Consolidation cetuximab after concurrent triplet radiochemotherapy+cetuximab in patients with advanced head and neck cancer: A randomized phase II study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cetuximab should be continued after end of concurrent radiotherapy+cetuximab due to its efficacy against residual tumor cells in the irradiated tumor bed. Based on this concept the phase II add-on cetuximab (AOC) study was designed. MATERIALS AND METHODS: Altogether 63 patients with advanced head and neck cancer were treated with radiochemotherapy (70 Gy, cisplatin 40 mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400 mg/m2, then 250 mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly × 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) was performed. RESULTS: Median follow-up was 24 months. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab, respectively. Higher than median levels of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p ≤ 0.05). A radiomics model consisting of two radiomics features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (concordance index 0.66). No correlation was found between biological and imaging markers. CONCLUSIONS: There was no evidence that consolidation cetuximab would improve the 2-year LRC rate. Prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to correlate biological and imaging markers.

Precision of Simultaneous Guided Dental Implantation in Microvascular Fibular Flap Reconstructions With and Without Additional Guiding Splints.

PURPOSE: Dental rehabilitation in patients receiving free flap reconstructive surgery on the mandible or maxilla is an important part of bringing patients back to normality in both a physical and psychological way. It is therefore important to be able to do this in the fastest way possible. Virtual preplanned reconstructions of jaws with implants placed simultaneously are a good way to expedite this process and have the advantage of allowing true backward planning to achieve bone placement where it prosthetically needs to be. Thus, the precise transfer of the virtually preplanned implant position to the intraoperative situation is crucial for prosthetic rehabilitation. PATIENTS AND METHODS: We compared a control group of patients (4 patients with 15 implants) with preplanned fibular reconstructions of the mandible with implants incorporated in the planning and a trial group of patients (4 patients with 13 implants) with an additional intraoperative splint for the verification of the implants' angulation. The preoperative planning and postoperative computed tomography scans were compared. RESULTS: The average positioning error at bone level was 0.9 mm in the trial group and 1.3 mm in the control group. The average angulation error in the buccolingual plane was 2.9° in the trial group and 5.5° in the control group; axially, the difference was 6.3° in the trial group and 4.1° in the control group. CONCLUSIONS: The use of digitally backward-planned fibula cutting guides with direct dental implant positioning is feasible, and the precision found is comparable with that of standard splint-guided implant placement in the general population. Although the axial angulation error has more to do with anatomic variance and positioning of the bony cutting guide, the trial population clearly profited from the additional splint in the important buccolingual angulation. Overall, we showed a high level of precision over all implants in both groups.

Denosumab as a Treatment Alternative for Central Giant Cell Granuloma: A Long-Term Retrospective Cohort Study.

PURPOSE: Giant cell granuloma (GCG) of the jaw is a rare disease with high morbidity. Various treatment options have been discussed in the past. Since 2010, a pharmaceutical therapy with denosumab seems to have been successful for giant cell tumors of the femur. The authors hypothesized the equally successful use of denosumab for GCGs of the jaws. MATERIALS AND METHODS: In the present retrospective cohort study, 5 patients with large GCGs of the jaws were treated with denosumab with a follow-up of 25 to 49 months. Frequent clinical follow-ups and a radiologic follow-up were performed and systematically analyzed. RESULTS: All patients showed a curative treatment response and complete metabolic resolution of the GCGs under treatment with denosumab. CONCLUSION: A brief review of the relevant literature and a detailed evaluation of current cases led to the conclusion that denosumab therapy should be considered a therapeutic option for large central GCGs of the jaws. The results of this study suggest denosumab is a successful treatment option. A treatment length no shorter than 12 months is recommended and monitoring of treatment response can be well managed by positron-emission tomographic computed tomography or magnetic resonance imaging.

Short-term effectiveness of inpatient cancer rehabilitation: A longitudinal controlled cohort study.

