Primary leptomeningeal melanomatosis successfully treated with PD-1 inhibitor pembrolizumab: A case report.

RATIONALE: Primary leptomeningeal melanoma is an extremely rare disease of the central nervous system. There are no standard treatment protocols with a poor prognosis in very few reported cases. Immunotherapy in primary brain melanoma has not been successfully applied so far. PATIENT CONCERNS: We describe a female patient 72-year-old diagnosed in the Neurosurgery Department which presented with generalized seizures. DIAGNOSES: Histological examination confirmed atypical melanocytes immunohistochemically positive for melan A, HMB45 and S-100 protein in the meninges, BRAF V600E negative. Dermatological, ophthalmological examinations, and 18-FDG PET/CT were negative. INTERVENTIONS: The patient was successfully treated with pembrolizumab 2 mg/kg every 3 weeks for 2 years. OUTCOMES: The disease was stable for 2 years and the patient had no significant toxicity. LESSONS: Our report describes durable intracranial tumor response suggesting the efficacy of PD-1 inhibitor pembrolizumab for central nervous system primary leptomeningeal melanoma.

Fulminant Fournier's gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel.

Fournier's gangrene (FG) is an uncommon form of necrotizing fasciitis, localized on the external genital organs, perianal region, and abdominal wall, accompanied by thrombosis of the feeding arteries, leading to gangrene of the skin and subcutaneous tissue, with manifestations of rapid clinical progression and multiple organ failure. Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of vascular endothelial growth factor receptor-2 (VEGFR-2) and prevents the binding of all VEGFR ligands. The literature describes bevacizumab, aflibercept, and regorafenib associated with FG in patients with colorectal cancer. According to our knowledge this is the first report of FG possibly related to ramucirumab in a patient with gastric cancer. If not recognized in time, it can lead to fatal complications.

The Appearance of 4-Hydroxy-2-Nonenal (HNE) in Squamous Cell Carcinoma of the Oropharynx.

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4-hydroxy-2-nonenal (HNE), which is considered as a "second messenger of free radicals" that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately-differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer.

Environmental and behavioural head and neck cancer risk factors.

OBJECTIVES: The high incidence of head and neck cancer (HNC), significantly associated with living environment and behaviour, can be prevented more efficiently. The aim of this study was to evaluate the environmental and behavioural risk factors for HNC. METHODS: Using a detailed questionnaire on social status, education, living and occupational environment exposures, family cancer and lifestyle, HNC patients (103 cases, 76.7% of men) were compared with control subjects (244 subjects, 73% of men) balanced by age: mean (standard deviation) 63.8 (9.3) and 63.8 (9.0) for cases and controls, respectively. RESULTS: The results of this study showed that smoking and low education were significant risk factors for HNC regardless of sex. Family HNC and breast cancer were significant predictors of HNC risk. CONCLUSION: The study confirmed previous results that smoking and low education are significantly associated with HNC. Additionally, results pointed to significant HNC and breast cancer risk in HNC patient's families that may have originated from passive smoking or a smoking habit stemming from social environments that support it. Better dissemination programmes regarding smoking risks for children and adults are needed, targeting not only individuals but also families.

Cisplatin-based chemoradiotherapy vs. cetuximab-based bioradiotherapy for p16-positive oropharyngeal cancer: an updated meta-analysis including trials RTOG 1016 and De-ESCALaTE.

PURPOSE: Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is a special entity among head and neck squamous cell carcinomas (HNSCCs). Given its favorable prognosis, one of the de-escalating strategies in the treatment of OPC includes the introduction of cetuximab (C225) instead of cisplatin (CDDP) in conjunction with radiotherapy. An updated meta-analysis of published studies has been performed, which directly compared the efficacy of CDDP vs. C225 given concurrently with radiotherapy as definitive treatment of p16-positive OPC. METHODS: A systematic literature search was performed for studies published between 2006 and 2018. A total of 1490 citations were obtained and 8 studies met inclusion criteria, with a total of 1665 patients. RESULTS: The data from seven studies were available for the analysis of 2-year overall survival (OS). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy, was 0.45 (P < 0.0001). The data from eight studies were available for the analysis of 2-year locoregional recurrence (LRR). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy was 0.35 (P < 0.0001). Patients receiving CDDP with irradiation had 2.2- and 2.9-fold decreased risk for death from any cause and LRR, respectively. CONCLUSIONS: For patients with HPV-positive OPC, radiotherapy plus C225 showed inferior OS and higher LRR rates compared with radiotherapy plus CDDP. CDDP-based chemoradiotherapy should remain standard of definitive treatment of p16-positive OPC.

