Evaluation of a new two-step frailty assessment of head and neck patients in a prospective cohort.

PURPOSE: Assessing frailty, in head and neck cancer (HNC) patients is key when choosing appropriate treatment. Optimal screening is challenging, as it should be feasible and should avoid over-referral for comprehensive geriatric assessment (CGA) This study aims to evaluate the association between geriatric assessment using a new two-step care pathway, referral to geriatrician and adverse outcomes. METHODS: This institutional retrospective analysis on a prospective cohort analysed the multimodal geriatric assessment (GA) of newly diagnosed HNC patients. Uni- and multivariable logistic regression was performed to study the association between the screening tests, and referral to the geriatrician for complete geriatric screening, and adverse outcomes. RESULTS: This study included 539 patients, of whom 276 were screened. Patients who underwent the GA, were significantly older and more often had advanced tumour stages compared to non-screened patients. Referral to the geriatrician was done for 30.8% of patients. Of the 130 patients who underwent surgery, 26/130 (20%) experienced clinically relevant postoperative complications. Of the 184 patients who underwent (radio)chemotherapy, 50/184 (27.2%) had clinically relevant treatment-related toxicity. Age, treatment intensity, polypharmacy and cognitive deficits, were independently associated with referral to geriatrician. A medium to high risk of malnutrition was independently associated with acute radiation induced toxicity and adverse outcomes in general. CONCLUSION: The current study showed a 30.8% referral rate for CGA by a geriatrician. Age, treatment intensity, cognitive deficits and polypharmacy were associated with higher rates of referral. Furthermore, nutritional status was found to be an important negative factor for adverse treatment outcomes, that requires attention.

Incidental findings during the diagnostic work-up in the head and neck cancer pathway: Effects on treatment delay and survival.

OBJECTIVES: As a result of the increasing number of diagnostic scans, incidental findings (IFs) are more frequently encountered during oncological work-up in patients with head and neck squamous cell carcinomas (HNSCC). IFs are unintentional discoveries found on diagnostic imaging. Relevant IFs implicate clinical consequences, resulting in delay in oncologic treatment initiation, which is associated with unfavorable outcomes. This study is the first to investigate the incidence and nature of IFs over the years and establish the effect of relevant IFs on delay. MATERIAL AND METHODS: This retrospective study compared two time periods (2010-2011 and 2016-2017), described associations between relevant IFs and delay in carepathway interval (days between first visit and treatment initiation) and assessed the effect of relevant IFs on overall two-year survival. RESULTS: In total, 592 patients were included. At least one IF was found in 61.5% of the patients, most frequently on chest-CT. In 128 patients (21.6%) a relevant IF was identified, resulting for the majority in radiologist recommendations (e.g. additional scanning). Presence of a relevant IF was an independent significant factor associated with delay in treatment initiation. The risk of dying was higher for patients with a relevant IF, although not significant in the multivariable model (HR: 1.46, p = 0.079). CONCLUSION: In diagnostic work-up for HNSCC patients, relevant IFs are frequently encountered. As the frequency of additional imaging rises over the years, the number of IFs increased simultaneously. These relevant IFs yield clinical implications and this study described that relevant IFs result in significant delay in treatment initiation.

A comparison of the Thunderbeat and standard electrocautery devices in head and neck surgery: a prospective randomized controlled trial.

