A retrospective analysis of iv ketamine outcome on hospitalisations in an unselected psychiatric sample.

OBJECTIVE: This study aims to explore the outcome with iv ketamine treatment in a real-world clinical setting, primarily measured as posttreatment days hospitalised. METHODS: The psychiatric medical records of 46 patients having received iv ketamine on a psychiatric treatment indication between 2015 and 2018 were retrospectively examined. Analysis comparing the number and duration of hospital admissions before and after ketamine treatment as well as logistic regression analysis to investigate clinical predictors of effectiveness, were performed. To assess patients' severity of depressed symptoms records were screened for MADRS-S scores. RESULTS: No significant difference between pre- and posttreatment hospital days (p = 0.170), or number of hospitalisations (p = 0.740) were found. The response rate was 31% and remission rate 21%. None of the predictors showed statistical significance in the logistic model. CONCLUSION: Iv ketamine treatment showed effectiveness in reducing depressive symptoms even with complex patients in a real-world clinical setting. However, this did not translate to a reduction in hospitalisation. Highlighting the multifaceted challenges posed when implementing iv ketamine treatment in clinical practice.

Prognostic value of bone marrow and tumor 18 F-FDG uptake on PET/CT in patients with oropharyngeal cancer and the interplay between inflammation and FDG uptake.

AIMS: To examine the prognostic value of F-18 fluorodeoxyglucose (FDG) uptake in the bone marrow (BM) for disease recurrence and survival in patients with oropharyngeal squamous cell carcinoma (OP-SCC). The secondary aims were to evaluate the prognostic value of PET/CT parameters for the primary oropharyngeal tumor and total tumor burden, and to assess the correlation between FDG uptake variables and serum inflammatory markers. METHODS: This was an observational study of 91 patients with OP-SCC who underwent pretreatment FDG-PET/CT. The patients' blood samples were collected before treatment, and treatment was administered with the intention to cure. The median follow-up time was 40 months. The PET parameters measured were SUVmean BM for the assessment of BM FDG uptake, SUVmean , SUVmax , total lesion glycolysis (TLG), and metabolic tumor volume (MTV) for the evaluation of primary oropharyngeal tumor and total tumor burden. Blood samples were analyzed to determine each patient's white cell, red cell, and platelet cell counts, hemoglobin, and C-reactive protein level. In a subgroup of 33 patients, blood serum was analyzed to evaluate the expression of serum immune proteins using a proximity extension assay (Olink Proteomics). RESULTS: The univariate analysis revealed that SUVmean BM and tumor-specific parameters (SUVmax tumor, SUVmean total, SUVmax total, MTVtotal, TLGtotal) were significantly associated with recurrence-free survival (RFS). After adjusting for age, sex, and stage only SUVmean BM remained significantly associated with RFS. Spearman's correlation identified several correlations between PET parameters and inflammatory markers. CONCLUSIONS: Our results show that several FDG-PET/CT parameters may have a prognostic value of treatment outcome in patients with OP-SCC. However, SUVmean BM was the only independent PET parameter that showed a prognostic value for RFS in the study cohort. Moreover, the study findings might suggest an association between systemic inflammation and the metabolic activity in the BM.

Squamous cell carcinoma of the mobile tongue in young adults: A Swedish head & neck cancer register (SweHNCR) population-based analysis of prognosis in relation to age and stage.

Increased incidence of squamous cell carcinoma (SCC) of the tongue has been reported in young adults (YA) in several countries since the 1980s and confirmed in later studies. The etiology is unclear, the prognosis has been debated, and conflicting results have been published. Some studies show better survival in young adults than in older patients, some worse, and others no difference. Most studies are based on selected series or include other sites in the oral cavity. The definition of "YA" is arbitrary and varies between studies. It is thus difficult to use in general conclusions. This work uses data from the population-based Swedish Head and Neck Cancer register (SweHNCR), which has > 98% coverage. SweHNCR data includes age, gender, TNM, treatment intention, treatment given, lead times, performance status, and to a lesser degree, smoking habits. The current Swedish population is around 10 million. We analyzed outcomes for 1416 patients diagnosed with SCC of the oral tongue from 2008 to 2017 using 18-39 years to define YA age because it is the range most commonly used. We found no significant difference in relative survival (a proxy for diagnosis-specific survival) between age groups of patients treated with curative intent for SCC of the oral tongue. The stage at time of diagnosis was equally distributed among the age groups. Excess mortality rate correlated mainly with stage, subsite of the tongue, performance status, and lead time to treatment.

