Predictors of survival in advanced oral cancers after salvage surgery with free tissue flap reconstruction.

OBJECTIVE: To identify prognostic factors for patients with advanced persistent, recurrent, or 2nd primary oral cavity squamous cell carcinoma (OCSCC) potentially unsuitable for salvage surgery with free tissue flap (FTF) reconstruction. MATERIALS AND METHODS: A population-based cohort of 83 consecutive patients with advanced OCSCC who underwent salvage surgery with FTF reconstruction at a tertiary referral centre between 1990 and 2017. Retrospective uni- and multivariable analyses were performed to identify factors affecting all-cause mortality (ACM), i.e., overall survival (OS), as well as disease-specific mortality (DSM), i.e., disease-specific survival (DSS) after salvage surgery. RESULTS: Median disease-free interval until recurrence was 15 months with recurrent stage I/II in 31% and III/IV in 69%. Median age at salvage surgery was 67 years (range 31-87) and the median follow-up (alive patients) 126 months. At 2, 5, and 10 years after salvage surgery, respectively, DSS rates were 61%, 44%, and 37% and OS rates 52%, 30%, and 22%. Median DSS was 26 and OS 43 months. Multivariable analysis identified recurrent clinical regional (cN-plus) disease [HR 3.57; p < .001] and elevated gamma-glutamyl transferase (GGT) [HR 3.30; p = .003] as independent pre-salvage predictors for poor OS after salvage, whereas initial cN-plus [HR 2.07; p = .039] and recurrent cN-plus disease [HR 5.14; p < .001] predicted poor DSS. Among post-salvage factors, extranodal extension according to histopathology [HR ACM 6.11; HR DSM 9.99; p < .001] as well as positive [HR ACM 4.98; DSM 7.51; p < 0.001] and narrow surgical margins [HR ACM 2.12; DSM HR 2.80; p < 0.01] emerged as independent factors for poor survival. CONCLUSION: While salvage surgery with FTF reconstruction is the primary curative option for patients with advanced recurrent OCSCC, the present findings may help guide discussions with patients who have advanced recurrent regional disease and high GGT preoperatively, especially if there is a small chance of reaching surgical radicality.

Transoral robotic surgery in the management of head and neck squamous cell cancer with unknown primary.

Background: Transoral robotic surgery (TORS) assisted base of the tongue (BOT) resection has been suggested as part of the work-up for head and neck squamous cell cancer with unknown primary (HNSCC-CUP). Success rates vary with regard to identification of primary BOT lesions, and cases with likely such lesions appear to be included in previous reports.Objectives: To analyse the possible benefits of a superficial TORS-assisted BOT resection in thoroughly investigated HNSCC-CUP.Material and methods: Retrospectively, 13 patients subjected to superficial TORS-assisted BOT resections due to HNSCC-CUP, where previous thorough work-ups including PET-scans had been performed and primary lesions had still not been identified, were reviewed.Results: Nodal status, according to the TNM-8 classification, was N1, N2, N2a, N2b, N2c, and N3, respectively, for 7, 1, 1, 4, 0, and 0 patients. In 38% of the cases, T1 BOT cancers were identified using superficial TORS-assisted BOT resections and treatments adjusted.Conclusion: Addition of a superficial TORS-assisted BOT resection to the work-up of HNSCC-CUP frequently identifies primary lesions and alters the treatment for this group of patients even after thorough work-up.

Survival benefits from concomitant chemoradiotherapy before radical surgery in stage IVA sinonasal mucosal melanoma?

BACKGROUND: The aim of the study was to review a local treatment protocol for sinonasal mucosal melanoma (SNMM) focusing on triple modality treatment (TMT), that is, neoadjuvant concomitant chemoradiotherapy (CRT) and surgery. METHODS: In a retrospective design, data on clinical presentation, treatment, and survival were retrieved for 22 consecutive patients from a tertiary referral center. RESULTS: The mean overall survival (OS) for all patients (3 stage III, 16 stage IVA, and 3 stage IVB) was 62 months, and the 5-year OS rate 50%. Four of the 22 patients received treatment with palliative intention. Of the 18 patients who received treatment with curative intention, patients with stage IVA disease who received TMT (n = 10) had a 5-year OS of 70% and 10-year OS of 20%. The median disease-free survival for these patients was 51 months compared with 9 months for stage IVA not receiving TMT (n = 4). CONCLUSION: A seemingly favorable survival outcome for a disease with characteristically poor prognosis was observed. The lead finding was a high survival rate (70% 5-year OS) for stage IVA patients who received neoadjuvant TMT. The observations suggest the possibility that patients with advanced SNMM (stage IVA) might benefit from concomitant CRT before surgery by delaying the onset of local recurrences and distant metastases. LEVEL OF EVIDENCE: Level 4, case series (with or without comparison).

