Malnutrition risk and frailty in head and neck cancer patients: coexistent but distinct conditions.

PURPOSE: Both malnutrition and frailty are associated with adverse treatment outcomes. Malnutrition (risk) and frailty are each commonly present in patients with head and neck cancer (HNC). However, their coexistence and association is unknown. Main goal of this study is to determine the coexistence of, and the association between malnutrition risk and frailty in patients with HNC. METHODS: In this retrospective analysis on prospectively collected data, newly diagnosed patients with HNC, enrolled in the OncoLifeS databiobank were included. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) was used to assess malnutrition risk. The Groningen Frailty Indicator (GFI) was used to assess frailty status. Multivariate logistic regression analyses were performed, taking into account several patient- and tumor-related factors. RESULTS: In total, 197 patients were included. Seventy-six patients (39%) had a medium or high malnutrition risk and 71 patients (36%) were frail. In 38 patients (19%), malnutrition risk coexisted with frailty. Patients with medium and high malnutrition risk were, respectively, 4.0 (95% CI 1.5-11.2) and 13.4 (95% CI 4.0-48.7) times more likely to be frail, compared to patients with low malnutrition risk. In turn, frail patients were 6.4 times (95% CI 2.6-14.9) more likely to have malnutrition risk compared to non-frail patients. CONCLUSIONS: Malnutrition risk and frailty frequently coexist but not fully overlap in newly diagnosed patients with HNC. Therefore, screening for both conditions is recommended.

The use of stretching devices for treatment of trismus in head and neck cancer patients: a randomized controlled trial.

PURPOSE: To compare the effects of two stretching devices, the TheraBite® Jaw Motion Rehabilitation System™ and the Dynasplint Trismus System®, on maximal mouth opening in head and neck cancer patients. METHODS: Patients were randomly assigned to one of two exercise groups: the TheraBite® Jaw Motion Rehabilitation System™ group or the Dynasplint Trismus System® group. Patients performed stretching exercises for 3 months. During the three study visits, maximal mouth opening was measured and the patients completed questionnaires on mandibular function and quality of life. RESULTS: In our study population (n = 27), five patients did not start the exercise protocol, eight patients discontinued exercises, and two patients were lost to follow-up. No significant differences regarding the change in mouth opening between the two devices were found. Patients had an increase in MMO of 3.0 mm (IQR - 2.0; 4.0) using the TheraBite® Jaw Motion Rehabilitation System™ and 1.5 mm (IQR 1.0; 3.0) using the Dynasplint Trismus System®. Exercising with either stretching device was challenging for the patients due to the intensive exercise protocol, pain during the exercises, fitting problems with the stretching device, and overall deterioration of their medical condition. CONCLUSIONS: The effects of the two stretching devices did not differ significantly in our study population. The factors described, influencing the progression of stretching exercises, need to be taken into account when prescribing a similar stretching regimen for trismus in head and neck cancer patients. TRIAL REGISTRATION: NTR - Dutch Trial Register number: 5589.

Reasons for low uptake of a psychological intervention offered to cancer survivors with elevated depressive symptoms.

OBJECTIVE: In line with screening guidelines, cancer survivors were consecutively screened on depressive symptoms (as part of standard care), with those reporting elevated levels of symptoms offered psychological care as part of a trial. Because of the low uptake, no conclusions could be drawn about the interventions' efficacy. Given the trial set-up (following screening guidelines and strict methodological quality criteria), we believe that this observational study reporting the flow of participation, reasons for and characteristics associated with nonparticipation, adds to the debate about the feasibility and efficiency of screening guidelines. METHODS: Two thousand six hundred eight medium- to long-term cancer survivors were consecutively screened on depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9). Those with moderate depressive symptoms (PHQ-9 ≥ 10) were contacted and informed about the trial. Patient flow and reasons for nonparticipation were carefully monitored. RESULTS: One thousand thirty seven survivors (74.3%) returned the questionnaire, with 147 (7.6%) reporting moderate depressive symptoms. Of this group, 49 survivors (33.3%) were ineligible, including 26 survivors (17.7%) already receiving treatment and another 44 survivors (30.0%) reporting no need for treatment. Only 25 survivors (1.0%) participated in the trial. CONCLUSION: Of the approached survivors for screening, only 1% was eligible and interested in receiving psychological care as part of our trial. Four reasons for nonparticipation were: nonresponse to screening, low levels of depressive symptoms, no need, or already receiving care. Our findings question whether to spend the limited resources in psycho-oncological care on following screening guidelines and the efficiency of using consecutive screening for trial recruitment in cancer survivors.