Loco-Regional Control and Sustained Difference in Serum Immune Protein Expression in Patients Treated for p16-Positive and p16-Negative Head and Neck Squamous Cell Carcinoma.

The main prognostic factors for patients with head and neck cancer are the tumour site and stage, yet immunological and metabolic factors are certainly important, although knowledge is still limited. Expression of the biomarker p16INK4a (p16) in oropharyngeal cancer tumour tissue is one of the few biomarkers for the diagnosis and prognosis of head and neck cancer. The association between p16 expression in the tumour and the systemic immune response in the blood compartment has not been established. This study aimed to assess whether there is a difference in serum immune protein expression profiles between patients with p16+ and p16- head and squamous cell carcinoma (HNCC). The serum immune protein expression profiles, using the Olink® immunoassay, of 132 patients with p16+ and p16- tumours were compared before treatment and one year after treatment. A significant difference in the serum immune protein expression profile was observed both before and one year after treatment. In the p16- group, a low expression of four proteins: IL12RB1, CD28, CCL3, and GZMA before treatment conferred a higher rate of failure. Based on the sustained difference between serum immune proteins, we hypothesise that the immunological system is still adapted to the tumour p16 status one year after tumour eradication or that a fundamental difference exists in the immunological system between patients with p16+ and p16- tumours.

Serum Proteomics in Patients with Head and Neck Cancer: Peripheral Blood Immune Response to Treatment.

In this real-world study, the aims were to prospectively evaluate the expression of inflammatory proteins in serum collected from head and neck cancer patients before and after treatment, and to assess whether there were differences in expression associated with treatment modalities. The mixed study cohort consisted of 180 patients with head and neck cancer. The most common tumor sites were the oropharynx (n = 81), the oral cavity (n = 53), and the larynx (n = 22). Blood tests for proteomics analysis were carried out before treatment, 7 weeks after the start of treatment, and 3 and 12 months after the termination of treatment. Sera were analyzed for 83 proteins using an immuno-oncology biomarker panel (Olink, Uppsala, Sweden). Patients were divided into four treatment groups: surgery alone (Surg group, n = 24), radiotherapy with or without surgery (RT group, n = 94), radiotherapy with concomitant cisplatin (CRT group, n = 47), and radiotherapy with concomitant targeted therapy (RT Cetux group, n = 15). For the overall cohort, the expression levels of 15 of the 83 proteins changed significantly between the pretreatment sample and the sample taken 7 weeks after the start of treatment. At 7 weeks after the start of treatment, 13 proteins showed lower expression in the CRT group compared to the RT group. The majority of the inflammatory proteins had returned to their pretreatment levels after 12 months. It was clearly demonstrated that cisplatin-based chemoradiation has immunological effects in patients with head and neck cancer. This analysis draws attention to several inflammatory proteins that are of interest for further studies.

Mandibular resection in patients with head and neck cancer: acute and long-term complications after reconstruction.

BACKGROUND: The treatment of head and neck cancer is an intensive multimodal treatment that has a great impact on the individual patient. AIMS/OBJECTIVES: This study aimed to evaluate acute and long-term complications associated with mandibular resections and reconstructions. MATERIAL AND METHODS: We retrospectively retrieved data on complications and recurrences among patients that underwent mandibular resections and reconstructions for treating oral cavity cancer (n = 190 patients) and osteoradionecrosis (ORN, n = 72). Reconstructions included composite grafts (n = 177), soft tissue flaps (n = 61), or primary closure without any graft (n = 24). RESULTS: Forty-two patients that underwent reconstructions with composite grafts displayed serious complications (Clavien-Dindo ≥ IIIa). The complication rates were similar between patients treated for oral cavity cancer and patients treated for ORN. Patients that underwent a primary closure without any graft, had a significantly lower risk of complications compared to patients that underwent the other treatments. After hospitalization, 181 patients (69%) had at least one complication. CONCLUSIONS: A majority of patients undergoing resection and reconstruction due to oral cancer/ORN suffered from postoperative complications regardless of indication, comorbidity status or reconstruction technique. The risk of Clavien-Dindo grade IIIa-V events was significantly lower for patients treated with primary closure without grafts. SIGNIFICANCE: The results from this study clarifies the importance of in-depth analyse prior to decision of treatment for patients with head and neck cancer.