Transoral Robotic Surgery in the Nordic Countries: Current Status and Perspectives.

Background: The five Nordic countries with a population of 27 M people form a rather homogenous region in terms of health care. The management of head and neck cancer is centralized to the 21 university hospitals in these countries. Our aim was to gain an overview of the volume and role of transoral robotic surgery (TORS) and to evaluate the need to centralize it in this area as the field is rapidly developing. Materials and Methods: A structured questionnaire was sent to all 10 Departments of Otorhinolaryngology-Head and Neck Surgery in the Nordic countries having an active programme for TORS in December 2017. Results: The total cumulative number of performed robotic surgeries at these 10 Nordic centers was 528 and varied between 5 and 240 per center. The median annual number of robotic surgeries was 38 (range, 5-60). The observed number of annually operated cases remained fairly low (<25) at most of the centers. Conclusions: The present results showing a limited volume of performed surgeries call for considerations to further centralize TORS in the Nordic countries.

Benefits of initial CT staging before sentinel lymph node biopsy in patients with head and neck cutaneous melanoma.

BACKGROUND: The value of CT at the time of diagnosis for patients with cutaneous head and neck melanoma clinically asymptomatic for metastatic disease is unclear. METHODS: A retrospective medical chart review was performed on 198 consecutive patients identified with primary T1b-T4b head and neck melanoma clinically asymptomatic for metastatic disease referred for sentinel lymph node biopsy procedures between 2004 and 2014. RESULTS: Initial CTs identified clinically occult melanoma metastases in 8.1% and advanced second primary tumors in 3.5% of patients. CT findings were false-negative in 1% and false-positive in 6% of patients. Overall survival (OS) for patients with true-positive CT findings was lower than for the other patients (P < .001). CONCLUSION: CT imaging when staging patients with head and neck melanoma seems to identify more metastases than has been reported for melanoma at other sites. Preoperative CTs decreased the number of sentinel lymph node biopsy (SLNBs), thus avoiding the stress and cost of this surgical procedure in 12% of patients.

Aspiration as a late complication after accelerated versus conventional radiotherapy in patients with head and neck cancer.

Conclusion Neck dissection after radiotherapy increased the risk of aspiration as a late effect in a sub-sample of patients treated for head and neck cancer in the ARTSCAN study. Patients treated with accelerated fractionation (AF) developed aspiration, with or without coughing, more frequently than patients treated with conventional fractionation (CF). Objectives A long-term follow-up study was conducted to determine the frequency of aspiration as a late effect in patients with head and neck cancer treated with AF or CF. Method One-hundred and eight patients were recruited from two centres of the Swedish multi-centre study, ARTSCAN, where AF and CF were compared. Patients with positive lymph nodes were treated with neck dissection after completing radiotherapy. The follow-up was performed at a median of 65 months after initiation of radiotherapy and included an ENT and a videofluoroscopic examination. Results Aspiration was found in 51/108 (47%) and silent aspiration in 34/96 (35%) patients. Neck dissection (n = 47 patients) was significantly associated with both aspiration and silent aspiration. Aspiration was more common among patients treated with AF (34/61; 56%) compared to CF (17/47; 36%; p = 0.053). Silent aspiration was also more common after AF (24/54; 44%) than after CF (10/42; 24%; p = 0.052).

Sentinel lymph node biopsy staging for cutaneous malignant melanoma of the head and neck.

Conclusion Sentinel lymph node biopsies (SLNBs) can be performed safely and with reasonable accuracy in HNM patients. The outcome provides important prognostic information concerning DFS and further treatment. However, one must recognize that SLNB is a multidisciplinary procedure with a learning curve for all. Objectives To evaluate efficacy of performing SLNBs in a series of consecutive patients with cutaneous head and neck melanoma (HNM) ≥ T1b from introduction of the procedure and 10 years onward. Method End-points comprised of SLNB outcome, disease-free survival (DFS), and overall survival (OS). Results SNs were harvested in 128 of 160 patients (median Breslow = 2.0 mm, 29% ulcerated); success rate = 80.0%, or 92.1% if excluding patients where SLNBs were omitted due to non-localization on pre-operative imaging or because of SN-location in the parotid basin. Ten patients (7.8%) had positive SLNBs and were offered early completion neck dissections. Of the 146 patients available for follow-up (median = 27 months), 15.8% had recurrent disease. The risk of a regional nodal recurrence after a negative SLNB was 7.5%. SN-negative patients had improved DFS c.f. SN-positive patients (p < 0.001). A positive SLNB was the most important prognostic predictor of decreased DFS (hazard ratio = 5.70; p < 0.005), but had no significant impact on OS.

