Petr Szturz

Treatment of elderly Patients with Squamous Cell Carcinoma of the Head and Neck

The demographics of squamous cell carcinoma of the head and neck (SCCHN) is marked by a growing number of patients aged 65 and over, which is in line with global projections for other cancer types. In developed countries, more than half of new SCCHN cases are diagnosed in older people, and in 15 years from now, the proportion is expected to rise by more than 10%. Still, a high-level evidence-based consensus to guide the clinical decision process is strikingly lacking. The available data from retrospective studies and subset analyses of prospective trials suffer from a considerable underrepresentation of senior participants. The situation is even more challenging in the recurrent and/or metastatic setting, where usually only palliative measures are employed. Nevertheless, it is becoming clear that, if treated irrespective of chronological age, fit elderly patients in a good general condition and with a low burden of comorbidities may derive a similar survival advantage as their younger counterparts. Despite that, undertreatment represents a widespread phenomenon and, together with competing non-cancer mortality, is suggested to be an important cause of the worse treatment outcomes observed in this population. Due to physiological changes in drug metabolism occurring with advancing age, the major concerns relate to chemotherapy administration. In locally advanced SCCHN, concurrent chemoradiotherapy in patients over 70 years remains a point of controversy owing to its possibly higher toxicity and questionable benefit. However, accumulating evidence suggests that it should, indeed, be considered in selected cases when biological age is taken into account. Results from a randomized trial conducted in lung cancer showed that treatment selection based on a comprehensive geriatric assessment (CGA) significantly reduced toxicity. However, a CGA is time-consuming and not necessary for all patients. To overcome this hurdle, geriatric screening tools have been introduced to decide who needs such a full evaluation. Among the various screening instruments, G8 and Flemish version of the Triage Risk Screening Tool were prospectively verified and found to have prognostic value. We, therefore, conclude that also in SCCHN, the application of elderly specific prospective trials and integration of clinical practice-oriented assessment tools and predictive models should be promoted.

Weekly Low‐Dose Versus Three‐Weekly High‐Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non‐Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta‐Analysis of Aggregate Data

BACKGROUND Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, due to unsatisfactory patient tolerance, various weekly low-dose schedules have been increasingly used in clinical practice. The aim of this meta-analysis was to compare the efficacy, safety, and compliance between these two approaches. MATERIALS AND METHODS We systematically searched literature for prospective trials of patients with LA-SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60-66 gray (Gy) in the postoperative setting and 66-70 Gy in the definitive setting. Standard, three-weekly high-dose cisplatin (100 mg/m2, 3 doses) was compared with the weekly low-dose protocol (≤50 mg/m2, ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance. RESULTS Fifty-two studies with 4,209 patients were included in two separate meta-analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose three-weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3-4) myelosuppression (leukopenia p = .0083; neutropenia p = .0024), severe nausea and/or vomiting (p < .0001), and severe nephrotoxicity (p = .0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin-induced toxicities, the weekly approach induced more grade 3-4 dysphagia (p = .0026) and weight loss (p < .0001). CONCLUSION In LA-SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low-dose weekly approach needs to be prospectively compared with the standard three-weekly high-dose schedule. IMPLICATIONS FOR PRACTICE Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach.

Contrast-enhanced ultrasonography compared to gray-scale and power doppler in the diagnosis of peripheral lymphadenopathy.

