Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo.

BACKGROUND: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs. METHODS: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3). RESULTS: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure. CONCLUSION: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.

Association between human papillomavirus status and health-related quality of life in oropharyngeal and oral cavity cancer survivors.

OBJECTIVES: The human papillomavirus (HPV) is a risk factor for a subgroup of head and neck cancers (HNC). HPV-positive and HPV-negative HNC patients encompass heterogeneous groups regarding risk factors, sociodemographic and clinical characteristics, which may influence health-related quality of life (HRQL) differently. Since this has been sparsely studied, our study investigated the association between HPV status and HRQL in HNC survivors in Denmark. MATERIALS AND METHODS: This cross-sectional study included 179 recurrence-free oropharyngeal and oral cavity squamous cell carcinoma (OSCC) survivors. HRQL was assessed on the EORTC QLQ-C30 and QLQ-H&N35 questionnaires. Linear and logistic regression models were adjusted for sociodemographic, clinical and lifestyle factors. RESULTS: Most unadjusted results showed better HRQL among HPV-positive (n = 119) compared to HPV-negative (n = 60) OSCC survivors (average 18 months since diagnosis). After adjustments, the HPV-positive survivors reported higher role functioning (mean difference [MD] 9.2, 95% confidence interval [CI] 0.1 to -18.4), and fewer problems with speech (MD -9.0, 95% CI -18.0 to -0.1), sexuality (MD -21.9, 95% CI -38.0 to -5.9) and opening mouth (MD -13.7, 95% CI -26.6 to -0.8) compared to HPV-negative survivors. CONCLUSION: Our findings support that HPV-positive OSCC survivors experience better HRQL than HPV-negative survivors. However, results indicate that sociodemographic, clinical and lifestyle factors explain most of the association between HPV status and HRQL. Findings suggest increased focus on the HPV-negative OSCC survivors with deteriorated HRQL in rehabilitation programs and future research to investigate the long-term effects of treatment among HPV-positive OSCC survivors who may develop symptoms later in survivorship.

Effectiveness of multidisciplinary nutritional support in older hospitalised patients: A systematic review and meta-analyses.

Malnutrition is common in older hospitalised patients. As the aetiology is multifactorial, nutritional care should involve a multidisciplinary team. However, the knowledge of the effectiveness of this strategy is limited. This systematic review aims at investigating the effectiveness of multidisciplinary nutritional support on mortality, readmissions and quality of life (QoL) in patients aged 65 years and above during hospitalisation and after discharge compared to usual practise. We conducted a series of systematic literature search from 2013 to 2017, with additional studies hand-searched from reference lists of retrieved publications. Eligible studies were controlled trials with a multidisciplinary nutritional intervention during hospitalisation and after discharge in older (65+) patients. A intervention by more than one profession incorporating a nutritional component was defined as "Multidisciplinary". The nutritional intervention included use of oral nutritional supplements (ONS), improved nutritional care, and/or dietary counselling. For quality assessment of studies, "Cochrane Collaboration's tool for assessing risk of bias" was used. Conduction of meta-analyses were by combining data from homogenous trials. The search resulted in five studies fulfilling the inclusion criteria, but varied in quality and type of interventions used. 598 patients were included. Meta-analyses found improved QoL (MD 0.13 (0.02, 0.23), P = 0.01) and indicated tendencies towards lower mortality (OR 0.50 (0.22, 1.14), P = 0.10), in the intervention group vs. control group. Meta-analysis showed no difference between intervention and control group regarding readmissions during intervention (OR 1.04 (0.40, 2.70)) or at a 26 weeks follow-up (OR 0.84 (0.18, 3.82)) Although a small number of studies and a relatively small sample size, a suggestion is that provision of multidisciplinary nutritional support may have a positive effect on mortality and improves quality of life in older patients. There is a need for more high-quality studies including multidisciplinary nutritional support to verify these findings. Study registration in PROSPERO is no. CRD42016047997.

A controlled study of use of patient-reported outcomes to improve assessment of late effects after treatment for head-and-neck cancer.