Base of tongue squamous cell carcinomas, outcome depending on treatment strategy and p16 status. A population-based study from the Swedish Head and Neck Cancer Register.

BACKGROUND: The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated. MATERIAL AND METHODS: Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition. RESULTS: Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16-. 5-year overall survival (OS) was 68% (95% CI: 64-72%), with76% and 37% for p16+ patients and p16- patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II-III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone. CONCLUSION: In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16- tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies.

Mapping of human papilloma virus, p16, and epstein-barr virus in non-malignant tonsillar disease.

OBJECTIVES: Due to their location in the entrance of the aero-digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein-Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs. AIM: To investigate if tonsils are infected with HPV and EBV, to study the co-expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease. MATERIALS AND METHODS: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER-ISH (Epstein-Barr encoding region-in situ hybridization). RESULTS: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER-positive cell was seen in 65% of cases. Larger numbers of EBER-expressing cells were only seen in two cases. CONCLUSION: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship. LEVEL OF EVIDENCE: Cross-sectional study.

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.

Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases.

Surgically removed palatine tonsils provide a conveniently accessible source of T and B lymphocytes to study the interplay between foreign pathogens and the host immune system. In this study we have characterised the distribution of human adenovirus (HAdV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in purified tonsillar T and B cell-enriched fractions isolated from three patient age groups diagnosed with tonsillar hypertrophy and chronic/recurrent tonsillitis. HAdV DNA was detected in 93 out of 111 patients (84%), while EBV DNA was detected in 58 patients (52%). The most abundant adenovirus type was HAdV-5 (68%). None of the patients were positive for HCMV. Furthermore, 43 patients (39%) showed a co-infection of HAdV and EBV. The majority of young patients diagnosed with tonsillar hypertrophy were positive for HAdV, whereas all adult patients diagnosed with chronic/recurrent tonsillitis were positive for either HAdV or EBV. Most of the tonsils from patients diagnosed with either tonsillar hypertrophy or chronic/recurrent tonsillitis showed a higher HAdV DNA copy number in T compared to B cell-enriched fraction. Interestingly, in the majority of the tonsils from patients with chronic/recurrent tonsillitis HAdV DNA was detected in T cells only, whereas hypertrophic tonsils demonstrated HAdV DNA in both T and B cell-enriched fractions. In contrast, the majority of EBV positive tonsils revealed a preference for EBV DNA accumulation in the B cell-enriched fraction compared to T cell fraction irrespective of the patients' age.

Efficient Isolation Protocol for B and T Lymphocytes from Human Palatine Tonsils.

Tonsils form a part of the immune system providing the first line of defense against inhaled pathogens. Usually the term "tonsils" refers to the palatine tonsils situated at the lateral walls of the oral part of the pharynx. Surgically removed palatine tonsils provide a convenient accessible source of B and T lymphocytes to study the interplay between foreign pathogens and the host immune system. This video protocol describes the dissection and processing of surgically removed human palatine tonsils, followed by the isolation of the individual B and T cell populations from the same tissue sample. We present a method, which efficiently separates tonsillar B and T lymphocytes using an antibody-dependent affinity protocol. Further, we use the method to demonstrate that human adenovirus infects specifically the tonsillar T cell fraction. The established protocol is generally applicable to efficiently and rapidly isolate tonsillar B and T cell populations to study the role of different types of pathogens in tonsillar immune responses.

In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study.

BACKGROUND: Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours. METHODS: The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup. RESULTS: Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys. CONCLUSIONS: We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.

Improved tumor-to-organ ratios of a novel 67Ga-human epidermal growth factor radionuclide conjugate with preadministered antiepidermal growth factor receptor affibody molecules.