Criterion for trismus in head and neck cancer patients: a verification study.

PURPOSE: Several cut-off points for trismus in head and neck cancer patients have been used. A mouth opening of 35 mm or less is most frequently used as cut-off point. Due to the variation in cut-off points, prevalence, risk factors and treatment outcomes of trismus cannot be studied in a uniform manner. To provide uniformity, we aimed to verify the cut-off point of 35 mm or less. Additionally, we aimed to determine associated covariates with reported difficulties when opening the mouth. METHODS: In a cross-sectional design, we measured the mouth opening in 671 head and neck cancer patients at the Department of Oral and Maxillofacial Surgery, at the University Medical Center Groningen. The cut-off point was determined using the receiver operating characteristic curve and Youden index, with reported difficulties when opening the mouth as criterion for trismus. Cut-off points for significant covariates were also determined. RESULTS: The Youden index was highest at 35 mm, with a sensitivity of 0.71 and a specificity of 0.86. Of the covariates analysed, type of treatment modality was significantly associated with reported difficulties when opening the mouth. The highest Youden index for patients treated with surgery alone was 37 mm and for patients treated with radiotherapy alone 33 mm. CONCLUSIONS: The cut-off point of 35 mm or less for trismus was confirmed in a head and neck cancer population and is recommended to be used in future studies. Patients receiving different treatment modalities experience difficulty when opening the mouth differently.

Effect of adjuvant radiotherapy on the local recurrence of oral squamous cell carcinoma with perineural invasion: A systematic review.

OBJECTIVES OF THE REVIEW: The decision whether to include postoperative radiotherapy on patients with oral squamous cell carcinoma depends on the risk of local recurrence. The objectives of this study were to systematically review literature on whether perineural invasion in oral squamous cell carcinoma patients is associated with higher local recurrence rates and whether local recurrence is influenced by the administration of postoperative radiotherapy in patients presenting with perineural invasion. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: Embase, PubMed, Web Of Science. EVALUATION METHOD: The databases above were searched for studies that analysed: the treatment of oral squamous cell carcinoma patients with perineural invasion, local recurrence and postoperative radiotherapy. The data of seven studies were analysed qualitatively. RESULTS: The overall quality of the studies was moderate to low. There was no evidence of the effect of postoperative radiotherapy on local recurrence rates in patients presenting with perineural invasion. Some evidence suggests that local recurrence rates may increase in cases of multifocal perineural invasion, especially if nerves >1 mm are involved but these data should be interpreted with caution due to the low-quality evidence. CONCLUSIONS: High-quality evidence regarding the prognostic value of perineural invasion and the impact of postoperative radiotherapy in patients presenting with perineural invasion is lacking in the literature, making it difficult to select a postoperative strategy for early-stage tumours.

Epidermal growth factor receptor (EGFR) density may not be the only determinant for the efficacy of EGFR-targeted photoimmunotherapy in human head and neck cancer cell lines.

OBJECTIVE: The aim of this study was to investigate the effects of targeted photoimmunotherapy (PIT) in vitro on cell lines with various expression levels of epidermal growth factor receptor (EGFR) using an anti-EGFR targeted conjugate composed of Cetuximab and IR700DX, phthalocyanine dye. MATERIALS AND METHODS: Relative EGFR density and cell binding assay was conducted in three human head & neck cancer cell lines (scc-U2, scc-U8, and OSC19) and one reference cell line A431. After incubation with the conjugate for 1 or 24 hours, cellular uptake and localization were investigated by confocal laser scanning microscopy and quantified by image analysis. Cell survival was determined using the MTS assay and alamarBlue assay after PIT with a 690 nm laser to a dose of 7 J.cm-2 (at 5 mW.cm-2 ). The mode of cell death was examined with flow cytometry using apoptosis/necrosis staining by Annexin V/propidium iodide, together with immunoblots of anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL. RESULTS: A431 cells had the highest EGFR density followed by OSC19, and then scc-U2 and scc-U8. The conjugates were localized both on the surface and in the cytosol of the cells after 1- and 24-hour incubation. After 24-hour incubation the granular pattern was more pronounced and in a similar pattern of a lysosomal probe, suggesting that the uptake of conjugates by cells was via receptor-mediated endocytosis. The results obtained from the quantitative imaging analysis correlate with the level of EGFR expression. Targeted PIT killed scc-U8 and A431 cells efficiently; while scc-U2 and OSC19 were less sensitive to this treatment, despite having similar EGFR density, uptake and localization pattern. Scc-U2 cells showed less apoptotic cell dealth than in A431 after 24-hour targeted PIT. Immunoblots showed significantly higher expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in scc-U2 cell lines compared to scc-U8. CONCLUSION: Our study suggests that the effectiveness of EGFR targeted PIT is not only dependent upon EGFR density. Intrinsic biological properties of tumor cell lines also play a role in determining the efficacy of targeted PIT. We have shown that in scc-U2 cells this difference may be caused by differences in the apoptopic pathway. Lasers Surg. Med. 50:513-522, 2018. © 2018 Wiley Periodicals, Inc.