OBJECTIVES The aim of the study was to evaluate the ability of contrast-enhanced ultrasonography compared to gray-scale B-mode and power Doppler in distinction between benign and malignant lymphadenopathy. METHODS In a prospective study ultrasonography was performed in 133 patients with superficial lymphadenopathy (73 men, 60 women; mean age of 51 years, range: 18-86 years), who were examined for palpable mass in the neck, axilla or groin (104/133) and for clinical suspicion of lymphoma on the basis of positive PET/CT (29/133). 133 nodes were examined, subsequently preoperatively localized under ultrasound guidance and surgically removed; longitudinal to transverse ratio, location of nodal vessels by power Doppler and pattern of enhancement by contrast-enhanced ultrasonography with 1.5ml intravenous bolus of sulphur hexafluoride contrast agent were documented. The ultrasound findings were compared with the histology. RESULTS Of all the nodes extirpated, 33 were benign, 100 were malignant (40 metastases, 60 lymphomas). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of conventional techniques were 72%, 63.6%, 85.7%, 42.9%, 67.8% for longitudinal to transverse ratio; 73%, 60.6%, 84.9%, 42.6%, 68.3% for power Doppler versus 98.0%, 54.5%, 86.7%, 90.0%, 76.3% for contrast-enhanced ultrasonography according to Receiver Operating Characteristic analysis. CONCLUSIONS Receiver Operating Characteristic analysis confirmed higher degree of diagnostic accuracy of contrast-enhanced ultrasonography in comparison with conventional techniques. Evaluation of nodal perfusion after intravenous administration of microbubble contrast agent can be helpful in differentiation of benign from malignant nodes.

Understanding c-MET signalling in squamous cell carcinoma of the head & neck

c-MET is a membrane spanning receptor tyrosine kinase for hepatocyte growth factor (HGF) also termed scatter factor. Transmitting signals from mesenchymal to epithelial cells, the HGF/c-MET axis mediates a range of biological processes that stimulate proliferation, motility, invasiveness, morphogenesis, apoptosis, and angiogenesis. Aberrant c-MET signal transduction favours tumorigenesis with the acquisition of invasive and metastatic phenotypes. Biological functions of c-MET may strongly vary according to microenvironmental changes, which occur at different stages of tumorigenesis and include also HGF/c-MET activation in stromal cells. In this review, we focused on abnormalities in non-nasopharyngeal squamous cell carcinoma of the head & neck. While the prevalence of c-MET mutations and amplifications ranges 0-25%, c-MET upregulation can be found in the majority of squamous head & neck carcinomas. Despite marked heterogeneity in published scoring methods, immunohistochemical overexpression of c-MET has been typically linked to advanced stages and associated with impaired survival and/or resistance to radiotherapy, chemoradiotherapy, and cetuximab. Experimental studies in cell lines and patient-derived xenografts using various c-MET antagonists (both as single-agents and in combination with cytotoxic and epidermal growth factor receptor [EGFR]-directed agents) yielded promising results, albeit benefit in clinical trials remains to be demonstrated. Consequently, selecting more active agents and integrating them effectively in studies, which incorporate predictive biomarkers such as c-MET gene mutations, amplifications, and overexpression, remains challenging. Further investigations should increase emphasis on disentangling the role of tumour-stromal interactions and analyse their potential as modifiers of drug response.

Measuring diffuse metabolic activity on FDG-PET/CT: new method for evaluating Langerhans cell histiocytosis activity in pulmonary parenchyma

INTRODUCTION Pulmonary Langerhans cell histiocytosis (PLCH) is a rare cause of interstitial lung disease characterized by formation of nodules in the active phase of the disease that evolve into nonactive cystic lesions later on. To evaluate PLCH activity in patients, we developed a new method for measuring diffuse metabolic activity on fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) using a lung-to-liver activity ratio. MATERIAL AND METHODS We retrospectively studied a series of 4 FDG-PET and 23 FDG-PET/CT scans from 7 patients with PLCH and analyzed a sample of 100 randomly chosen FDG-PET/CT studies free from any known lung or hepatic diseases. Maximum standardized uptake value (SUVmax) in a spherical volume (6-8 cm in diameter) in the right lung was put into relation with SUVmax in a spherical volume (9-10 cm in diameter) in the reference liver parenchyma to set up the SUVmaxPULMO/SUVmaxHEPAR index. The index values were compared to the disease course in each patient. RESULTS In patients with PLCH, a close correlation between the index value and the disease course was found in all seven subjects, where the increasing index values indicated disease activity, while decreasing index values were observed after therapy administration. In the group of 100 healthy control subjects, we found index values lower than 0.3 in 80% and lower than 0.4 in 96% [range: 0.14-0.43; 0.24±0.07 (100)]. CONCLUSION Measuring SUVmaxPULMO/SUVmaxHEPAR values and their time-trend monitoring represent simple, noninvasive screening tools allowing an early diagnosis and treatment response follow-up assessment in patients with PLCH.

