Successful implementation of handheld reflectance confocal microscopy as the standard of care in the (surgical) management of lentigo maligna (melanoma).

BACKGROUND: Reflectance confocal microscopy (RCM) has shown promise in predicting surgical outcomes by non-invasively detecting subclinical lentigo maligna (melanoma) (LM/LMM). OBJECTIVES: To assess the effects of presurgical mapping using handheld RCM (HH-RCM) on surgical treatment, follow-up outcomes and management decisions. METHODS: A total of 117 consecutive LM/LMM cases (2015-2023) were included. The diagnostic accuracy of HH-RCM in detecting subclinical LM and invasive components was evaluated. The primary endpoints included histological margin status and changes in management based on the outcomes of the HH-RCM mapping procedure. Margin and follow-up outcomes were compared to a historical cohort before HH-RCM was introduced in our center (n = 94) (2003-2014). RESULTS: HH-RCM detected subclinical LM in 60% (n = 60) of cases. The median mapping duration was 14 min (range 4-50). In 27% (n = 33), the mapping procedure resulted in modified management, the majority consisting of limited surgery with adjuvant imiquimod (n = 15) or imiquimod monotherapy (n = 14). The remaining cases (n = 84) underwent HH-RCM-assisted surgery. Histological margins were cleared in 96.5% of the patients with a median histological margin of 3.0 mm, significantly higher than 81% in the historical cohort (median 2.0 mm) (p = 0.001). The sensitivity and specificity for detecting the extent of subclinical LM were 94% (95% CI 80.4-99.3) and 84% (95% CI 70.3-92.7), respectively. The negative predictive value for the detection of LMM was 94% (95% CI 84.4-97.7), and 75% of the initially missed LMM (n = 12) were identified during the HH-RCM mapping procedure. The study cohort had a 1.6% local recurrence rate compared with 25% in the historical cohort. CONCLUSIONS: Integrating HH-RCM as the standard of care could lead to more personalized treatment strategies for LM/LMM and allows for the selection of patients suitable for nonsurgical treatment.

Treatment-related hearing loss in weekly versus triweekly cisplatin chemoradiation for head and neck cancer.

PURPOSE: Cisplatin-induced hearing loss is a common side effect in patients treated with cisplatin-based chemoradiation (CRT) for head and neck squamous cell carcinoma. The extent of hearing loss after concurrent CRT was compared between triweekly (3 × 100 mg/m2) and weekly (7 × 40 mg/m2) cisplatin CRT. METHOD: This retrospective cohort study was conducted in the Antoni van Leeuwenhoek Hospital and included 129 patients with cisplatin-based CRT for head and neck cancer (72 treated in the triweekly and 57 in the weekly regimen). Baseline and follow-up pure tone audiometry was conducted to assess hearing loss. Clinically relevant hearing loss was defined as a decline upon treatment of ≥ 10 decibel at a pure tone average 1-2-4 kHz and/or 8-10-12.5 kHz. RESULTS: The incidence of clinically relevant cisplatin CRT induced hearing loss was 42% in the triweekly versus 19% in the weekly group (p < 0.01). The mean threshold shift at a pure tone average (PTA) 1-2-4 kHz was 9.0 decibel in the triweekly compared to 4.3 decibel in the weekly CRT group (p < 0.01). At PTA 8-10-12.5 kHz, the incidence of clinically relevant hearing loss was 75% in the triweekly compared to 74% in the weekly CRT group (p = 0.87). The mean threshold shift at PTA 8-10-12.5 kHz was 20.2 decibel versus 15.6 decibel, respectively (p = 0.07). CONCLUSION: Cisplatin-dose reduction to a weekly cisplatin CRT regimen for head and neck cancer may reduce the incidence of clinically relevant hearing loss at frequencies vital for speech perception.

Lentigo maligna (melanoma): A systematic review and meta-analysis on surgical techniques and presurgical mapping by reflectance confocal microscopy.