Multidisciplinary first-day consultation accelerates diagnostic procedures and throughput times of patients in a head-and-neck cancer care pathway, a mixed method study.

BACKGROUND: Head and neck cancers are fast growing tumours that are complex to diagnose and treat. Multidisciplinary input into organization and logistics is critical to start treatment without delay. A multidisciplinary first-day consultation (MFDC) was introduced to reduce throughput times for patients suffering from head and neck cancer in the care pathway. In this mixed method study we evaluated the effects of introducing the MFDC on throughput times, number of patient hospital visits and compliance to the Dutch standard to start treatment within 30 calendar-days. METHODS: Data regarding 'days needed for referral', 'days needed for diagnostic procedures', 'days to start first treatment', and 'number of hospital visits' (process indicators) were retrieved from the medical records and analysed before and after implementation of the MFDC (before implementation: 2007 (n = 21), and after 2008 (n = 20), 2010 (n = 24) and 2013 (n = 24)). We used semi-structured interviews with medical specialists to explore a sample of outliers. RESULTS: Comparing 2007 and 2008 data (before and after MFDC implementation), days needed for diagnostic procedures and to start first treatment reduced with 8 days, the number of hospital visits reduced with 1.5 visit on average. The percentage of new patients treated within the Dutch standard of 30 calendar-days after intake increased from 52 to 83%. The reduction in days needed for diagnostic procedures was sustainable. Days needed to start treatment increased in 2013. Semi-structured interviews revealed that this delay could be attributed to new treatment modalities, patients needed more time to carefully consider their treatment options or professionals needed extra preparation time for organisation of more complex treatment due to early communication on diagnostic procedures to be performed. CONCLUSIONS: A MFDC is efficient and benefits patients. We showed that the MFDC implementation in the care pathway had a positive effect on efficiency in the care pathway. As a consequence, the extra efforts of four specialist disciplines, a nurse practitioner, and a coordinating nurse seeing the patient together during intake, were justified. Start treatment times increased as a result of new treatment modalities that needed more time for preparation.

Identification and validation of WISP1 as an epigenetic regulator of metastasis in oral squamous cell carcinoma.

Lymph node (LN) metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC) patients. However, in approximately one third of OSCC patients nodal metastases remain undetected, and thus are not adequately treated. Therefore, clinical assessment of LN metastasis needs to be improved. The purpose of this study was to identify DNA methylation biomarkers to predict LN metastases in OSCC. Genome wide methylation assessment was performed on six OSCC with (N+) and six without LN metastases (N0). Differentially methylated sequences were selected based on the likelihood of differential methylation and validated using an independent OSCC cohort as well as OSCC from The Cancer Genome Atlas (TCGA). Expression of WISP1 using immunohistochemistry was analyzed on a large OSCC cohort (n = 204). MethylCap-Seq analysis revealed 268 differentially methylated markers. WISP1 was the highest ranking annotated gene that showed hypomethylation in the N+ group. Bisulfite pyrosequencing confirmed significant hypomethylation within the WISP1 promoter region in N+ OSCC (P = 0.03) and showed an association between WISP1 hypomethylation and high WISP1 expression (P = 0.01). Both these results were confirmed using 148 OSCC retrieved from the TCGA database. In a large OSCC cohort, high WISP1 expression was associated with LN metastasis (P = 0.05), disease-specific survival (P = 0.022), and regional disease-free survival (P = 0.027). These data suggest that WISP1 expression is regulated by methylation and WISP1 hypomethylation contributes to LN metastasis in OSCC. WISP1 is a potential biomarker to predict the presence of LN metastases.