A prospective study of positron emission tomography for evaluation of neck node response 6 weeks after radiotherapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to evaluate if a positron emission tomography (PET) scan, 6 weeks after radiotherapy (RT), adequately selects patients in whom a neck node dissection can be omitted. Primary endpoints were isolated neck recurrences and overall survival (OS). METHODS: One hundred five patients, mainly with oropharyngeal human papillomavirus (HPV)-positive tumors, with a positive PET scan before treatment, were evaluated regarding the neck response 6 weeks post-RT. The PET results determined the management of the neck: observation versus neck dissection. RESULTS: Median follow-up was 25 months. Positive predictive value (PPV) and negative predictive value (NPV) were 56% and 94%, respectively. Four isolated neck recurrences occurred. The 2-year OS rate was 86.3%. CONCLUSION: PET scans performed 6 weeks after RT have a high NPV and can obviate neck dissections but the PPV is insufficient. A later scheduled scan is recommended. © 2015 Wiley Periodicals © 2015 Wiley Periodicals, Inc. Head Neck 38: E473-E479, 2016.

Qualitative interpretation of PET scans using a Likert scale to assess neck node response to radiotherapy in head and neck cancer.

PURPOSE: The aim of this study was to determine whether PET scans after radiotherapy (RT), visually interpreted as equivocal regarding metabolic neck node response can be used to accurately categorize patients as responders or nonresponders using a Likert scale and/or maximum standardized uptake value (SUVmax). Other aims were to determine the performance of different methods for assessing post-RT PET scans (visual inspection, a Likert scale and SUVmax) and to establish whether any method is superior in predicting regional control (RC) and overall survival (OS). METHODS: In 105 patients with neck node-positive head and neck cancer, the neck node response was evaluated by FDG PET/CT 6 weeks after RT. The scans were clinically assessed by visual inspection and, for the purposes of this analysis, re-evaluated using the Deauville criteria, a five-point Likert scale previously used in lymphoma studies. In addition, SUVmax was determined. RESULTS: All assessment methods were able to significantly predict RC but not OS. The methods were also able to significantly predict remission of tumour after completion of RT. Of the 105 PET scans, 19 were judged as equivocal on visual inspection. The Likert scale was preferable to SUVmax for grouping patients as responders or nonresponders. CONCLUSION: All methods (visual inspection, SUVmax and the Likert scale) identified responders and nonresponders and predicted RC. A Likert scale is a promising tool to reduce to a minimum the problem of PET scans judged as equivocal. Consensus regarding qualitative assessment would facilitate PET reporting in clinical practice.

Radiotherapy response in head and neck cancer - evaluation of the primary tumour site.

CONCLUSION: PET-CT scans seem to be sufficient to rule out residual tumour at the primary site. Patients with positive or equivocal PET findings should be scheduled for endoscopy with biopsy or a second PET-CT scan. OBJECTIVES: Assessment of remission at the primary site, in patients treated with organ preservation therapy with curative intent, is important to identify residual tumours requiring treatment with salvage surgery. The aim of this study was to evaluate the diagnostic accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) after radiotherapy with or without chemotherapy in assessing primary site response in patients with head and neck cancer. METHODS: A total of 82 patients, with a positive baseline PET-CT scan before start of treatment, were evaluated with a PET-CT scan 6-7 weeks post-radiotherapy and with a clinical examination/endoscopy with or without biopsy 1-2 weeks later. The majority of patients had p16-positive oropharyngeal tumours. RESULTS: Post-treatment, 77% of the patients had no visible hypermetabolism. If equivocal PET scans are regarded as positive, the sensitivity, specificity, negative (NPV) and positive predictive value (PPV) and accuracy were 100%, 78%, 100%, 6% and 78%, respectively. Eight patients suffered from relapses involving the primary site during the 9-month follow-up.

Weight loss and body mass index in relation to aspiration in patients treated for head and neck cancer: a long-term follow-up.