Because of an increased risk of local recurrence following surgical treatment of lentigo maligna (melanoma) (LM/LMM), the optimal surgical technique is still a matter of debate. We aimed to evaluate the effect of different surgical techniques and reflectance confocal microscopy (RCM) on local recurrence and survival outcomes. We searched MEDLINE, Embase and PubMed databases through 20 May 2022. Randomized and observational studies with ≥10 lesions were eligible for inclusion. Bias assessment was performed using the Methodological Index for Non-Randomized Studies instrument. Meta-analysis was performed for local recurrence, as there were insufficient events for the other clinical outcomes. We included 41 studies with 5059 LM and 1271 LMM. Surgical techniques included wide local excision (WLE) (n = 1355), staged excision (n = 2442) and Mohs' micrographic surgery (MMS) (n = 2909). Six studies included RCM. The guideline-recommended margin was insufficient in 21.6%-44.6% of LM/LMM. Local recurrence rate was lowest for patients treated by MMS combined with immunohistochemistry (<1%; 95% CI, 0.3%-1.9%), and highest for WLE (13%; 95% CI, 7.2%-21.6%). The mean follow-up varied from 27 to 63 months depending on surgical technique with moderate to high heterogeneity for MMS and WLE. Handheld-RCM decreased both the rate of positive histological margins (p < 0.0001) and necessary surgical stages (p < 0.0001). The majority of regional (17/25) and distant (34/43) recurrences occurred in patients treated by WLE. Melanoma-associated mortality was low (1.5%; 32/2107), and more patients died due to unrelated causes (6.7%; 107/1608). This systematic review shows a clear reduction in local recurrences using microscopically controlled surgical techniques over WLE. The use of HH-RCM showed a trend in the reduction in incomplete resections and local recurrences even when used with WLE. Due to selection bias, heterogeneity, low prevalence of stage III/IV disease and limited survival data, it was not possible to determine the effect of the different surgical techniques on survival outcomes.

Merkel cell carcinoma of the head and neck: emphasizing the risk of undertreatment.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. It occurs predominantly in the head and neck area and often behaves aggressively. In this single-institution retrospective observational cohort study, we describe the results of a treatment strategy that we developed over the past decades. Endpoints of this study were local, regional and distant control, disease-specific survival and overall survival. In total 47 patients with head and neck MCC, diagnosed in the Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AvL) between 1984 and 2012, were included in this study. Local tumor control was 82 % (95 % CI 71-95 %) at 5 years. Regional lymph node metastases were found at the moment of diagnosis in 13 cases (28 %). In the group of patients who were initially cN0, the 5-year regional control was 80 % (68-95 %). The 5-year metastasis-free interval probability was 80 % (68-94 %). The disease-specific survival (DSS) at 5 years was 70 % (56-86 %). An overall survival of 54 % (40-72 %) was found at 5-year follow-up and of 37 % (23-59 %) at 10-year follow-up. Univariable Cox regression analysis of many clinical and pathological variables did not identify any predictors for DSS. The MCC has a high propensity for locoregional and distant spread in the head and neck region. Undertreatment, especially of the lymph nodes in the neck, is a serious problem as regional (micro)metastasis are common even in T1 tumors. Future research will have to elucidate the role of the sentinel lymph node procedure versus the elective selective node dissection and standardized elective local and regional radiotherapy in the head and neck area.

Hearing loss in survivors of childhood head and neck rhabdomyosarcoma: a long-term follow-up study.

OBJECTIVES: To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. DESIGN: Cross-sectional long-term follow-up study. SETTING: Tertiary comprehensive cancer centre. PARTICIPANTS: Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). MAIN OUTCOME MEASURES: We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. METHODS: We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). RESULTS: Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. CONCLUSIONS: One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors.

Evaluation of lasersurgery and radiotherapy as treatment modalities in early stage laryngeal carcinoma: tumour outcome and quality of voice.