Trends in oral cavity cancer incidence, mortality, survival and treatment in the Netherlands.

Information on epidemiology is essential to evaluate care for the growing group of oral cancer patients. We investigated trends in incidence, mortality and relative survival rates for oral cavity cancer (OCC) and its subsites in the Netherlands from 1991 to 2010, and relate these to changes in stage and treatment. Patient (age, sex), tumour (subsite, stage) and treatment characteristics of patients diagnosed with OCC (ICD-O-3: C02-C06) in 1991-2010 were extracted from the Netherlands Cancer Registry. Incidence, mortality and 5-year relative survival rates over time are presented, as well as trends in type of treatment. The incidence of OCC increased with +1.2% (95%CI: +0.9%;+1.6%) per year: more strongly in women, stage I and IV disease, and in cancers of the tongue and gum. The mortality rate slightly rose (+0.8%, 95%CI: +0.3%;+1.3% per year), but differed by subsite. The 5-year relative survival improved from 57% in 1991-1995 to 62% in 2006-2010. The 5-year relative survival was better for women compared with men (64% and 55%, respectively), decreased with increasing stage, was the best for tongue cancer (63%) and the worst for cancer of the gum (56%) and floor of mouth cancer (55%). The relative excess risk of dying was higher for non-surgery-based treatments. Surgery was the main treatment option and the proportion of "surgery only" rose in stage I and III disease. The incidence and, to a lesser extent, mortality of OCC are increasing and therefore, even with slightly improving survival rates, OCC is an increasingly important health problem.

Reproducibility and prognostic value of pattern of invasion scoring in low-stage oral squamous cell carcinoma.

AIMS: To evaluate and compare the prognostic value and reproducibility of different methods of pattern of invasion scoring in oral squamous cell carcinomas. The additional prognostic value to established histopathological prognostic factors was also analysed. METHODS AND RESULTS: The study group was confined to 211 previously untreated patients who underwent surgery for low-stage oral squamous cell carcinoma between 1997 and 2008. Median follow-up was 64 months (range 0-193 months). Pattern of invasion was scored using five previously described methods, at random and independently, by two observers. Pattern of invasion scoring showed moderate interobserver reproducibility (Cohen's κ = 0.52-0.58). The predominant pattern of invasion and the summed predominant and worst pattern of invasion were independent prognosticators for locoregional recurrence-free survival (LRRFS) [hazard ratio (HR): 2.1, P = 0.033 and HR 2.2, P = 0.024, respectively] and disease-specific survival (DSS) (HR 2.3, P = 0.032 and HR 2.1, P = 0.044, respectively) in multivariate Cox regression analyses. The Harrell's C index for proven prognostic histopathological factors was 0.66 for LRRFS and 0.67 for DSS. This improved to 0.69 and 0.73 with the addition of pattern of invasion. CONCLUSIONS: Pattern of invasion is an independent prognostic factor in low-stage oral squamous cell carcinoma. However, it has a moderate reproducibility, and the contributory value next to other prognostic histopathological factors is minimal.

Predictors for trismus in patients receiving radiotherapy.

BACKGROUND: Trismus, a restricted mouth opening in head and neck cancer patients may be caused by tumor infiltration in masticatory muscles, radiation-induced fibrosis or scarring after surgery. It may impede oral functioning severely. The aims of our study were to determine: (1) the incidence of trismus at various time points; and (2) the patient, tumor, and treatment characteristics that predict the development of trismus after radiotherapy in head and neck cancer patients using a large database (n = 641). METHODS: Maximal mouth opening was measured prior to and 6, 12, 18, 24, 36, and 48 months after radiotherapy. Patient, tumor, and treatment characteristics were analyzed as potential predictors for trismus using a multivariable logistic regression analysis. RESULTS: At six months after radiotherapy, 28.1% of the patients without trismus prior to radiotherapy developed trismus for the first time. At subsequent time points the incidence declined. Over a total period of 48 months after radiotherapy, the incidence of trismus was 3.6 per 10 person years at risk. Patients who had tumors located in the oral cavity, oropharynx or nasopharynx, and the salivary glands or ear, and who had a longer overall treatment time of radiotherapy, were more likely to develop trismus in the first six months after radiotherapy. Maximal mouth opening was a predictor for developing trismus at all time points. CONCLUSION: Incidence of trismus is 3.6 per 10 person years at risk. Tumor localization and overall treatment time of radiotherapy are predictors for developing trismus the first six months after radiotherapy. Maximal mouth opening is a significant predictor for developing trismus at all time points. Regular measurements of maximal mouth opening are needed to predict trismus.

Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The current knowledge about potential risk factors for lymph node (LN) metastasis in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) is primarily based on studies that lack adjustment for confounding variables. OBJECTIVES: We sought to identify independent risk factors for LN metastasis in patients with HNcSCC and to evaluate the impact of LN metastasis on prognosis. METHODS: Patients with primary HNcSCC were retrospectively included. Potential risk factors were analyzed by univariate and multivariate Cox regression models. Survival was compared using the Kaplan-Meier method. RESULTS: Three hundred thirty-six patients with 545 primary HNcSCCs were included. The median follow-up period was 43 months (range, 1-176 months). LN metastasis occurred in 55 patients (16.4%). The following independent risk factors of HNcSCC for the development of LN metastasis were identified: location on the ear, tumor diameter >50 mm, moderate and poor differentiation, and tumor thickness >2 mm. There was a significant decline in disease-specific survival and overall survival in patients with LN metastasis compared to patients without LN metastasis. LIMITATIONS: The retrospective study design. CONCLUSION: LN metastases from HNcSCC are common with diminished survival rates. This study confirmed some well-known risk factors, but also found moderate differentiation as an independent risk factor for LN metastasis.

Dynasplint Trismus System exercises for trismus secondary to head and neck cancer: a prospective explorative study.

PURPOSE: The Dynasplint Trismus System (DTS) can be used to treat trismus secondary to head and neck cancer. We conducted a prospective study with the following aims: (1) to determine the effects of DTS exercises on changes in mouth opening, pain, mandibular function, quality of life (QoL), and symptomatology and (2) to analyze the patients' perception on DTS exercises, including user satisfaction, experiences, comfort, and compliance. METHODS: The patients were instructed to exercise with the DTS for at least 16 weeks. Changes in mouth opening, pain, mandibular function, QoL, and symptomatology were evaluated, as well as the patients' perception of DTS exercises. RESULTS: Eighteen consecutive patients were included. Baseline mouth opening was 22.6 mm (sd 7.6). After the patients completed the DTS exercise program, mouth opening increased (7.1 mm, sd 4.7) and perceived difficulty of opening the mouth improved significantly (p < 0.05). No significant effects were found in mandibular function, QoL, and overall symptomatology. The patients' perception was diverse. They reported effectiveness and positive feelings of the results and would recommend DTS exercises to other patients. About half of them thought DTS exercises were burdensome. CONCLUSIONS: Mouth opening increased significantly after the DTS exercise program, relative to baseline. About one third of the gained increase was lost in the follow-up period. In general, the patients were satisfied about the effects and the DTS exercise program.

Free flap reconstruction for head and neck cancer can be safely performed in both young and elderly patients after careful patient selection.

Surgical treatment of head and neck cancer often results in complex defects requiring reconstruction with microvascular free tissue transfer. However, in elderly patients, curative treatment with radical surgery and free flap reconstruction is often withheld. The objective of this study is to assess the outcomes of free flap surgery in elderly patients, using a standard surgical complication classification system. A retrospective review was conducted of patients who underwent primary free flap reconstruction following major surgery for head and neck cancer between 1995 and 2010. Complications were assessed using the Clavien Dindo classification system, and grades III-V were classified as major complications. Comorbidity was classified according to the adult comorbidity evaluation index 27. A comparison was done between patients <70 and ≥70 years. Two hundred-two patients were included in this study. Multivariate analysis showed that only disease stage was a significant predictor of recipient site complications, and comorbidity was the only significant predictor of medical complications. Age was not a predictor of complications. There were no significant differences in disease specific or overall survival between young and elderly patients. Optimal patient selection for free flap surgery is essential. This requires thorough pre-operative assessment, including analysis of comorbidity in both young and elderly patients. Patients' biological age, and not chronological age, should be individually determined to assess feasibility of major surgery. Patients should not be denied surgery based on age alone.

Relation between age, comorbidity, and complications in patients undergoing major surgery for head and neck cancer.