Background: Inpatient rehabilitation for cancer patients has been demonstrated to improve patients' health related quality of life (HRQoL) effectively. The purpose of this study was to compare changes in general health and HRQoL of cancer patients who were referred to inpatient rehabilitation (IR) with those in two control groups who underwent outpatient management either with advice for inpatient rehabilitation (A+) or without (A-). Methods: In this naturalistic, longitudinal, controlled cohort study, changes in general health and HRQoL were assessed at either discharge of acute hospital or start of rehabilitation (baseline) and at the follow-up 3 weeks later or end of rehabilitation. Outcome variables included general health and HRQoL assessed by the Short Form 36 (SF-36) and the Functional Assessment of Cancer Therapy (FACT), and fatigue (FACT-F), depression and anxiety by the Hospital Anxiety and Depression Scale (HADS). Changes on the scores were compared with bivariate and multivariate analyses using standardized mean differences (SMD). Results: IR patients (n=133) were on average older, reported lower HRQoL and health, and suffered more frequently from carcinoma than patients of the A+ (n=30) and the A- (n=82) groups. In the IR patients, pain, physical functioning, mental health, vitality, and fatigue improved significantly compared to the A+ controls. Compared to the A- group, the bivariate effects were lower but still statistically significant on many scales. Conclusions: IR showed moderate, statistically significant superior effects over outpatient management of cancer patients after acute treatment. Findings indicate that inpatient cancer rehabilitation can be recommended as an effective management after acute treatment. As today, referrals to inpatient rehabilitation for cancer patients are still not based on structured standardized procedures, the implementation of such screening is needed to address patients' needs and to render the potential for rehabilitation more reliable.

Expression of CK19 is an independent predictor of negative outcome for patients with squamous cell carcinoma of the tongue.

OBJECTIVES: To explore the prognostic role of CK19 expression in squamous cell carcinomas within a well-defined cohort of oral tongue cancer patients. METHODS: In our retrospective study, we investigated 129 patients with tongue cancer that had suitable material for inclusion in a tissue microarray (TMA). Where possible, samples were taken from central and peripheral regions of the tumor to generate a representative sample of the tumor. The expression level of CK19 was assessed by immunohistochemical staining. RESULTS: Expression of CK19 in squamous cell carcinoma of the tongue was identified as a negative predictor for overall survival (OS; p<0.000) and disease specific survival (DSS; p=0.001). No significant difference could be shown for disease free survival (DFS) between patients with positive and negative CK19 staining (p=.094). CONCLUSION: This is the first description of the highly significant role of CK19 in a selective, organ specific head and neck cancer cohort. Our results are of special importance against the background that CK19 positive carcinomas revealed a significantly poorer prognosis and therefore emphasize its prognostic and possible diagnostic role in tongue cancer.

Current relevance of hypoxia in head and neck cancer.

Head and Neck cancer (HNC) is a complex mix of cancers and one of the more common cancers with a relatively poor prognosis. One of the factors that may assist us in predicting survival and allow us to adjust our treatment strategies is the presence of tumor hypoxia. In this overview we aim to evaluate the current evidence and potential clinical relevance of tumor hypoxia in head and neck cancer according to an extensive search of current literature.An abundance of evidence and often contradictory evidence is found in the literature. Even the contradictory evidence and comparisons are difficult to judge as criteria and methodologies differ greatly, furthermore few prospective observational studies exist for verification of the pre-clinical studies. Despite these discrepancies there is clear evidence of associations between prognosis and poor tumor oxygenation biomarkers such as HIF-1α, GLUT-1 and lactate, though these associations are not exclusive. The use of genetic markers is expanding and will probably lead to significantly more and complex evidence. The lack of oxygenation in head and neck tumors is of paramount importance for the prediction of treatment outcomes and prognosis. Despite the wide array of conflicting evidence, the drive towards non-invasive prediction of tumor hypoxia should continue.

IMRT/VMAT for malignancies in the head-and-neck region : Outcome in patients aged 80.