Lenalidomide proved effective in multisystem Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare idiopathic disease with diverse clinical manifestations ranging from a single osteolytic lesion to generalized disease. Various treatment regimens have been proposed for the multisystem type, however, with inconsistent outcomes. Herein we are the first to report on a therapy effect of a lenalidomide-based regimen in a patient with repeatedly relapsed aggressive form of multisystem LCH.

Upsampling from aorta and aortic branches: PET/CT hybrid imaging identified 18F-FDG hypermetabolism in inflamed temporal and occipital arteries.

Temporal arteries are typically below detectable levels of PET scanners, which repeatedly showed to be limiting in finding increased F-FDG accumulation even in histologically proven cases of giant cell arteritis. In 2010, Gaemperli and coworkers showed metabolic active inflammation in temporal arteries in an experimental study using PET with [C]-PK11195 combined with CT angiography. Herein, we present the case where an increased accumulation of routinely used tracer F-FDG can be identified directly in temporal and occipital arteries and even in smaller branches using a common hybrid PET/CT scanner if a brain acquisition protocol is applied.

Multiple Myeloma Associated IgA Pemphigus: Treatment With Bortezomib- and Lenalidomide-Based Regimen

Generally, monoclonal immunoglobulins do not bind an autologous antigen, except for some cases, when it causes immune damage to body’s own tissues. Vesiculopustulous dermatitis associated with immunoglobulin (Ig) A deposition in the epidermis represents an autoimmune skin manifestation of monoclonal gammopathy. It is commonly referred to as subcorneal pustular dermatosis type of IgA pemphigus.1 In our previous work, we reported on complete and long-term remission of multiple myeloma associated IgA pemphigus after treatment with a bortezomib (Velcade) based regimen.2 In this work, to our knowledge, we are the first to publish a convincing clinical remission and excellent drug tolerance of a subsequent lenalidomide (Revlimid) based regimen used in the same patient for management of the relapsed disease.

Lenalidomide: a new treatment option for Castleman disease

A male born in 1961, aged 46, was referred to our department for evaluation of splenomegaly and generalized lymphadenopathy aff ecting the cervical, axillary, mediastinal, retroperitoneal and inguinal regions. Laboratory data revealed an increased erythrocyte sedimentation rate (16 mm/h and 30 mm/2 h) and C-reactive protein level (35.4 mg/L). Total protein and full blood counts as well as renal and hepatic profi les were within normal ranges, and microbiological screening revealed no infectious etiology. Other fi ndings, including radiological examinations and bone marrow biopsy, showed no further pathologies. Th e patient ’ s other medical history was signifi cant for arterial hypertension, chronic infl ammatory demyelinating polyneuropathy and mild right hemi-paresis with expressive language disorder. Based on lymph node biopsies from retroperitoneal and both inguinal regions, the patient was diagnosed with the plasma-cell variant of CD. Th e presence of a large pelvic mass compressing adjacent structures indicated the patient for therapy initiation. During fi rst-line treatment (R-CHOP: rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 and vincristine 2 mg intravenously on day 1; prednisone 100 mg perorally on days 1 – 5 in a 21-day cycle, three cycles in total, 12/2008 – 2/2009), clinical progression of the disease was evident (gastrointestinal symptoms, swollen hands and feet with signs of vasculitis), and there was no radiological response on a restaging computed tomography (CT) examination after 3 months.

Complete remission of multiple myeloma associated scleredema after bortezomib-based treatment

Scleredema is a rare scleroderma-like fi bromucinosis characterized by progressive thickening of the skin caused by excessive collagen and mucin depositions in the dermis. Various treatment regimens have been proposed, however with inconsistent outcomes. Herein we are the fi rst to report a complete dermatological and hematological remission in a patient with multiple myeloma associated scleredema after bortezomib-based chemotherapy.