HPV-driven oropharyngeal squamous cell cancer in Croatia - Demography and survival.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Main HNSCC risk factors are tobacco, alcohol, and high-risk human papillomavirus (HPV). HPV+ oropharyngeal squamous cell cancer (OPSCC) usually have different etiology, increasing incidence and often show an improved survival when compared to HPV-negative cases. The objective of the current study was to retrospectively examine the influence of HPV on the survival of OPSCC patients in a non-Western population setting. MATERIALS AND METHODS: We determined the presence of HPV DNA and/or RNA in 99 formalin-fixed paraffin embedded (FFPE) tissue samples of OPSCC patients treated between 2002 and 2015. Patients were compared based on laboratory, demographic, clinical, life style characteristics and survival. RESULTS: HPV RNA was found in 29.3% cases. However, groups based on HPV data (either RNA, DNA or retrospectively collected p16 staining) did not show significant differences. Overall, 5-year survival was 30% with minimal influence of the HPV positivity. CONCLUSIONS: The HPV influence on survival of OPSCC patients is not identical between populations probably due to other factors overshadowing the HPV effect. This should be taken into account when treatment or policy decisions are made in each particular setting.

Significance of stroma in biology of oral squamous cell carcinoma.

The worldwide annual incidence of oral squamous cell carcinoma (OSCC) is over 300,000 cases with a mortality rate of 48%. This cancer type accounts for 90% of all oral cancers, with the highest incidence in men over 50 years of age. A significantly increased risk of developing OSCC exists among smokers and people who consume alcohol daily. OSCC is an aggressive cancer that metastasizes rapidly. Despite the development of new therapies in the treatment of OSCC, no significant increase in 5-year survival has been recorded in the past decades. The latest research suggests focus should be put on examining tumor stroma activation within OSCC, as the stroma may contain cells that can produce signal molecules and a microenvironment crucial for the development of metastases. The aim of this review is to provide an insight into the factors that activate OSCC stroma and hence faciliate neoplastic progression. It is based on the currently available data on the role and interaction between metalloproteinases, cytokines, growth factors, hypoxia factor and extracellular adhesion proteins in the stroma of OSCC and neoplastic cells. Their interplay is additionally presented using the Systems Biology Graphical Notation in order to sublimate the collected knowledge and enable the more efficient recognition of possible new biomarkers in the diagnostics and follow-up of OSCC or in finding new therapeutic targets.

Comparison of intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) and a 3-dimensional conformal parotid gland-sparing radiotherapy (ConPas 3D-CRT) in treatment of nasopharyngeal carcinoma: a mono-institutional experience.

AIM: To compare intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) and a 3-dimensional conformal parotid gland-sparing radiotherapy (ConPas 3D-CRT) in treatment of nasopharyngeal carcinoma with regard to outcomes and dose distribution to the planning target volumes (PTVs) and to the organs at risk (OARs). METHODS: The treatment records of 24 patients with histologically proven carcinoma of the nasopharynx treated with ConPas 3D-CRT or IMRT-SIB technique between May 2009 and December 2016 were assessed. RESULTS: The mean dose and dose to 50% parotid glands volume as well as the maximal dose to the spinal cord were significantly lower in the IMRT-SIB than in the ConPas 3-CRT group (p < 0.05; p < 0.05; p < 0.01, respectively). IMRT-SIB was also superior in coverage of PTVs. The 3-year overall survival (OS) and disease-free survival (DFS) of patients in the IMRT-SIB and ConPas 3D-CRT groups were 77 and 81% (p = 0.93), 51.9 and 70.7% (p = 0.83), respectively. CONCLUSION: IMRT-SIB provided additional spearing to parotid glands and spinal cord in comparison to ConPas 3D-CRT technique but without improvement of OS and DFS.

A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma.

Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.

The prognostic and predictive value of excision repair cross-complementation group 1 (ERCC1) protein in 1288 patients with head and neck squamous cell carcinoma treated with platinum-based therapy: a meta-analysis.

Excision repair cross-complementation group 1 (ERCC1) protein has been extensively investigated as a prognostic and predictive factor for platinum-based treatment in head and neck squamous cell carcinoma (HNSCC) but with inconsistent results. We performed the present meta-analysis to better elucidate this issue in advanced HNSCC. A literature search was conducted using the PubMed and Web of Science databases. The inclusion criteria were head and neck cancer patients with platinum-based treatment and evaluation of the correlation between ERCC1 expression and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), both unadjusted and adjusted estimates]. In high vs. low pooled analyses, high ERCC1 expression was associated with unfavorable OS [hazard ratio (HR) = 1.95, 95 % confidence interval (CI) 1.18-3.21, p = 0.009], PFS (HR = 2.39, 95 % CI 1.74-3.28, p = 0.000) and ORR (odds ratio = 0.48, 95 % CI 0.23-0.98, p = 0.044). In the subgroup analysis of adjusted OS estimates, ERCC1 was a predictor of shorter survival in Asians (HR = 3.13, 95 % CI 2.09-4.70, p = 0.000) and Caucasians (HR = 2.02, 95 % CI 1.32-3.07, p = 0.001) but of longer survival in South Americans (HR = 0.17, 95 % CI 0.07-0.40, p = 0.000). Immunohistochemistry proved to be of predictive value irrespective of used antibody (p = 0.009). In the stratified analysis according to the tumor site, ERCC1 expression was associated with OS in nasopharyngeal cancer (HR = 2.72, 95 % CI 1.79-4.13, p = 0.000). ERCC1 has a potential to become predictive and prognostic factor enabling treatment tailoring in HNSCC patients.