PURPOSE: Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment. METHODS: Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures. RESULTS: Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up. CONCLUSIONS: Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction.

Radiation-induced trismus in the ARTSCAN head and neck trial.

UNLABELLED: Trismus, a well-known sequelae after treatment of head and neck cancer, decreases a patient's oral function and quality of life. The main objectives of this study were to: 1) investigate the long-term prevalence of radiation-induced trismus in patients treated for head and neck cancer according to two different fractionation schedules; and 2) model a dose-response relationship for trismus. MATERIAL AND METHODS: Patients were recruited from the Swedish ARTSCAN trial, a prospective randomised multicentre study comparing conventional and accelerated fractionation. A total of 124 patients agreed to a clinical ENT examination 21-127 months (median 66 months) after beginning radiation therapy. Trismus-related scores were assessed using the EORTC H&N35 Quality of Life questionnaire. The TheraBite(®) range of motion scale was used to measure maximal interincisal distance. The dose-response relationship for structures important for mastication and the temporomandibular joints was investigated by normal tissue complication probability modelling. RESULTS: No significant differences in patient-reported trismus or maximal interincisal distance were found between the two trial arms. Patient-reported moderate to high scores regarding trismus increased from 3% at the start of radiation therapy to 25% at the long-term follow-up. Maximal interincisal distance correlated significantly with patient-reported scores of trismus. The best dose-response fit to the endpoint data was found for the dose to the ipsilateral masseter. CONCLUSIONS: Trismus is a persistent complication after radiotherapy with 3D-conformal radiation therapy. We found no difference between the severity and prevalence of trismus between conventional and accelerated fractionation, but a significant correlation between the absorbed dose to the mastication structures and opening of the mouth. Further prospective studies may determine whether a reduced dose to structures important for mastication using intensity-modulated radiation therapy will reduce problems with trismus.

The anti-tumour effect of cisplatin and ifosfamide on xenografted squamous cell carcinoma of the head and neck is schedule-dependent.

The role of chemotherapy (CHX) in squamous cell carcinoma of the head and neck (SCCHN) has been expanding. Although combination chemotherapy regimens regularly produce significantly high response rates, meta-analyses show little benefit regarding final outcome. One way to improve induction CHX is to improve drug combinations and schedules for CHX. Cisplatin (CDDP) is one of the most active drugs in the treatment of patients with SCCHN, and it is used in most combinations. Ifosfamide (IFO) is another agent that has shown activity in the treatment of patients with SCCHN. A poorly differentiated squamous cell carcinoma xenografted to nude mice was used. CDDP (2.5 mg/kg) and IFO (100 mg/kg) as single bolus doses induced significant retardation of tumour growth. Single drug administration was compared with CDDP given before IFO and IFO given before CDDP. Mean specific growth delay (SGD) for untreated controls was 0. For CDDP as single drug it was 1.50, for IFO as single drug it was 0.79, for CDDP given 4 h before IFO it was 1.79, and for IFO given 4 h before CDDP it was 2.90. Maximum toxicity, calculated as change in median weight at day 7, was less than 10%. The efficacy and toxicity of CDDP and IFO is schedule-dependent, with IFO given before CDDP being more effective than CDDP given before IFO. This is in contrast to most schedules used clinically. The toxicities were comparable. The number of combinations of drugs with respect to order and time interval is of a magnitude that would not be possible to test clinically. In the pursuit of more efficient combinations, the importance of order and schedule of drugs and also the potential of xenografted SSCHN are underestimated.

[Chronic Lyme borreliosis--fact or fiction?]. / Voiko Lymen borrelioosi kroonistua?

Persistent infection after proper antibiotic treatment in Lyme borreliosis is rare. Symptoms may sometimes continue, especially from the nervous and the articular systems. There are many possible mechanisms for persistence of inflammation even after successful treatment of the infection. The lack of indicators of active infection impedes diagnostics. Early diagnosis and treatment are the most important means for preventing prolonged symptoms and signs. The differential diagnostics are crucial. Repeated treatment with antibiotics is seldom needed, and overlong treatments should be avoided. Lyme borreliosis may sometimes cause permanent tissue damage for which there is no cure.

Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck.

BACKGROUND: The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24-35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers.The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status. METHODS: Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test (crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry. RESULTS: Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake. CONCLUSION: In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.

Chemorefractory rhabdomyosarcoma treated with radiotherapy, bevacizumab, statins and surgery and maintenance with bevacizumab and chemotherapy.