PURPOSE: New energy-based sutureless vessel ligation devices, such as the Thunderbeat (Olympus Medical Systems Corp., Tokyo, Japan), could reduce operative time and limit blood loss in head and neck surgery; however, efficacy and safety in major head and neck surgery have not been investigated in a prospective, randomized study. METHODS: This prospective, double-arm, randomized controlled trial consisted of two parts: total laryngectomy (TL) and neck dissection (ND). Thirty patients planned for TL were randomized in two groups. For the ND part, forty-two operative sides were likewise randomized. In both parts, Thunderbeat was used in addition to the standard instrumentation in the intervention groups, while only standard instrumentation was used in the control groups. Primary outcome values were blood loss, operative time and complication rate. RESULTS: For the TL part there was no difference in mean blood loss (p = 0.062), operative time (p = 0.512) and complications (p = 0.662) between both hemostatic techniques. For the neck dissection part, there was a reduction in blood loss (mean 210 mL versus 431 mL, p = 0.046) and in operative time (median 101 (IQR 85-130) minutes versus 150 (IQR 130-199) minutes, p = 0.014) when Thunderbeat was used. There was no difference in complication rate between both hemostatic systems (p = 0.261). CONCLUSION: The Thunderbeat hemostatic device significantly reduces operative blood loss and operative time for neck dissections, without increase in complications. In TL, blood loss using Thunderbeat was comparable with the standard technique, but the operative time tended to be shorter. TRIAL REGISTRATION: UMCG Research Register, Reg. no. 201700041, date of registration: 18/1/2017.

Treatment of keratinocyte carcinoma in elderly patients - a review of the current literature.

A large percentage of the patients with keratinocyte carcinoma (KC, formerly known as non-melanoma skin cancer) is of advanced age and often too frail for standard therapies. However, no specific treatment recommendations are given for this population. This review aimed to give an overview of the current literature on the best practice for the treatment of elderly patients with KC. A literature search was performed in MEDLINE, using 'keratinocyte carcinoma', 'elderly', 'treatment' and various synonyms. Case reports, reviews, comments, non-English literature and studies with a sample size <15 were excluded. After selection, a total of 47 studies were reviewed. Two types of studies were identified, focusing on (I) the effect of age on treatment outcomes and (II) alternative treatment schedules for elderly patients. Studies on surgery, the gold standard, describe larger lesions and defect size in the elderly population. Recurrence rate, complication rate and disease-specific survival were not affected by age. Depending on the expected morbidity of a suggested (re-)excision and patient preferences, a conservative watchful waiting policy can be agreed upon as a shared decision. Other common treatment modalities, such as adjuvant radiotherapy, photodynamic therapy and systemic therapy for basal cell carcinoma (BCC), show comparable results in the elderly and younger population. Alternative treatment schedules for elderly patients include primary hypofractionated radiotherapy, which seems effective and well-tolerated, although research is limited to case series. Additionally, localized and topical treatments seem safe and effective especially for low-risk tumours. Data are lacking on the efficacy of systemic therapies of metastatic KC in elderly patients. Efficacy of most treatments (with the exception of photodynamic therapy) is not dependent on age. There is need for more research on the efficacy of adjusted treatment modalities, such as hypofractionated radiotherapy and palliative or curative systemic treatment.

High sensitivity and negative predictive value of sentinel lymph node biopsy in a retrospective early stage oral cavity cancer cohort in the Northern Netherlands.

OBJECTIVES: In cT1-2N0, oral squamous cell carcinoma (OSCC) occult metastases are detected in 23%-37% of cases. Sentinel lymph node biopsy (SLNB) was introduced in head and neck cancer as a minimally invasive alternative for an elective neck dissection in neck staging. Meta-analyses of SLNB accuracy show heterogeneity in the existing studies for reference standards, imaging techniques and pathological examination. The aim of this study was to assess the sensitivity and negative predictive value (NPV) of the SLNB in detecting occult metastases in cT1-2N0 OSCC in a well-defined cohort. DESIGN: Retrospective study. The SLNB procedure consisted of lymphoscintigraphy, SPECT/CT-scanning and gamma probe detection. Routine follow-up was the reference standard for the SLNB negative neck. Histopathological examination of sentinel lymph nodes (SLN) consisted of step serial sectioning, haematoxylin-eosin and cytokeratin AE1/3 staining. SETTING: Two comprehensive oncology centres. PARTICIPANTS: A total of 91 consecutive patients with primary cT1-2N0 OSCC treated by primary resection and neck staging by SLNB procedure between 2008 and 2016. MAIN OUTCOME MEASURES: Sensitivity and negative predictive value. RESULTS: In all cases, SLNs were harvested. A total of 25 (27%) patients had tumour-positive SLNs. The median follow-up was 32 months (range 2-104). Four patients were diagnosed with an isolated regional recurrence in the SLNB negative neck side resulting in an 85% sensitivity and a 94% NPV. CONCLUSION: In our cohort, the SLNB detected occult metastases in early OSCC with 85% sensitivity and 94% NPV. This supports that SLNB is a reliable procedure for surgical staging of the neck in case of oral cT1-2N0 SCC.