The overexpression of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis. Targeted nuclear imaging of the EGFR expression could improve the diagnostics in patients with HNSCC. However, the high expression of EGFR in normal organs may conceal the tumor uptake and therefore limit the use. This study assesses the biodistribution of a novel human epidermal growth factor (hEGF) radionuclide conjugate after preinjection with anti-EGFR affibody molecules. hEGF was conjugated with p-SCN-Bn-NOTA and labeled with (67)Ga. The biodistribution of [(67)Ga]Ga-NOTA-Bn-NCS-hEGF in nude mice with EGFR-expressing xenografts was evaluated either alone or 45 minutes after preinjection with one of the anti-EGFR affibody molecules Z(EGFR:1907), (Z(EGFR:1907))(2), or (Z(EGFR:955))(2). The novel radioimmunoconjugate, [(67)Ga]Ga-NOTA-Bn-NCS-hEGF, demonstrated high stability in vitro and specific binding to hEGF in vitro and in vivo. Preinjection with anti-EGFR affibody molecules improved the tumor-to-organ ratio in the liver, salivary glands, and colon. Overall, the dimeric high-affinity affibody molecule (Z(EGFR:1907))(2) exhibited the best results. These findings show that preblocking with an anti-EGFR affibody molecule is a promising tool that could improve the outcome of radionuclide-based imaging of EGFR-expressing tumors.

Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF.

Overexpression of epidermal growth factor receptor (EGFR) in several types of malignant tumors correlates with disease progression. EGFR could, therefore, be an excellent candidate for targeted radionuclide diagnostics. However, the high natural expression of EGFR in the liver may be problematic. The aim of this study was to improve the tumor-to-liver ratio of radiolabeled epidermal growth factor (EGF) by blocking its uptake by the liver with a nonradiolabeled EGFR-targeting molecule in tumor-bearing mice. Intraperitoneally injected nonradiolabeled EGF was first evaluated as a blocking agent, preadministered at various time intervals before intravenous injection of (125)I-labeled EGF. The anti-EGFR Affibody molecule (Z(EGFR:955))(2) was then assessed as a blocking agent of (111)In-labeled EGF in a dual isotope study (50, 100, and 200 microg, preadministered 30 or 60 min before (111)In-EGF). The 30-min preadministration of nonradiolabeled EGF significantly decreased (125)I-EGF uptake in the liver, whereas uptake in the tumor remained unchanged. Furthermore, preadministration of only 50 microg (Z(EGFR:955))(2) as a blocking agent 30 min before the (111)In-EGF decreased the uptake of (111)In-EGF by the liver and increased its uptake by the tumor, thereby increasing the tumor-to-liver ratio sixfold. We conclude that the Affibody molecule (Z(EGFR:955))(2) shows promise as a blocking agent that could enhance the outcome of radionuclide-based EGFR-expressing tumor diagnostics and imaging.

Targeting CD44v6 expressed in head and neck squamous cell carcinoma: preclinical characterization of an 111In-labeled monoclonal antibody.

In patients with head and neck squamous cell carcinoma (HNSCC) radioimmunodiagnosis could offer a more specific and sensitive tumor diagnostic method. Our aim was to evaluate the labeling and biodistribution of the novel radioimmunoconjugate (111)In-cMAb U36. In this study cMAb U36, targeting CD44v6, and huA33, as a negative control, were labeled with indium-111, using the chelator CHXA''-DTPA. Immunoreactivity assays and binding studies were performed in vitro. Biodistribution and tumor imaging were conducted after intravenous injection of the radioimmunoconjugate to nude mice bearing HNSCC xenografts expressing CD44v6. The immunoreactive fraction was very high and the binding was CD44v6-specific. In vivo results demonstrated a promising biodistribution, with tumors clearly accumulating radioactivity with time. At 168 h postinjection (p.i.) the tumor uptake was 54.7 +/- 16.6% injected dose/g. The cMAb U36 had significantly (p < 0.05) higher uptake in tumors 72 h p.i. compared to huA33. We produced a novel radioimmunoconjugate targeting CD44v6 for possible use in the detection of HNSCC. The conjugate demonstrates no adverse effects from labeling and a favorable biodistribution.