OBJECTIVE: Elderly patients with malignant head-and-neck tumors (HNT) often pose a therapeutic challenge. They frequently have significant comorbidities which may influence their ability to tolerate tumor-specific therapies. Our aim was to investigate the outcome of patients aged 80+ years undergoing curative intent intensity- or volume-modulated radiation therapy (IMRT/VMAT). METHODS: We retrospectively reviewed our HNT patients aged 80+ treated with curative IMRT/VMAT from December 2003 to November 2015. Overall survival (OS), disease-free survival (DFS), local control (LC), and treatment tolerance were assessed. Outcome results were compared with that of a younger HNT patient cohort from our hospital. RESULTS: A total of 140 consecutive patients were included (65 postoperative, 75 definitive). Mean/median age at treatment start was 84.8/84.1 years (range 80-96 years). Mean/median follow-up time was 25/16 months (range 2-92 months). Of the 140 patients, 80 were alive with no evidence of disease when last seen, 28 had died due to the cancer, 12 remained alive with disease, the remaining 20 died intercurrently. Systemic concomitant therapy was administered in 7 %. Late grade 3-4 toxicity was observed in 2 %. All patients completed treatment. Hospitalization and feeding tube rates were 26 % and 11 %, respectively. The 2­/3-year LC, DFS, and OS rates for the entire cohort were 81/80 %, 69/63 %, and 68/66 %, respectively. Squamous cell carcinoma (SCC) patients showed an inferior 3-year OS rate as compared to non-SCC patients (62 % vs 77 %, p = 0.0002), while LC and DFS did not differ. Patients undergoing postoperative radiation attained a higher OS compared to the definitively irradiated subgroup with 74 vs. 60 % at 3 years (p = 0.01); however, DFS rates were similar for both groups (68 vs. 61 %, p = 0.15). Corresponding rates for >1400 HNT patients <80 years treated during the same time interval were 81/80 %, 69/67 %, and 77/72 %, respectively. CONCLUSIONS: Treatment tolerance in our patients aged 80+ was high. These results suggest that elderly HNT patients should not be denied potentially curative treatment strategies.

Risk profile for osteoradionecrosis of the mandible in the IMRT era.

BACKGROUND: The risk for osteoradionecrosis (ORN) of the mandible is positively related to bone volume exposed to > ~ 60 Gy. We hypothesized that in combined treatment, surgery may also be a risk factor. PATIENTS AND METHODS: The impact of mandibular surgery on ORN in locally disease-free IMRT cohorts was retrospectively analyzed. RESULTS: Between October 2002 and October 2013, 531 of 715 patients with oral cavity cancer (OCC), mesopharyngeal cancer (MC), or salivary gland tumor were treated with the mandible bone exposed to ~ > 60 Gy (mean follow-up, 38 months; 7-143 months). Of the 531 patients, 36 developed ORN (7 %; 1.5 % with grade 3-4). The ORN rate in definitive IMRT MC (16/227) and in postoperative IMRT OCC patients with no mandibular surgery (3/46) was 7 % each; in OCC patients with mandibular surgery the rate was 29 % (15/60, p = 0.002). Marginal or periosteal bone resection was found to be a high risk factor (39 %, vs. 7 % followed by segmental or no resection, p < 0.0001). CONCLUSION: Marginal or periosteal bone resection of the mandible was identified as the highest ORN risk factor in our IMRT cohort.

Scapular Free Vascularised Bone Flaps for Mandibular Reconstruction: Are Dental Implants Possible?

OBJECTIVES: Free fibula flap remains the flap of choice for reconstruction of mandibular defects. If free fibula flap is not possible, the subscapular system of flaps is a valid option. In this study, we evaluated the possibility of dental implant placement in patients receiving a scapular free flap for oromandibular reconstruction. MATERIAL AND METHODS: We retrospectively reviewed 10 patients undergoing mandible reconstruction with a subscapular system free-tissue (lateral border of the scapula) transfer at the University Hospital Zürich between January 1, 2010 and January 1, 2013. Bone density in cortical and cancellous bone was measured in Hounsfield units (HU). Changes of bone density, height and width were analysed using IBM SPSS Statistics 22. Comparisons of bone dimensions as well as bone density were performed using a chi-square test. RESULTS: Ten patients were included. Implantation was conducted in 50%. However, all patients could have received dental implants considering bone stock. Loss of bone height and width were significant (P < 0.001). There was a statistical significant increase in bone density in cortical (P < 0.001) and cancellous (P = 0.004) bone. CONCLUSIONS: Dental implants are possible after scapular free flap reconstruction of oromandibular defects. Bone height and width were reduced, while bone density increased with time.