[CLINICAL RECOMMENDATIONS FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH ESOPHAGEAL AND ESOPHAGOGASTRIC JUNCTION CANCERS].

Esophageal and esophagogastric junction cancers comprise histologically and biologically different malignant tumors in which the progress in the understanding of the disease has not been followed by the improvement in the survival. Diagnosis is set by tumor biopsy during endoscopy. Multimodal approaches containing surgery, radiotherapy and chemotherapy are frequently applied in the treatment of locoregionally advanced disease. However, the optimal sequence of the treatment options is still the issue of numerous clinical trials and meta-analyzes. Metastatic disease is treated with palliative chemotherapy and best supportive care. Treatment decisions should be individualized according to patients' characteristics and made after multidisciplinary team discussion. The following text presents the clinical guidelines in order to standardize the diagnostic procedures, treatment and monitoring of patients with esophageal and esophagogastric junction cancers in the Republic of Croatia.

Sudden bilateral hearing loss in gastric cancer as the only symptom of disease.

This paper reports a case of sudden bilateral deafness as the first symptom of gastric cancer, an extremely rare and atypical clinical situation. Because common signs of stomach cancer were absent, the patient was first evaluated in the Department of Otolaryngology, University Hospital Center, Zagreb. Only after expanded diagnostic evaluation and rapid progression of the disease in such a case is a malignant tumor suspected. Treatment is mostly ineffective. The unusual presentation of the disease and the rapid course may indicate a hereditary predisposition. Inactivation of tumor suppressor gene DFNA5 was found in 50% of gastric cancers, but of a non-metastasized phenotype. Inactivated DFNA5, otherwise described in hereditary bilateral deafness, perhaps favors the development of deafness in patients with gastric cancer. Our patient had a positive multiple viral antibody titer in serum, inactivated DFNA5 in both gastric cancer tissues and cerebellar metastases, and a metastatic form of the disease. If sudden deafness occurs in elderly patients, the possibility of malignant tumor should be taken into consideration. The link between gastric cancer and the DFNA5 gene is unclear and requires further research.

[CLINICAL GUIDELINES FOR DIAGNOSING, TREATING AND MONITORING OF ADULT PATIENTS WITH GLIOMAS OF CENTRAL NERVOUS SYSTEM]. / KLINICKE UPUTE ZA DIJAGNOZU, LIJECENJE I PRACENJE ODRASLIH BOLESNIKA OBOLJELIH OD GLIOMA SREDISNJEGA ZIVCANOG SUSTAVA.

Gliomas of the central nervous system are glial cell tumors that are divided in low and high grade group. Multidisciplinary approach to treatment consists of surgery, radiotherapy and chemotherapy. The type and order of treatment depend on the characteristics of the tumor and the patient. We present the clinical guidelines for diagnostic procedures, surgical treatment, oncological treatment and follow up of patients with this type of tumor in the Republic of Croatia.

Treatment of patients with anaplastic thyroid cancer during the last 20 years: whether any progress has been made?

Anaplastic thyroid cancer (ATC) is one of the most deadly cancers in humans. Searching a PubMed database, studies published during the last 20 years, 63 publications dealing with treatment of patients were identified. Cohort studies comprised 6,609 patients with the median age 68 years (range 57-77 years). The median survival was 3.9 months, and 1 year survival, 20%. The median survival of patients treated with multimodal therapy was 10.5 months. There was significant difference in median survival (7.0 vs. 3.8 months; p < 0.05) and 1 year survival (30.5 vs. 16.8 months; p < 0.05) between the patients <68 and 68 or more years old. Clinical trials, both randomized and non-randomized, comprised 205 patients. Unfortunately, considerable improvement in the understanding of the pathogenesis and genetics of the ATC has not yet resulted in the improvement of the outcome of these patients.

Fatal outcome of posterior "reversible" encephalopathy syndrome in metastatic colorectal carcinoma after irinotecan and fluoropyrimidine chemotherapy regimen.