Age-specific incidence and treatment patterns of head and neck cancer in the Netherlands-A cohort study.

OBJECTIVES: To explore the incidence and treatment pattern of head and neck cancer in different age groups. DESIGN: Cohort study. SETTING: Netherlands Cancer Registry. PARTICIPANTS: All new primary head and neck cancer cases diagnosed between 2010 and 2014 were included and categorised into different age groups. MAIN OUTCOME MEASURES: Tumour site, stage, treatment modality, location of diagnosis and treatment. RESULTS: The study population was composed of 11 558 tumours. Oral cancer was the most common primary site (31%), followed by laryngeal (25%) and oropharyngeal cancer (22%). Ninety-six per cent of the entire study population was diagnosed and/or treated in a certified head and neck oncology centre which was lower in the 80+ population (92%). Multimodality treatment was less frequently applied with increasing age (eg oral cavity: 17% in 80+ vs 34% in 60-; P < .001). The percentage of patients not receiving tumour-directed treatment increased with age (eg oropharyngeal cancer: 25% in 80+ vs 6% in 80-; P < .001). CONCLUSIONS: This study confirms that less multimodal and tumour-directed treatment is applied with the increasing age of head and neck cancer patients.

Clinical outcome of salvage neck dissections in head and neck cancer in relation to initial treatment, extent of surgery and patient factors.

OBJECTIVE: Salvage surgery has a higher complication rate compared to primary surgical treatment. We evaluated clinical outcome of salvage neck dissections in relation to initial treatment modality, extent of surgery and patient-related factors. DESIGN: Single institution consecutive case series. SETTING: Tertiary Head and Neck Cancer Centre. PARTICIPANTS: In all, 87 patients with head and neck squamous cell carcinoma, who underwent salvage neck dissection after initial radiotherapy (n = 30), radiotherapy with carboplatin/5-fluorouracil (n = 43) or radiotherapy with cetuximab (n = 14). MAIN OUTCOME MEASURES: Incidence of complications, disease-specific survival. RESULTS: Complications occurred in 28% of the patients. Multivariate analysis identified extent of neck dissection as the only independent predictor of surgical complications (P = 0.010). Surgical complication rate was 16% after radiotherapy with systemic treatment, and 47% after radiotherapy alone (P = 0.171). The 5-year disease-specific survival was 55%, independent of complications, initial treatment, extent of surgery and patient-related factors. CONCLUSION: The only predictor for surgical complications was extent of surgery. Survival was not influenced by complications.

Treatment in elderly patients with head and neck cancer : A challenging dilemma.

Despite the increasing number of elderly patients requiring treatment for head and neck cancer, there is insufficient available evidence about the oncological results of treatment and its tolerability in such patients. Owing to comorbidities, elderly patients often need complex evaluation and pretreatment management, which often results in their exclusion from clinical trials. The question of which patients constitute the highest-risk groups regarding treatment-related morbidity and mortality, and who can tolerate and benefit from aggressive treatment, has not been adequately studied. Biologic rather than chronologic age should be a more important factor in treatment protocols. Age-specific prospective clinical studies are needed on the treatment of head and neck cancer in elderly patients.