Unknown primary of the head and neck: A long-term follow-up.

BACKGROUND: A diagnosis of squamous cell carcinoma of an unknown primary (CUP) is a major burden for patients. Because the location of the primary tumor is unclear, patients remain fearful of recurrence, which aggravates the uncertain prognosis of the disease. This study evaluates factors associated with long-term recurrence-free and overall survival of patients with CUP of the head and neck. Additionally, patient survival rates are compared with those of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 293 consecutive patients operated on between January 1999 and December 2009 with at least a 5-year follow-up (survival permitting), were evaluated retrospectively. RESULTS: Twenty-six patients with a CUP of the head and neck were identified. Patients with CUP had a low overall survival rate, comparable with that of patients with pN + HNSCC, and recurrent disease occurred with a similar likelihood as in patients with pN + HNSCC. The median recurrence-free survival in the CUP group was 28.5 months compared with 48 months in the whole of the HNSCC group. The median overall survival of the CUP group was 56 months versus 65 months for the HNSCC group. Extracapsular spread was the only independent prognostic factor for overall survival for CUP patients. CONCLUSION: Patients diagnosed with CUP syndrome have a poorer prognosis for overall survival compared with other HNSCC patients. Postoperative radiotherapy diminished disease recurrence and improved overall survival. Omission of postoperative radiotherapy resulted in a very high recurrence rate (75%) for CUP patients. Based on these results we suggest postoperative radiotherapy including the oral mucosa for all patients, regardless of histopathological results, possible favorable nodal disease, or favorable lymph node ratios.

Mass spectrometric characterization of limited proteolysis activity in human plasma samples under mild acidic conditions.

We developed a limited proteolysis assay for estimating dynamics in plasma-borne protease activities using MALDI ToF MS analysis as readout. A highly specific limited proteolysis activity was elicited in human plasma by shifting the pH to 6. Mass spectrometry showed that two singly charged ion signals at m/z 2753.44 and m/z 2937.56 significantly increased in abundance under mild acidic conditions as a function of incubation time. For proving that a provoked proteolytic activity in mild acidic solution caused the appearance of the observed peptides, control measurements were performed (i) with pepstatin as protease inhibitor, (ii) with heat-denatured samples, (iii) at pH 1.7, and (iv) at pH 7.5. Mass spectrometric fragmentation analysis showed that the observed peptides encompass the amino acid sequences 1-24 and 1-26 from the N-terminus of human serum albumin. Investigations on peptidase specificities suggest that the two best candidates for the observed serum albumin cleavages are cathepsin D and E. Reproducibility, robustness, and sensitivity prove the potential of the developed limited proteolysis assay to become of clinical importance for estimating dynamics of plasma-borne proteases with respect to associated pathophysiological tissue conditions.

Tenosynovial, diffuse type giant cell tumor of the temporomandibular joint, diagnosis and management of a rare tumor.

The purpose of this paper was to describe a rare unusual case of primary mandibular condylar tenosynovial giant cell tumor of diffuse type with predominantly intraosseous growth and its management by resection and functional reconstruction with a vascularized costochondral graft. Clinical presentation was swelling in the right condylar area and limited mouth opening with radiological evidence of central bone destruction and magnetic resonance imaging showed central hemosiderin deposition. Fine needle aspiration did not lead to a diagnosis and an open biopsy had to be performed. Management consisted of tumor resection and reconstruction with a free vascularized costochondral graft. Tenosynovial diffuse type giant cell tumor of the temporomandibular joint is very rare. Complete resection leads to a low recurrence rate and reconstruction with a costochondral free vascularized flap leads to an excellent functional outcome.

Splintless orthognathic surgery: a novel technique using patient-specific implants (PSI).