BACKGROUND: Rhabdomyosarcoma is a rare disease in children and young adults, usually responsive to chemotherapy. Here we report on a patient with chemorefractory disease, treated in an unconventional approach. CASE REPORT: A young woman presented with an embryonal rhabdomyosarcoma of the retromaxillary space. She exhibited progressive disease to two chemotherapy regimens. The patient started hyperfractionated radiotherapy that due to lack of response was changed to 3 Gy fractions once daily to a total absorbed dose of 53 Gy. The therapeutic predicament led us to add bevacizumab and hydroxymethylglutaryl-CoA reductase inhibitors (statins), for which some experimental support could be found. RESULTS: The tumour responded clearly, and a radical R0 resection followed. The patient was treated postoperatively with bevacizumab and chemotherapy. The combined treatment was accompanied by side effects such as mucositis grade IV, impaired healing of the mandibulotomy as well as a prominent cystitis. Side effects subsided following treatment with hyperbaric oxygen. CONCLUSION: Rhabdomyosarcoma refractory to chemotherapy may respond to radiotherapy and the addition of bevacizumab and statins. Although the contribution of the adjuncts is unclear, the unexpected tumour control in this case may help in decision-making in similar cases and may encourage the investigation of these adjuncts in protocols.

Fluorescence investigations to classify malignant laryngeal lesions in vivo.

BACKGROUND: The extent of surgical resection for malignant laryngeal lesions influences voice quality. An instrument to estimate histopathologic grading of dysplasia in vivo may spare normal tissue without increasing the risk of local failure. METHODS: Laryngeal lesions (N = 39; 21 after administration of delta-aminolevulinic acid (ALA)) were investigated with laser-induced fluorescence, and the results correlated to histopathologic grading in 4 groups: non/mild dysplasia (I), moderate dysplasia (II), severe dysplasia/cancer in situ (III), and carcinoma. RESULTS: At 337-nm excitation, there were differences in the fluorescence ratio I(431)/I(390) between groups I/III and carcinoma. Following 405-nm excitation, I(500 nm) group I differed significantly from group III and cancer. The sensitivity for the fluorescence method was 89%, and the specificity was 100%. CONCLUSIONS: There are differences in the in vivo tissue fluorescence between tissue with different gradings of dysplasia and carcinoma.

2-Deoxy-2-[18F] fluoro-D-glucose uptake and correlation to intratumoral heterogeneity.

UNLABELLED: The aim of this study was to investigate the pattern of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake in relation to the intratumoral histopathological appearance. MATERIALS AND METHODS: Intratumoral distribution of FDG in nude mice with xenografted tumours originating from an established head and neck squamous cell carcinoma was studied. FDG uptake and the correlation to histopathological appearance was evaluated in four separate quarters of each tumour. RESULTS: Variations in FDG uptake correlating to the presence of tumour cells was demonstrated. Quarters containing more than 50% tumour cells showed a significantly higher FDG uptake (p = 0.028) than quarters with more stromal tissue and necrosis. CONCLUSION: This study shows that the heterogenic FDG uptake within a tumour correlates to histopathological findings and that the variable appearance of tracer uptake on the PET scan depends on distribution of different tissue components in the tumour. This intratumoral heterogeneity calls for caution when evaluating a PET scan where median values of larger areas will be misguiding and thus small areas with high uptake should be regarded as the regions of interest.

TBE in Aland Islands 1959-2005: Kumlinge disease.

Tick-borne encephalitis, TBE, has been observed in Aland Islands (population 26,500) for more than 60 years. Because of the small population, the relative incidence is high. Antibodies to TBE virus have been found in ca. 5% of healthy blood donors, indicating that subclinical infection must be common. This study is a review of the symptoms and signs of all the 301 serologically verified cases of TBE seen in Aland during 1959-2005. It also aims at analysing any possible changes in the symptoms and signs of TBE over time. The annual number of patients has been from 1 to 26, and has increased over time. The clinical picture has not undergone any conspicuous changes during these years. A few patients have had permanent neurological damage. There were no certain deaths from TBE. Simple practical measures may be taken to diminish, but not to eliminate, the risk of tick bites. Vaccination of exposed people is recommended, and general vaccination against TBE has commenced in Aland, beginning 2006. This is expected to reduce the incidence of TBE among the population to almost nil, provided that new inhabitants are vaccinated and that booster vaccinations are carried out as required.