ATP-Evoked Intracellular Ca²âº Signaling of Different Supporting Cells in the Hearing Mouse Hemicochlea.

Hearing and its protection is regulated by ATP-evoked Ca(2+) signaling in the supporting cells of the organ of Corti, however, the unique anatomy of the cochlea hampers observing these mechanisms. For the first time, we have performed functional ratiometric Ca(2+) imaging (fura-2) in three different supporting cell types in the hemicochlea preparation of hearing mice to measure purinergic receptor-mediated Ca(2+) signaling in pillar, Deiters' and Hensen's cells. Their resting [Ca(2+)]i was determined and compared in the same type of preparation. ATP evoked reversible, repeatable and dose-dependent Ca(2+) transients in all three cell types, showing desensitization. Inhibiting the Ca(2+) signaling of the ionotropic P2X (omission of extracellular Ca(2+)) and metabotropic P2Y purinergic receptors (depletion of intracellular Ca(2+) stores) revealed the involvement of both receptor types. Detection of P2X2,3,4,6,7 and P2Y1,2,6,12,14 receptor mRNAs by RT-PCR supported this finding and antagonism by PPADS suggested different functional purinergic receptor population in pillar versus Deiters' and Hensen's cells. The sum of the extra- and intracellular Ca(2+)-dependent components of the response was about equal with the control ATP response (linear additivity) in pillar cells, and showed supralinearity in Deiters' and Hensen's cells. Calcium-induced calcium release might explain this synergistic interaction. The more pronounced Ca(2+) leak from the endoplasmic reticulum in Deiters' and Hensen's cells, unmasked by cyclopiazonic acid, may also suggests the higher activity of the internal stores in Ca(2+) signaling in these cells. Differences in Ca(2+) homeostasis and ATP-induced Ca(2+) signaling might reflect the distinct roles these cells play in cochlear function and pathophysiology.

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.

This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.

Early feeding after total laryngectomy results in shorter hospital stay without increased risk of complications: a retrospective case-control study.

OBJECTIVES: To evaluate the effects of a reduced nil per os (NPO) period after total laryngectomy (TLE) on general and wound-related post-operative complications, swallowing function and duration of hospital stay. DESIGN, SETTING AND PARTICIPANTS: In a retrospective case-control study in 71 patients after TLE with primary closure (i e. without reconstruction with tissue transfer), complications and hospitalisation in 36 patients who started oral feeding on days 3-5 (early feeding) were compared with 30 patients who started oral feeding on days 7-10 (late feeding). MAIN OUTCOME MEASURES: Incidence of complications, swallowing function and duration of hospitalisation. RESULTS: There were no significant differences between the early- and late-feeding groups in the occurrence of pharyngocutaneous fistulae, neopharyngeal stenosis or wound complications in general. Swallowing function was comparable for both groups. Mean overall hospitalisation was 2 days shorter in the early-feeding group (mean: 17.4 days) as compared to the late-feeding group (mean: 19.4 days) (P < 0.05). CONCLUSIONS: Early feeding after TLE without flap reconstruction did not contribute to an increase in complications and led to a shorter hospital stay.

Predictive value of the Groningen Frailty Indicator for treatment outcomes in elderly patients after head and neck, or skin cancer surgery in a retrospective cohort.