For treatment of early stage (Tis-T2) laryngeal cancer the main choice is between microlaryngoscopy with carbon dioxide laser resection (laser surgery) and radiotherapy. Because both treatments provide excellent tumour control, secondary outcome variables such, as quality of voice may be of importance in treatment preference. In this study tumour outcomes and quality of voice were analysed for a cohort of patients with early stage (Tis-T2) laryngeal (glottic) carcinoma. The "physical subscale" of the voice handicap index questionnaire (VHI) and a validated five-item screening questionnaire were used. Analysis of 89 patients treated with laser surgery and 159 patients treated with radiotherapy revealed a 5-year local control of 75 and 86 % (p = 0.07). Larynx preservation (5-year) was, however, superior in patients treated with laser surgery, 93 vs 83 % (p < 0.05). Tumour outcomes were also analysed per tumour stage and none were of significant difference. Quality of voice was analysed in 142 patients. VHI scores were 12.4 ± 8.9 for laser surgery and 8.3 ± 7.7 for radiotherapy (p < 0.05), with a higher score reflecting a worse outcome. VHI scores per tumour stage for laser surgery and radiotherapy were, respectively, 12.0 ± 9.9 and 7.9 ± 7.5 in T1a (p = 0.06), 16.7 ± 9.0 and 4.9 ± 6.6 in T1b (p < 0.05). Outcomes of the five-item questionnaire showed voice deficiency in 33 % for laser surgery and 23 % for radiotherapy in T1a (p = 0.330) and 75 and 5 % for T1b (p = 0.001). Oncologic outcomes of laser surgery and radiotherapy were comparable. Larynx preservation is, however, preferable in patients initially treated with laser surgery. According to subjective voice analysis, outcomes were comparable in T1a lesions. Depth of laser resection is of influence on voice deficiency displayed by a significantly higher percentage of voice deficiency in patients treated with laser surgery for T1b lesions.

Is locally advanced head and neck cancer 'increasing' in the Netherlands? The paradox of absolute numbers, standardized incidence rates and proportional share.

BACKGROUND: Several reports have indicated that locally advanced head and neck cancer (LAHNC) has increased in the past decade. However, incidence trends cannot be easily compared because slightly different definitions of LAHNC were used. AIM: To investigate if the incidence of locally advanced disease (LAD) in the oral cavity, oropharynx, hypopharynx and larynx is indeed increasing over time, considering the growing and ageing population in the Netherlands. PATIENTS AND METHODS: Data were obtained from the Netherlands Cancer Registry (NCR). Primary head and neck squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx and larynx diagnosed between 1989 and 2017 were included. Yearly numbers and European standardized incidence rates (ESRs) were reported by extent of disease. The annual percentage change (APC) over time in ESRs was calculated to assess trends. RESULTS: Absolute numbers and ESRs of LAD increased over time for oral cavity and most prominently for oropharynx carcinomas (before 1996, APC: 0.4, 95%CI: 0.1; 0.8 and APC: 5.7 (95%CI: 3.1; 8.4) after 1996: 1.5 (1.0; 2.0) respectively. For hypopharynx cancer the absolute number and ESR of LAD increased until 1997 and declined with 0.8% per year since 1997. Absolute numbers of patients with larynx cancer stayed stable over time, while ESR decreased (APC: -0.8 (95%CI: -1.1; -0.6)). CONCLUSION: The perception of an increasing trend in LAD in the Netherlands can be attributed to the increasing incidence of oral cavity and oropharynx carcinomas. For LAD of the hypopharynx a decreasing trend was observed. In larynx cancer, the proportional share of LAD of the larynx increased, even though incidence rates declined.

Human papillomavirus status in young patients with head and neck squamous cell carcinoma.

The role of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) development has been recognized only in the last decade. Although younger patients develop HNSCC associated with HPV, the incidence in young patients has not been studied. Forty-five young HNSCC patients (<40 years) were tested for HPV and the expression of p16(ink4a) and p53 in tumor biopsies. The presence of HPV was correlated with the absence and presence of alcohol and tobacco exposure. Paraffin-embedded, archival biopsy materials from HNSCC of 45 patients younger than 40 years were analyzed. HPV subtypes were identified by PCR followed by genotyping. Expression of p16(ink4a) and p53 were determined by immunohistochemistry. Fourteen (31%) of the HNSCC specimens from 45 patients unequivocally exhibited HPV16 positivity. Sixty percentage of the oropharyngeal tumors and 5% of the oral cavity tumors were HPV16 positive. P16(ink4a) overexpression was detected in 93% of the HPV16-positive tumors. None of the HPV16 tumors showed p53 overexpression. There was no association of HPV positivity with (lack of) exposure to alcohol and smoking. HPV association was not exclusively detected in nonsmoking, nondrinking young HNSCC patients. The presence of p16(ink4a) accumulation and the absence of p53 overexpression are good surrogate markers for HPV-associated HNSCC.