BACKGROUND: Multiple factors have been identified as predictors of complication after head and neck surgery. However, little is known about the exact role of different comorbid conditions in the development of postoperative complications. This question is especially interesting in the elderly population. The aim of this study was to investigate the association between comorbidity and types of postoperative complications with special attention to age differences. METHODS: A retrospective analysis was performed of 1,201 major surgical interventions for head and neck malignancies in a tertiary referral center between 1995 and 2010. The Adult Comorbidity Evaluation 27 (ACE-27) index was used to analyze severity (mild, moderate, and severe comorbidity) and type (12 different organ systems) of comorbidity. The Clavien-Dindo index was used to evaluate grade and type of complications after treatment. RESULTS: In univariate analysis gender, comorbidity, stage, mandibulectomy, total laryngectomy, neck dissection, and length of surgery significantly predicted grade of complication. In a multivariate analysis, complication was predicted by age, stage, length of surgery, and various comorbidities. After specification of the complications, age was only a predictor of medical complications; tumor stage was a significant factor in surgical complications. Length of surgery was the only significant variable in all types of complications. CONCLUSIONS: Specific comorbidities are associated with specific complications; however, age itself seems not to be a contraindication for major head and neck surgery. With careful preoperative assessment and risk analysis, physicians can better individualize treatment recommendations.

Photochemical internalization (PCI)-mediated enhancement of bleomycin cytotoxicity by liposomal mTHPC formulations in human head and neck cancer cells.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) with photosensitizers that locate in endocytic vesicles of cancer cells can be exploited to promote the intracellular release of anticancer drugs entrapped in endolysosomal vesicles. This new approach is commonly referred to as Photochemical Internalization (PCI). Here we report on the PCI effects of three different formulations (Foscan, Foslip, and Fospeg) of the clinically approved photosensitizer, meta-tetrahydroxyphenyl chlorin (mTHPC) on the anticancer drug bleomycin (BLM) in the head and neck cancer cell lines. MATERIALS AND METHODS: Uptake and localization of Foscan, Foslip, and Fospeg in head and neck cancer cells were evaluated by fluorescence spectrophotometry and fluorescence microscopy. Photodynamic efficacy of Foscan, Foslip, and Fospeg were compared with cell proliferation assay. Moreover, PCI effects of Foscan, Foslip, and Fospeg on BLM were compared using protocols in which PDT was applied after or before BLM treatment. RESULTS: Cellular uptake of Foscan, Foslip, and Fospeg increased in a dose-dependent fashion with consistent higher uptakes of Foslip and Fospeg than Foscan. Fluorescence microscopy showed diffuse intracellular localization pattern for Foscan, Foslip, and Fospeg similar to that of a specific ER probe. However, the subcellular localization pattern of the Rhodamine-labelled same type of pegylated liposomes as Fospeg was similar to that of a specific endolysosomal probe, suggesting that Fospeg uptake appeared to initially proceed via endolysosomal trafficking. Foscan, Foslip, and Fospeg showed no apparent PCI-mediated cytotoxicity when PDT was performed after BLM treatment. However, significantly increased cytotoxicity of BLM (P < 0.05) was observed for both Foslip and Fospeg when PDT was performed before BLM treatment. The observed differences of PCI-mediated cytotoxicity between these two timing protocols appears to be related to the differential intracellular trafficking and localization of Foscan, Foslip, and Fospeg. CONCLUSION: Liposomal formulations of mTHPC may be candidates for developing mTHPC-based PCI protocols to enhance the efficacy of anticancer drugs entrapped in endolysosomal vesicles.

mTHPC-mediated photodynamic therapy of early stage oral squamous cell carcinoma: a comparison to surgical treatment.

BACKGROUND: mTHPC-mediated photodynamic therapy (PDT) is used for treatment of early head and neck squamous cell carcinoma. This study is a retrospective comparison of PDT with transoral surgery in the treatment of early primary squamous cell carcinoma of the oral cavity/oropharynx. METHODS: PDT data were retrieved from four study databases; surgical results were retrieved from our institutional database. To select similar primary tumors, infiltration depth was restricted to 5 mm for the surgery group. A total of 126 T1 and 30 T2 tumors were included in the PDT group, and 58 T1 and 33 T2 tumors were included in the surgically treated group. RESULTS: Complete response rates with PDT and surgery were 86 and 76% for T1, respectively, and for T2 63 and 78%. Lower local disease-free survival for PDT compared to surgery was found. However, when comparing the need for local retreatment, no significant difference for T1 tumors was found, while for T2 tumors surgery resulted in significantly less need for local retreatment. No significant differences in overall survival between surgery and PDT were observed. CONCLUSIONS: PDT for T1 tumors results in a similar need for retreatment compared to surgery, while for T2 tumors PDT performs worse. Local disease-free survival for surgery is better than for PDT. This may be influenced by the benefit surgery has of having histology available. This allows an early decision on reintervention, while for PDT one has to follow a wait-and-see policy. Future prospective studies should compare efficacy as well as morbidity.