In the past few years, advances in three-dimensional imaging have conducted to breakthrough in the diagnosis, treatment planning and result assessment in orthognathic surgery. Hereby error-prone and time-consuming planning steps, like model surgery and transfer of the face bow, can be eluded. Numerous positioning devices, in order to transfer the three-dimensional treatment plan to the intraoperative site, have been described. Nevertheless the use of positioning devices and intraoperative splints are failure-prone and time-consuming steps, which have to be performed during the operation and during general anesthesia of the patient. We describe a novel time-sparing and failsafe technique using patient-specific implants (PSI) as positioning guides and concurrently as rigid fixation of the maxilla in the planned position. This technique avoids elaborate positioning and removal of manufactured positioning devices and allows maxillary positioning without the use of occlusal splints.

Salivary duct carcinoma of the parotid gland: A case report and review of the literature.

Salivary duct carcinoma (SDC) is a rare and aggressive parotid malignancy that most commonly affects males in the fifth and sixth decades of life. Histopathology specimens obtained from SDC patients demonstrate a resemblance to ductal carcinoma of the breast. Therefore, to distinguish SDC from breast ductal carcinoma, several immunohistochemical markers exist that may enable surgeons to make an accurate diagnosis. In this study, the case of a 54-year-old male with salivary duct carcinoma of the right parotid gland is presented. The results of the present case study revealed that the SDC sample was positive for the expression of human epidermal growth factor 2 (Her-2), cytokeratin (CK) 8/CK 18, p63, high molecular weight CK and calponin, and negative for expression of the estrogen receptor and progesterone receptor. Based on the result, an ipsilateral selective neck dissection followed by adjuvant post-operative radiation therapy was suitable at the primary treatment stage. At one year of follow-up, the patient was alive and free of recurrence. In advanced cases of SDC, treatment with anti-HER-2 monoclonal antibodies, such as trastuzumab, is recommended.

Management of the temporomandibular joint after ablative surgery.

Management of the temporomandibular joint in ablative head and neck surgery is controversial with no standardized approach. The aim of the study was to establish risk-based guidelines for the management of the temporomandibular joint after ablative surgery. Analysis of all patients' records receiving ablative surgery involving the temporomandibular joint in the Department of Cranio-Maxillofacial and Oral Surgery, University Hospital of Zürich, from 2001 to 2012, was performed, identifying 15 patients and 14 reconstructive procedures. A literature search was done identifying all relevant literature on current approaches. Applicable cohorts were constructed, and relevant risks were extrapolated. Evaluated studies are not uniform in their reporting with nonhomogeneous patient groups. A diverse approach is used in the management of these patients with complications such as infection, ankylosis, limited mouth opening, plate penetration in the skull base, and plate loosening. Risk factors for complications appear to be radiation, costochondral graft, disk loss, and plate use alone. Clinical data suggest use of a plate with metal condyle reconstructions and previous radiation therapy as potential risks factors. Employing literature evidence and cumulated clinical data, a risk-based flowchart was developed to assist surgical decision making. Risk factors such as radiation, disk preservation, and soft tissue conditions are important complication-associated factors when planning surgery. Free vascularized fibula grafts appear to have the least complications that must be weighed against donor site morbidity.

Basaloid squamous cell carcinoma of the maxillary gingiva: A case report and review of the literature.

Basaloid squamous cell carcinoma (BSCC) is a rare, but distinct histologic variant of squamous cell carcinoma in the head and neck region. It is considered to have a poor prognosis due to its aggressive behavior and tendency to metastasize. The usual sites of BSCC are the floor of the mouth, hypopharynx and base of the tongue, and according to the English-language literature its presentation in the gingiva is somewhat uncommon. In the current report, the unusual case of a 40-year-old male is presented; the patient exhibited a painless irregular mass in the maxillary gingiva, which infiltrated the maxillary sinus, as observed by computed tomography. Hematoxylin and eosin-stained sections revealed a diagnosis of BSCC with typical central necrosis in the cancer nests, which contained basaloid and squamous cells. Immunohistochemistry revealed that p63 was weakly positive, high molecular weight cytokeratin (CK) was focally positive, and S-100, CK7, CK14 and vimentin were negative. It must be noted that histopathology results may be incorrectly interpreted as adenoid cystic carcinoma, undifferentiated carcinoma and basal cell adenocarcinoma.

Preservation of ipsilateral submandibular gland is ill advised in cancer of the floor of the mouth or tongue.