OBJECTIVES: Careful selection of patients eligible for extensive head and neck cancer surgery is extremely important. A reliable predictor for postoperative outcomes in the vulnerable elderly population is not yet available. The concept of frailty describes a clinical state of increased vulnerability and can be assessed using frailty tests, such as the Groningen Frailty Indicator. In the current study, the influence of Groningen Frailty Indicator-measured frailty on clinical outcome was investigated in elderly patients surgically treated for head and neck cancer. DESIGN: Retrospective, explorative cohort study. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 90 patients of 65 years and older receiving surgical treatment for head and neck cancer with different primary sites. MAIN OUTCOME MEASURES: The influence of frailty (Groningen Frailty Indicator) on postoperative complications (Clavien-Dindo classification), subjective postoperative experience of both patient and surgeon and survival were analysed. RESULTS: A total of 36 patients were considered as frail (40%). Postoperative complications could not be predicted by frailty status. However, the Groningen Frailty Indicator dimension 'health problems' was a significant predictor for postoperative complications (P = 0.020). Unlike age and comorbidity, frailty was associated with a poor subjective patients' experience of the postoperative recovery (P < 0.01). Although not statistically significant, survival analysis showed a worse 5-year overall survival in the frail group (33%) versus the non-frail group (74%). CONCLUSIONS: Analysis of frailty could identify elderly patients who might suffer more than expected during the postoperative period after head and neck cancer surgery. In this study, frailty was not identified as a new predictor of complications after head and neck cancer surgery.

Incidence of unplanned oophorectomy at laparoscopic ovarian cystectomy for clinically benign cysts.

Laparoscopic surgery is the preferred approach in women with ovarian cysts and a low risk of malignancy, and the aim in young women should be to preserve the ovary. We are not aware of any data on the success of conservative surgery in preserving the affected ovary and this is the reason why we decided to investigate the incidence of unplanned oophorectomy, when a woman is originally scheduled for laparoscopic ovarian cystectomy for clinically benign cysts. We reviewed the medical notes of the 123 women who underwent surgery for clinically benign ovarian cysts between November 2004 and May 2012. The operative procedures performed were ovarian cystectomies (n = 119), salpingo-oophorectomy (n = 2) and fenestration (n = 2). In total, 61 women underwent a concomitant procedure. In our study, we found that planned laparoscopic cystectomy was mostly successful, with only 1.6% of patients in our series requiring unplanned oophorectomy.

Growth hormone-releasing hormone antagonists inhibit growth of human ovarian cancer.

Epithelial ovarian carcinoma is the leading cause of cancer-related deaths among women with gynecologic malignancies. Antagonists of the growth hormone-releasing hormone (GHRH) have been shown to inhibit growth of various cancers through endocrine, autocrine, and paracrine mechanisms. In this study, we have investigated the effects of GHRH antagonists (GHRHa) in ES-2 human clear cell ovarian cancer and in UCI-107 human serous ovarian cancer in vitro and in vivo. We evaluated the expression of mRNA for GHRH receptor, the binding to GHRH receptors, in specimens of ES-2 ovarian cancer. We evaluated also the in vitro effects of GHRHa on ES-2 cells and the in vivo effect of 2 different GHRHa on ES-2 and UCI-107 tumors. Nude mice bearing xenografts on ES-2 and UCI-107 ovarian cancer were treated with JMR-132 and MZ-J-7-118, respectively. Tumor growth was compared to control. ES-2 cells expressed mRNA for the functional splice variant SV1 of the GHRH receptor. JMR-132 inhibited cell proliferation in vitro by 42% and 18% at 10 and 1 µM concentration, respectively. Specific high affinity receptors for GHRH were detected in ES-2 cancer samples. In vivo daily subcutaneous injections of GHRHa significantly reduced tumor growth compared to a control group in both animal models. Our results indicate that GHRHa such as JMR-132 and MZ-J-7-118 can inhibit the growth of human ovarian cancer. The efficacy of GHRHa in ovarian cancer should be assessed in clinical trials.

The inhibitory effect of a novel cytotoxic somatostatin analogue AN-162 on experimental glioblastoma.