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity characterized by headaches, altered mental status, seizures, and visual disturbances. It can occur in many different clinical entities such as severe hypertension and pre-eclampsia, or due to cytotoxic or immunosuppressive therapies. The pathogenesis of PRES is unclear, with dysregulated cerebral auto-regulation and endothelial dysfunction as important mechanisms proposed. Endothelial dysfunction is important especially in cases associated with cytotoxic therapies. Herein, we describe a patient with PRES with fatal outcome, who presented 5 days after the infusion of cycle 1 of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) regimen chemotherapy, without prior hypertension and other comorbidity, suggesting a link between PRES and FOLFIRI regimen. To our knowledge, this case report is the first describing PRES after FOLFIRI regimen, although others have described PRES after FOLFIRI with bevacizumab in colonic cancer patients.

Prognostic value of ERCC1 in head and neck carcinoma treated with definitive or adjuvant radiotherapy.

PURPOSE: To evaluate the prognostic significance of excision repair cross-complementation group 1 (ERCC1) expression in head and neck carcinoma patients treated with definitive radiotherapy (DR) or adjuvant radiotherapy (AR). METHODS: ERCC1 expression was assessed by immunohistochemical staining. A total of 48 patients were assessed. RESULTS: High ERCC1 expression was found in 23 patients (48 %). More ERCC1-positive tumours were detected in patients treated with DR than in patients treated with AR (73 vs. 36 %, respectively, p = 0.03). ERCC1 expression had no impact on overall survival neither in the whole cohort of patients (p = 0.16) nor in each particular treatment group (AR p = 0.98; DR p = 0.21). CONCLUSIONS: ERCC1 expression had no predictive value in head and neck carcinoma patients treated with DR or AR. There might be difference in ERCC1 positivity that comes out of whether the assessment is done on biopsy or surgical specimens.

[Hormonal therapy of prostate cancer: are there any dilemmas left?]. / Hormonska terapija raka prostate: ima li jos dilema?

The strategy for treating prostate cancer patients depends on the assessment of disease extent, assessment of the risk of disease relapse, assessment of life expectancy, comorbidities, affinities and life-style. Since the activity and survival of prostate cancer cells is at least initially dependent on androgen stimulation, hormonal therapy is one of the several standard treatment modalities. Hormonal therapy is aimed at decreasing this androgen stimulation either by lowering androgen production or by blocking receptor binding. Hormonal therapy is in fact androgen-suppressive therapy (AST) or androgen-deprivation therapy (ADT). If effective, it results in the lack of cancer cell stimulation, thus causing their apoptosis and consequently decline in tumor growth and size. Hormonal therapy is used as a first-line treatment modality for metastatic disease. In addition to this indication, hormonal therapy is also used as an adjunct to radiotherapy with curative intent for patients with non-metastic disease but having an intermediate and high risk of disease relapse. In combination with radiotherapy, hormonal therapy can be applied before, concomitantly and after radiotherapy for the duration of 6 months or 2 to 3 years depending on the risk estimation. Regarding hormonal therapy, it can be applied in combination with other treatments, in several ways, and sometimes there might be several options available. This possible lack of a specific recommendation is a consequence of the fact that there is a limited number of adequate clinical studies which, moreover, may have yielded inconsistent results sometimes simply due to the patients' heterogeneity. Moreover, thanks to the newer and better diagnostic methods enabling the discovery of prostate cancer in earlier disease stages, as well as to the more effective treatments, there is also a prolongation of relapse-free survival and possibly of overall survival in patients having metastic disease. Consequently, the results of earlier clinical studies might no longer be applicable to the new "generations" of upcoming patients. As regards this improved survival, issues of patient's quality of life and possible side-effects of hormonal therapy are also becoming increasingly relevant because hormonal adverse events are time-dependant and tend to increase in severity with prolongation of hormonal manipulation. Therefore, this paper aims to give an overview of the more recent findings, indications and observations regarding hormonal therapy.

Larynx preservation: advantages and limitations.

For a long time standard treatment approach for resectable squamous cell carcinoma of larynx was surgery with or without subsequent radiotherapy. Surgery, particulary total laryngectomy, has been associated with serious impairment of quallity of life. Between nonsurgical approaches, concurrent cisplatin based chemoradiotherapy has become a very promising treatment modality for larynx preservation. However, concurrent chemotherapy has been associated with serious toxicity. The most recent treatment approach in larynx preservation is related to taxan based induction chemotherapy.

Retroperitoneal and metachronous testicular germ cell tumors with different histology and teratoma growing syndrome--a case report.

It is presented a case of a 32-year-old male with the three primary tumors diagnosed within a time period of 3 years; retroperitoneal nonseminoma in 2002, retroperitoneal mature teratoma in 2004, and metachronous testicular seminoma in 2005. We discuss the unusual presentation of these three rare events occurring in the same patient without known risk factors.