OBJECTIVES/HYPOTHESIS: Preservation of the submandibular gland (SMG) during a neck dissection is gaining popularity and is showing an increasing tendency. The potential benefit, if the SMG is preserved, can be manifold. The aim of this study was to assess the benefit of the preservation of the SMG and the associated risk of recurrent disease in patients with oropharyngeal or oral cavity squamous cell carcinoma. STUDY DESIGN: Retrospective data analysis of 168 patients, with a follow-up of at least 3 years. METHODS: Log-rank test, univariate, and multivariate data analyses and P values for prediction of the excision of SMG on overall-, recurrence free-, and lymph node recurrence free survival. RESULTS: In patients with cancer of the floor of the mouth or tongue, lymph node recurrence-free survival was highly influenced by excision of the SMG (P < 0.001) and occurred in 28.5% of patients in whom the SMG was preserved. In all other tumor sites of the oral cavity and oropharyngeal region, excision of the SMG did not influence lymph node recurrence-free survival (P = 0.455). CONCLUSIONS: Patients with squamous cell carcinoma (SCC) of the oral cavity or oropharyngeal region will benefit from preservation of the ipsilateral SMG. This is not true for patients with SCC of the surrounding tissue nearest the SMG (i.e., floor of the mouth or the tongue). In such patients, the SMG must be excised.

Is lymph-node ratio a superior predictor than lymph node status for recurrence-free and overall survival in patients with head and neck squamous cell carcinoma?

INTRODUCTION: TNM status is questioned as an exact predictor of survival in different tumour entities. Recently, lymph node ratio (LNR) has been described as a predictor of survival in patients with HNSCC. The purpose of this study was to evaluate to which degree LNR could be used as a more accurate predictor than TNM staging? METHODS: A total of 291 patients, with a follow-up of at least 3 years, were analyzed using log-rank statistic, univariate and multivariate data analyzes, and p values, for prediction of lymph node ratio on overall and recurrence-free survival. RESULTS: Survival differed significantly if patients were stratified for LNR. Impact of LNR on survival was significantly different even in patients with extracapsular spread. Patients with pN0 had no survival benefit compared with patients with pN1 or higher with a LNR lower than 6 %. CONCLUSIONS: LNR is a prognostic tool in patients with a lymph node status pN0-pN2b. LNR remained significant even in patients with extracapsular spread, contrary to TNM status. With LNR, stratification for high-risk patients (higher than 6 % LNR) can be evaluated easily. We would suggest using LNR in the clinical routine.

Late term tolerance in head neck cancer patients irradiated in the IMRT era.

BACKGROUND: The aim was to quantify severe transient and persisting late term effects in our single institution head neck cancer (HNC) cohort treated with curatively intended intensity modulated radiation therapy (IMRT). Hypothesis was if a 2-year follow up (FU) is sufficient to estimate the long term tolerance in HNC irradiated in the IMRT era. METHODS: Between 01/2002-8/2012, 707/1211 (58%) consecutively treated IMRT patients met the inclusion criteria of a FU time >12 months and loco-regional disease control (LRC). 45% presented with loco-regionally advanced disease; 55% were referred for curative definitive IMRT (66 Gy-72 Gy in 30-35 fractions), 45% underwent postoperative IMRT (60-66 Gy in 30-33 fractions). Systemic concomitant therapy was administered in 85%. Highly consistent treatment procedures were performed with respect to contouring processes, dose constraints, radiation schedules, and the use of systemic therapy. Grade 3/4 late term effects were prospectively assessed and analyzed with respect to subgroups at particular risk for specific late effects. RESULTS: Mean/median FU of the cohort was 41/35 months (15-124). 13% of the patients (92/707) experienced any grade 3/4 late effects (101 events in 92/707 patients), 81% in the first 12 months after radiation. 4% of all developed persisting late grade 3/4 effects (25 events in 25/707 patients). CONCLUSIONS: IMRT led to a high late term tolerance in loco-regionally disease free HNC patients. The onset of any G3/4 effects showed a plateau at 2 years. The question of the cervical vessel tolerance in disease free long time survivors is still open and currently under evaluation at our institution.