Glioblastoma multiforme is the most common and most aggressive type of high grade tumor with a poor prognosis upon discovery. Based on earlier promising results earned with AN-162, a doxorubicin molecule linked to somatostatin (SST) analogue RC-160, it was our aim to determine the effect of AN-162 on DBTRG-05 glioblastoma cell line, and to test its efficacy in experimental brain tumors. We detected the expression of mRNA for somatostatin receptor (SSTR) subtypes 2 and 3 in DBTRG-05 cells with RT-PCR. Using ligand competition assay, specific high affinity receptors for somatostatin were found. The MTT assay showed that both AN-162 and doxorubicin (DOX) significantly inhibited cell proliferation and that there was no significant difference between the effects in vitro. Nude mice were xenografted with DBTRG-05 glioblastoma tumors. AN-162 showed a significant inhibition of tumor growth compared with the control group and the groups treated with equimolar doses of doxorubicin, somatostatin analogue RC-160, or the unconjugated mixture of doxorubicin plus RC-160. The tumor doubling time in the group of animals treated with AN-162 was extended and was significantly different from doubling times in the control group and in the other treatment groups. Our study clearly demonstrates a potent inhibitory effect of AN-162 in experimental glioblastoma, thus suggesting the possibility of its utilization in patients suffering from malignant brain cancer.

The role of N-methyl-D-aspartate receptors and nitric oxide in cochlear dopamine release.

Dopamine (DA) released from lateral olivocochlear (LOC) terminals may have a neuroprotective effect in the cochlea. To explore the role of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) in the modulation of a cochlear DA release, we measured the release of [3H]DA from isolated mouse cochlea in response to the application of NMDA. NMDA at 100 muM significantly increased the electrical-field stimulation-evoked and resting release of DA from the cochlea. The NO donor sodium nitroprusside enhanced the basal outflow of DA but failed to influence the evoked release. The administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) alone was ineffective, but it significantly inhibited the initial phase of the NMDA-induced elevation of DA outflow, which suggested the role of NO in the NMDA-induced DA release. The DA uptake inhibitor nomifensine increased the electrically evoked release of DA. Nomifensine failed to change the effect of NMDA on the resting or electrically-evoked DA release, which suggested that the uptake mechanism does not play a role in NMDA-evoked and NO-mediated DA release. In summary, we provide evidence that NO can modulate the release of DA from the cochlea following NMDA receptor activation, but does not affect the uptake of DA.

D2 autoreceptor inhibition reveals oxygen-glucose deprivation-induced release of dopamine in guinea-pig cochlea.

Dopamine (DA), released from the lateral olivocochlear (LOC) efferent terminals, the efferent arm of the short-loop feedback in the cochlea, is considered as a protective factor in the inner ear since it inhibits auditory nerve dendrite firing in ischemia- or noise-induced excitotoxicity leading to sensorineural hearing loss (SNHL). In the present study we investigated the effect of oxygen-glucose deprivation (OGD), an in vitro ischemia model, on guinea-pig cochlear [(3)H]DA release in a microvolume superfusion system. We found that OGD alone failed to induce a detectable elevation of [(3)H]DA level, but in the presence of specific D(2) receptor antagonists, sulpiride and L-741,626, it evoked a significant increase in the extracellular concentration of [(3)H]DA. D(2) negative feedback receptors are involved not exclusively in the regulation of synthesis and vesicular release of DA, but also in the activation of its reuptake. Thus, D(2) receptor antagonism interferes with the powerful reuptake of DA from the extracellular space. To explore the underlying mechanism of this DA-releasing effect we applied nomifensine and found that the effect of OGD on cochlear DA release in the presence of D(2) antagonists could be inhibited by this selective DA uptake inhibitor. This finding indicates that the OGD-evoked DA release was mainly mediated through the reverse operation of the DA transporter. The two structurally different D(2) antagonists also augmented the electrical field stimulation-evoked release of DA proving the presence of D(2) autoreceptors on dopaminergic LOC terminals. Our results confirm the presence and role of D(2) DA autoreceptors in the regulation of DA release from LOC efferents, and suggest a protective local mechanism during ischemia which involves the direct transporter-mediated release of DA. Increasing the release of the protective transmitter DA locally in the inner ear may form the basis of future new therapeutic strategies in patients suffering from SNHL.

New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs.

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.