The indwelling voice prosthesis for speech rehabilitation after total laryngectomy: a safe approach.

Primary prosthetic voice restoration by performing tracheoesophageal puncture (TEP) and immediate insertion of a voice prosthesis at the time of total laryngectomy (TLE) is presently the method of choice. This enables the easiest and most comfortable voice rehabilitation with the patient still under general anesthesia when the first prosthesis is inserted. Reconstruction of the pharynx with e.g. free revascularized or pedicled flaps does not preclude surgical prosthetic voice restoration. The TEP can even be done as a primary procedure after total laryngectomy and total pharyngectomy when the full circumference of the neopharynx has to be reconstructed, provided the esophagus is still present at the level of the trachea. Since indwelling devices may have a more robust construction, their device-life generally is longer than that of their non-indwelling counterparts. Indwelling devices have the unique advantage in that patient's dexterity plays a lesser role in the daily maintenance of the device. With a few refinements in the surgery of TLE several postlaryngectomy problems can be avoided or diminished such as hypertonicity of the pharyngoesophageal (PE) segment and a poor contour of the stoma. The combination of Heat and Moisture Exchanger (HME) and indwelling voice prosthesis contributes to a significant improvement of both pulmonary function and voice quality. The solution of the majority of prosthesis and TE-fistula related problems by the well trained physician, make prosthetic voice restoration a safe procedure.

Personalized biomechanical tongue models based on diffusion-weighted MRI and validated using optical tracking of range of motion.

For advanced tongue cancer, the choice between surgery and organ-sparing treatment is often dependent on the expected loss of tongue functionality after treatment. Biomechanical models might assist in this choice by simulating the post-treatment function loss. However, this function loss varies between patients and should, therefore, be predicted for each patient individually. In the present study, the goal was to better predict the postoperative range of motion (ROM) of the tongue by personalizing biomechanical models using diffusion-weighted MRI and constrained spherical deconvolution reconstructions of tongue muscle architecture. Diffusion-weighted MRI scans of ten healthy volunteers were obtained to reconstruct their tongue musculature, which were subsequently registered to a previously described population average or atlas. Using the displacement fields obtained from the registration, the segmented muscle fiber tracks from the atlas were morphed back to create personalized muscle fiber tracks. Finite element models were created from the fiber tracks of the atlas and those of the individual tongues. Via inverse simulation of a protruding, downward, left and right movement, the ROM of the tongue was predicted. This prediction was compared to the ROM measured with a 3D camera. It was demonstrated that biomechanical models with personalized muscles bundles are better in approaching the measured ROM than a generic model. However, to achieve this result a correction factor was needed to compensate for the small magnitude of motion of the model. Future versions of these models may have the potential to improve the estimation of function loss after treatment for advanced tongue cancer.

In-vivo tongue stiffness measured by aspiration: Resting vs general anesthesia.

Tongue cancer treatment often results in impaired speech, swallowing, or mastication. Simulating the effect of treatments can help the patient and the treating physician to understand the effects and impact of the intervention. To simulate deformations of the tongue, identifying accurate mechanical properties of tissue is essential. However, not many succeeded in characterizing in-vivo tongue stiffness. Those who did, measured the tongue At Rest (AR), in which muscle tone subsides even if muscles are not willingly activated. We expected to find an absolute rest state in participants 'under General Anesthesia' (GA). We elaborated on previous work by measuring the mechanical behavior of the in-vivo tongue under aspiration using an improved volume-based method. Using this technique, 5 to 7 measurements were performed on 10 participants both AR and under GA. The obtained Pressure-Shape curves were first analyzed using the initial slope and its variations. Hereafter, an inverse Finite Element Analysis (FEA) was applied to identify the mechanical parameters using the Yeoh, Gent, and Ogden hyperelastic models. The measurements AR provided a mean Young's Modulus of 1638 Pa (min 1035 - max 2019) using the Yeoh constitutive model, which is in line with previous ex-vivo measurements. However, while hoping to find a rest state under GA, the tongue unexpectedly appeared to be approximately 2 to 2.5 times stiffer under GA than AR. Explanations for this were sought by examining drugs administered during GA, blood flow, perfusion, and upper airway reflexes, but neither of these explanations could be confirmed.

