

BACKGROUND. The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ). METHODS. Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed. RESULTS. Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15. CONCLUSION. Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance. TRIAL REGISTRATION Clinical Trials Register NCT00349544.

Mandibular osteoradionecrosis in squamous cell carcinoma of the oral cavity and oropharynx: incidence and risk factors.

Objective. Mandibular osteoradionecrosis (ORN) is a serious complication of radiotherapy (RT) in head and neck cancer patients. The aim of this study was to analyze the incidence of and risk factors for mandibular ORN in squamous cell carcinoma (SCC) of the oral cavity and oropharynx.Study Design. Case series with chart review.Setting. University tertiary care center for head and neck oncology.Subjects and Methods. Seventy-three patients treated for stage I to IV SCC of the oral cavity and oropharynx between 2000 and 2007, with a minimum follow-up of 2 years, were included in the study. Treatment modalities included both RT with curative intent and adjuvant RT following tumor surgery. The log-rank test and Cox model were used for univariate and multivariate analyses.Results. The incidence of mandibular ORN was 40% at 5 years. Using univariate analysis, the following risk factors were identified: oral cavity tumors (P < .01), bone invasion (P < .02), any surgery prior to RT (P < .04), and bone surgery (P < .0001). By multivariate analysis, mandibular surgery proved to be the most important risk factor and the only one reaching statistical significance (P < .0002).Conclusion. Mandibular ORN is a frequent long-term complication of RT for oral cavity and oropharynx cancers. Mandibular surgery before irradiation is the only independent risk factor. These aspects must be considered when planning treatment for these tumors.