TheraBite exercises to treat trismus secondary to head and neck cancer.

PURPOSE: The aim of this study was to evaluate the effect of TheraBite exercises on mouth opening and to analyze factors influencing this effect in a patient record evaluation. METHODS: Effect of exercises with a TheraBite to treat trismus was evaluated in 69 head and neck cancer patients of two university medical centers. Mouth opening was measured as interincisal distance in millimeters. Patient, tumor, and treatment characteristics were analyzed for their relationship with change in mouth opening. Variables univariately associated (p ≤ 0.05) with change in mouth opening were entered in a logistic regression analysis as possible predictors for an increase in mouth opening of the smallest detectable difference of 5 mm or more. RESULTS: Mean initial mouth opening was 22.0 mm (SD 6.4); mean increase in mouth opening was 5.4 mm (SD 5.7). "Chemotherapy", "medical center", and "time from oncological treatment to start exercises" were significantly associated with an increase in mouth opening. In the logistic regression analysis, "medical center" (ß = 1.97) and "time from oncological treatment to start exercises" reduced the odds of reaching an increase in mouth opening of 5 mm or more, ß = -0.11 per month. CONCLUSIONS: After TheraBite exercises, mouth opening increased averagely with 5.4 mm. The odds of an increase in mouth opening of 5 mm or more reduces if the time from oncological treatment to start exercises lengthens, corrected for the effect of medical center.

Localization of liposomal mTHPC formulations within normal epithelium, dysplastic tissue, and carcinoma of oral epithelium in the 4NQO-carcinogenesis rat model.

BACKGROUND AND OBJECTIVE: Foslip and Fospeg are liposomal formulations of the photosensitizer mTHPC (Foscan), which is used for photodynamic therapy (PDT) of malignancies. Literature suggests that liposomal mTHPC formulations have better properties and increased tumor uptake compared to Foscan. To investigate this, we used the 4NQO-induced carcinogen model to compare the localization of the different mTHPC formulations within normal, precancerous, and cancerous tissue. In contrast to xenograft models, the 4NQO model closely mimics the carcinogenesis of human oral dysplasia. MATERIALS AND METHODS: Fifty-four rats drank water with the carcinogen 4NQO. When oral examination revealed tumor, the rats received 0.15 mg/kg mTHPC (Foscan, Foslip, or Fospeg). At 2, 4, 8, 24, 48, or 96 hours after injection the rats were sacrificed. Oral tissue was sectioned for HE slides and for fluorescence confocal microscopy. The HE slides were scored on the severity of dysplasia by the epithelial atypia index (EAI). The calibrated fluorescence intensity per formulation or time point was correlated to EAI. RESULTS: Fospeg showed higher mTHPC fluorescence in normal and tumor tissue compared to both Foscan and Foslip. Significant differences in fluorescence between tumor and normal tissue were found for all formulations. However, at 4, 8, and 24 hours only Fospeg showed a significant difference. The Pearson's correlation between EAI and mTHPC fluorescence proved weak for all formulations. CONCLUSION: In our induced carcinogenesis model, Fospeg exhibited a tendency for higher fluorescence in normal and tumor tissue compared to Foslip and Foscan. In contrast to Foscan and Foslip, Fospeg showed significantly higher fluorescence in tumor versus normal tissue at earlier time points, suggesting a possible clinical benefit compared to Foscan. Low correlation between grade of dysplasia and mTHPC fluorescence was found.

Alternative PET tracers in head and neck cancer. A review.

Positron emission tomography (PET) has become a standard in staging Head and Neck cancer. While (18)F-fluoro-2-deoxy-D-glucose (FDG) is the most frequently used radiopharmaceutical, glycolysis is not the only metabolic process that can be visualized. Different PET tracers can also be used to visualize other metabolic processes and in this manner, the disadvantages of FDG PET can be avoided. In this review, we describe a comprehensive overview of alternatives to FDG that can be used in identifying head and neck cancer. The potential advantages and disadvantages of these radiopharmaceuticals are discussed.