Differential diagnosis of pulmonary carcinoma following head and neck cancer by genetic analysis.

PURPOSE: Patients with head and neck cancer often develop a lung tumor that can be diagnosed as distant metastasis (DM) or second primary tumor (SPT). In this study, we use TP53 mutation analysis for validation of an allelic loss marker panel and a decision algorithm for distinguishing between DM and SPT. EXPERIMENTAL DESIGN: Tumor pairs of 39 patients were analyzed for TP53 mutations, for patterns of allelic loss and immunohistochemical analysis of p53 expression. Results of these three analyses were compared, using mutation analysis as gold standard. RESULTS: Loss of heterozygosity (LOH) analysis indicated DM in 15 and SPT in 23 cases (one inconclusive). TP53 mutation analysis was informative in 15 cases. Based on the p53 mutation status alone, nine tumors were diagnosed as SPT and six as DM. In all 15 cases the LOH analysis was in concordance with the TP53 mutation analysis. Immunostaining for p53 showed promise as a first scan to diagnose lung tumors as SPT but cannot be used to diagnose DM. CONCLUSION: The TP53 mutation data validate the suitability of the LOH marker panel and decision algorithm for differential diagnosis of DM and SPT in the lung. LOH analysis can theoretically be exploited in almost all cases and is less laborious than TP53 mutation analysis.

Validated Prognostic Nomograms for Patients With Parotid Carcinoma Predicting 2- and 5-Year Tumor Recurrence-Free Interval Probability.

Introduction: Salivary gland malignancies are rare tumors with a heterogenous histological and clinical appearance. Previously, we identified multiple prognostic factors in patients with parotid cancer and developed prognostic indices which have repeatedly been validated internationally, demonstrating their general applicability and lasting relevance. Recently, nomograms gained popularity as a prognostic tool. Thus, in this research we aimed to construct nomograms based on our previous validated prognostic models. Material and Methods: Nomograms were constructed using the previously reported dataset of 168 patients with parotid cancer which was used to develop pre- and postoperative prognostic scores, PS1 and PS2, respectively. Concordance indices for PS1 and PS2 were previously estimated at 0.74 and 0.71, respectively, and are in line with other, widely accepted oncological nomograms. Results: Pre- and postoperative nomograms predicting 2- and 5-year tumor recurrence-free survival probability are presented. All previously multivariately identified and validated prognostic factors, are incorporated (T size, N classification, pain, age at diagnosis, skin invasion, facial nerve dysfunction, perineural growth, and positive surgical margins). Examples of clinical application and interpretation are given. Conclusions: The presented prognostic nomograms for predicting 2- and 5-year tumor recurrence-free probability in patients with parotid cancer are powerful, user-friendly, visual tools and are based on internationally validated prognostic indices. They allow for a reliable prognostic assessment and result in a more individualized estimate of the risk for recurrence than the prognostic grouping based on PS1 and PS2. This facilitates assigning trial-patients to risk groups, and may assist in therapeutic decision making and determining appropriate follow-up intervals in clinical practice.

The surgical dilemma of 'functional inoperability' in oral and oropharyngeal cancer: current consensus on operability with regard to functional results.