BACKGROUND AND PURPOSE: To test the effect of longitudinal feedback on late effects reported by survivors of head-and-neck cancer (HNC) to clinicians during regular follow-up. MATERIAL AND METHODS: A total of 266 participants were sequentially assigned to either control or intervention group and filled in electronic versions of the EORTC QLQ C-30, H&N35, HADS and a study-specific list of symptoms at up to two consecutive follow-up visits. Participants' symptoms displayed according to severity were provided to the clinician for the intervention group but not for the control group. Linear mixed-effects models were used to examine the number of symptoms assessed by clinicians (primary outcome). Multivariate linear regression models examined participants' long-term symptom control and QoL (secondary outcome). RESULTS: More symptoms were assessed by clinicians in the intervention group at all three visits (P<0.001, <0.001, and P=0.04). No effect was observed on most patient outcomes. When prompted by patient-reported outcomes at consultations, clinicians and patients were in better agreement about the occurrence of severe symptoms at all three visits. CONCLUSION: Timely patient-reported outcomes to clinicians in routine follow-up of HNC survivors enhanced clinicians' rates of assessment of late symptoms. Giving reports of patient-reported outcome to clinicians had limited impact on participants' QoL or symptom burden.

Influence of social factors on patient-reported late symptoms: Report from a controlled trial among long-term head and neck cancer survivors in Denmark.

BACKGROUND: The incidence of head and neck cancer and morbidity and mortality after treatment are associated with social factors. Whether social factors also play a role in the prevalence of late-onset symptoms after treatment for head and neck cancer is not clear. METHODS: Three hundred sixty-nine survivors completed questionnaires on late symptoms and functioning. RESULTS: Survivors with short education were more likely to report severe problems than those with medium or long education. In the fully adjusted model, the risk for problems with opening the mouth remained significantly increased (odds ratio [OR] = 3.20; 95% confidence interval [CI] = 1.18-8.63). For survivors who lived alone, the adjusted ORs were significantly increased for physical functioning (2.17; 95% CI = 1.01-4.68) and trouble with social eating (OR = 2.26; 95% CI = 1.14-4.47). CONCLUSION: Self-reported severe late symptoms were more prevalent in survivors with short education and in those living alone, suggesting differences in perception of late symptoms between social groups. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1713-E1721, 2016.

Do we reach the patients with the most problems? Baseline data from the WebCan study among survivors of head-and-neck cancer, Denmark.

PURPOSE: This study seeks to assess the differences in disease and socioeconomic characteristics, late effects and long-term quality of life (QoL) after head-and-neck cancer (HNC) among participants and non-participants. METHODS: Five hundred sixty recurrence-free survivors treated for HNC at least 6 months previously were invited to participate in a repeated measure, controlled intervention study of computerized Patient Reported Outcome (PRO), which is provided to treating physicians at the point of care. Two hundred sixty-six consented to participate, and 292 declined; of those who declined, 103 filled in the baseline questionnaire. Late effects and QoL were evaluated on the EORTC QLQ C-30 and EORTC QLQ H&N35 and HADS questionnaires, and an empirically derived symptom list was prepared with hospital clinicians. RESULTS: Participants were younger, had a higher educational level, were more likely to cohabit, less likely to smoke, used less alcohol and were more likely to have HPV than those who declined but did not differ by gender, cancer site, stage or time since diagnosis. Participants reported significantly better QoL and functioning and less severe symptoms than those who declined participation other than filling in the baseline questionnaire. CONCLUSIONS: Late symptoms are common in HNC survivors. A wide diversity of self-reported late effects was found in this trial with participants significantly less affected than non-participants. IMPLICATIONS FOR CANCER SURVIVORS: Generalizable data on non-participation may aid in the interpretation of studies on HNC survivors in general and may have relevance for targeting recruitment and maintenance in rehabilitation and follow-up care, outside clinical trials.

Changes from 1992 to 2002 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: a Danish nationwide survey from DAHANCA.

In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx and larynx, seen at the five Danish oncology centers in January-April 1992 and 2002, respectively, were reviewed. Of the 288 patients identified, definitive treatment was radiotherapy in 264 cases, surgery in one case. Twenty-three patients had neither surgery nor radiotherapy. Total time from first health care contact to start of definitive treatment was significantly longer in 2002 than in 1992 (median 70 versus 50 days, p<0.001). There was no significantly difference in time used for diagnosis. Time for treatment preparation and planning was 46 days in 2002 versus 31 days in 1992 (p<0.001). Significantly more diagnostic procedures (CT, MR, US, PET) were done in 2002. In conclusion, this nationwide study showed that waiting time before start of radiotherapy was significantly longer in 2002 compared to 1992. An increasing number of imaging procedures including CT-based dose planning was observed. The prolongation was mainly related to shortage of radiotherapy capacity. The three weeks extra pretreatment delay could theoretically lead to a 10% lower tumor control probability in 2002 compared to 1992.