OBJECTIVES: If surgical resection of a tumour results in an unacceptable loss of function, this is defined as 'functional inoperability'. The current survey aims to define the borders of functional inoperability in oral and oropharyngeal carcinoma and evaluate its current use by obtaining opinions from the experts in the field. DESIGN: A web base survey. PARTICIPANTS: Dutch head-neck surgeons and radiotherapists. MAIN OUTCOME MEASURES: Assessment of functional results after tumour resection in twenty-two statements and five cases. RESULTS: Response on the survey is 93% and the reactions are variable. Reactions vary slightly by the size of the clinic or discipline (radiation oncology versus head and neck surgery). There is agreement about the unacceptable function loss after total glossectomy. There is no absolute consensus about the functional outcome after certain surgical procedures, namely: bilateral maxillectomy, resection of a tonsil and resection of base of tongue carcinoma including removal of the vallecula and epiglottis, and total soft palate resection. Disagreement of operability is also observed for T3 and T4 base of tongue carcinomas based on case descriptions and Magnetic Resonance Images. Assessment of whether one hypoglossal nerve can be preserved is agreed to be a key factor for functional operability. CONCLUSIONS: The term functional inoperability appears to be clinically used by Dutch experts in the decision making process in advanced head and neck carcinomas. According to the experts who took part in the survey, primary total glossectomy or sacrificing both hypoglossal nerves is an operation that causes too much and therefore unacceptable function loss. In several case scenarios a consensus over operability could not be reached by the experts. The decision varies per physician, institute and patient. Functional inoperability is variable and difficult to determine, but it is clinically used and therefore important to bring under attention.

Quantification of tongue mobility impairment using optical tracking in patients after receiving primary surgery or chemoradiation.

PURPOSE: Tongue mobility has shown to be a clinically interesting parameter on functional results after tongue cancer treatment which can be objectified by measuring the Range Of Motion (ROM). Reliable measurements of ROM would enable us to quantify the severity of functional impairments and use these for shared decision making in treatment choices, rehabilitation of speech and swallowing disturbances after treatment. METHOD: Nineteen healthy participants, eighteen post-chemotherapy patients and seventeen post-surgery patients were asked to perform standardized tongue maneuvers in front of a 3D camera system, which were subsequently tracked and corrected for head and jaw motion. Indicators, such as the left-right tongue range and the deflection angle with the horizontal axis were extracted from the tongue trajectory to serve as a quantitative measure for the impaired tongue mobility. RESULTS: The range and deflection angle showed an excellent intra- and interrater reliability (ICC 0.9) The repeatability experiment showed an average standard deviation of 2.5 mm to 3.5 mm for every movement, except the upward movement. The post-surgery patient group showed a smaller tongue range and higher deflection angle overall than the healthy participants. Post-chemoradiation patients showed less difference in tongue ROM compared with healthy participants. Only a few patients showed asymmetrical movement after treatment, which could not always be explained by T-stage or the side of treatment alone. CONCLUSION: We introduced a reliable and reproducible method for measuring the ROM and to quantify for motion impairments, that was able to show differences in tongue ROM between healthy subjects and patients after chemoradiation or surgery. Future research should focus on measuring patients with oral cancer pre- and post-treatment in combination with the collection of detailed information about the individual tongue anatomy, so that the full ROM trajectory can be used to identify changes over time and to quantify functional impairment.

An interactive surgical simulation tool to assess the consequences of a partial glossectomy on a biomechanical model of the tongue.

Oral cancer surgery has a negative influence on the quality of life (QOL). As a result of the complex physiology involved in oral functions, estimation of surgical effects on functionality remains difficult. We present a user-friendly biomechanical simulation of tongue surgery, including closure with suturing and scar formation, followed by an automated adaptation of a finite element (FE) model to the shape of the tongue. Different configurations of our FE model were evaluated and compared to a well-established FE model. We showed that the post-operative impairment as predicted by our model was qualitatively comparable to a patient case for five different tongue maneuvers.

Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor.

PURPOSE: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. METHODS: Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m(2)) cisplatin, weekly 40 mg/m(2), three-weekly 100 mg/m(2). A (32)P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. RESULTS: Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine-guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC (P<0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. CONCLUSIONS: In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy.

Salivary gland pleomorphic adenoma in the Netherlands: A nationwide observational study of primary tumor incidence, malignant transformation, recurrence, and risk factors for recurrence.

INTRODUCTION: Whereas salivary gland pleomorphic adenoma (SGPA) is the most common type of salivary gland tumor, little is known about its epidemiology because national cancer registries do not register this disease. OBJECTIVES: To establish SGPA incidence trends, rates of secondary malignant transformation and recurrence and associated factors in the Netherlands. MATERIALS AND METHODS: Data on incidence, epidemiology, secondary malignant transformation and recurrence were retrieved from the Dutch pathology registry (PALGA) for the years 1992, 1997, 2002, 2007, and 2012. Multivariate analysis was performed to discover the risk factors for recurrence. RESULTS: 3506 cases of SGPA were recorded implying an overall European standardized rate of 4.2-4.9 per 100,000 person-years. Our figures showed a female preponderance (1:1.43) with an annual 1% rise in female incidence (95% confidence interval [CI]: 0.2-1.8) and a bimodal age distribution in women (p<0.0001). The overall 20-year recurrence rate was 6.7%, and median time to first recurrence was 7years. Positive and uncertain resection margins and younger age at diagnosis were risk factors for recurrence, with odds ratios (ORs) of 4.62 (95%CI 2.84-7.51), 4.08 (95%CI 2.24-7.43), and 0.42 (95%CI 0.29-0.63) respectively. Tumor locations in the minor salivary glands had lower odds of recurrence than tumors in the parotid (OR 0.24; 95% CI: 0.07-0.77; p<0.016). Malignant transformation occurred in 0.15% of SGPAs (3.2% of recurrences). CONCLUSION: This first nationwide study clearly showed sex differences in SGPA epidemiology, possibly suggesting some underlying hormonal mechanism. Long-term recurrence risks were low, and secondary malignant transformation risks were very low.

Variation in head and neck cancer care in the Netherlands: A retrospective cohort evaluation of incidence, treatment and outcome.

BACKGROUND: To explore variation in numbers and treatment between hospitals that treat head and neck cancer (HNC) in the Netherlands. MATERIAL AND METHODS: Patient, tumor and treatment characteristics were collected from the Netherlands Cancer Registry, while histopathological features were obtained by linkage to the national pathology record register PALGA. Inter-hospital variation in volume, stage, treatment, pathologically confirmed loco-regional recurrence and overall survival rate was evaluated by tumor site. RESULTS: In total, 2094 newly diagnosed patients were included, ranging from 65 to 417 patients in participating hospitals treating HNC in 2008. Oral cavity cancer was mainly treated by surgery only, ranging from 46 to 82% per hospital, while the proportion of surgery with (chemo)radiotherapy ranged from 18 to 40%. Increasing age, male sex, and high stage were associated with a higher hazard of dying. In oropharynx cancer, the use of (chemo)radiotherapy varied from 31 to 82% between hospitals. We found an indication that higher volume was associated with a lower overall hazard of dying for the total group, but not by subsite. Low numbers, e.g. for salivary gland, nasopharynx, nasal cavity and paranasal sinus, did not permit all desired analyses. CONCLUSION: This study revealed significant interhospital variation in numbers and treatment of especially oropharyngeal and oral cavity cancer. This study is limited because we had to rely on data recorded in the past for a different purpose. To understand whether this variation is unwanted, future research should be based on prospectively collected data, including detailed information on recurrences, additional case-mix information and cause of death.

Future opportunities in preventing cisplatin induced ototoxicity.

Cisplatin is one of the most commonly used cytotoxic agents. Ototoxicity is an important and dose-limiting side-effect of cisplatin therapy. It is believed that cisplatin suppresses the formation of endogenous anti-oxidants that normally prevent the inner ear against reactive oxygen species (ROS). These ROS affect the outer hair cells (OHCs) in the organ of Corti. Results from clinical trials with amifostine, an anti-oxidant with possible otoprotective action during cisplatin therapy, were disappointing. A variety of agents with chemoprotective action against cisplatin-induced ototoxicity were successfully tested in animal models. It is important to translate these promising results from animal models into clinical practice. The possible routes of administration are systemic and transtympanic. An important condition when using such an agent systemically is that the compound may not affect the anti-tumor effect of cisplatin. The critical step at transtympanic administration is the diffusion of the compound through the round window membrane (RWM). This diffusion depends on the characteristics of the medication as on the properties of the RWM. Positive results of an otoprotector in clinical practice may increase the effectiveness of cisplatin therapy and can improve the quality of life for a large group of patients.