Association of the combined parameters including the frequency of primary cilia, CD8+ tumor infiltrating lymphocytes and PD-1 expression with the outcome in intestinal cancer.

PURPOSE: Primary cilium (PC) is considered to be a functional homologue of the immune synapse. Microtubule structures, PC of cancer associated fibroblasts and immune synapses between cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) and cancer cells, are regularly found in varying amounts in the microenvironment of solid tumors. The purpose of this study was to find out the potential association and combined prognostic significance of the frequency of PC, PD-1 and CD8+ TILs in patients with intestinal cancer. METHODS: The frequency of PC, programmed cell death protein-1 receptor (PD-1) expression and the frequency of stromal and intraepithelial CD8+TILs were evaluated in samples of colorectal adenocarcinoma (32 patiens) and small bowel cancer (8 patients). RESULTS: The median frequency of PC was 0.25%. The expression of PD1 was <5% in 34 patients, 5-25% in 5 patients and 26-50% in 1 patient. The frequency of stromal CD8+ TILs was negative in 3 patients, <25% in 26, 26-50% in 10 and >50% in 1 patient, respectively. Intraepithelial CD8+ TILs were not detectable in 14, <25% in 24 and 26-50% in 2 patients, respectively. Statistically, the frequency of PC and PD-1 positivity were significantly associated (p=0.004). An association between the PC frequency and intraepithelial CD8+ TILs was of borderline statistical significance (p=0.059). An index combining the frequency of PC and stromal CD8+ TILs, but not the combination of frequency of PC and intraepithelial CD8+ TILs, was of borderline prognostic significance (p=0.067). CONCLUSIONS: The present study provides the first data on the potential association and combined prognostic significance of frequency of PC, PD-1 and CD8+ TILs in patients with intestinal cancer.

Prognostic significance of the frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma.

PURPOSE: The primary cilium is a solitary, sensory, immotile microtubule-based structure that arises from the centrosome and is projected from the surface of most human cell types. It has been hypothesized that primary cilia could serve as a tumor suppressor organelle. The objective of this pilot study was to investigate the presence and frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma and to evaluate the prognostic significance of their frequency. METHODS: The presence of primary cilia in cells in samples of small bowel (8 patients) and colorectal adenocarcinoma (32 patients) was evaluated. The primary cilia of cells were immunofluorescently labeled using primary monoclonal anti-acetylated agr;-tubulin antibody and cell nuclei were labeled using DAPI. RESULTS: Primary cilia were identified in all examined specimens. The median frequency of primary cilia was 0.49% in cells of small bowel cancer and 0.22% in cells in colorectal cancer. Overall survival according to frequency of primary cilia in all intestinal adenocarcinomas was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) in univariate analysis (p=0.007) and also in the Cox proportional hazard model (p=0.032). Overall survival according to frequency of primary cilia in colorectal adenocarcinoma was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) (p=0.028). CONCLUSIONS: The present pilot study provides the first evidence of the prognostic significance of the frequency of primary cilia in small bowel and colorectal adenocarcinoma. Because of significantly higher median frequency of primary cilia in the rare small bowel adenocarcinoma than in the frequent colorectal adenocarcinoma (p<0.001), the results of this study support a potential role for primary cilia as a biomarker in these types of cancer.

Bevacizumab with 5-fluorouracil, leucovorin, and oxaliplatin versus bevacizumab with capecitabine and oxaliplatin for metastatic colorectal carcinoma: results of a large registry-based cohort analysis.

BACKGROUND: Data from the Czech national registry were analysed retrospectively to describe treatment outcomes for capecitabine and oxaliplatin (XELOX) regimen with bevacizumab versus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen with bevacizumab in the first-line therapy for metastatic colorectal cancer (mCRC). METHODS: A national registry containing anonymised individual data on patients treated with targeted therapies was used as a data source. In total, 2,191 mCRC patients who received a first-line therapy with bevacizumab combined with either FOLFOX regimen (n = 1,218, 55.6%) or XELOX regimen (n = 973, 44.4%) were included in the present analysis. RESULTS: No statistically significant difference in survival was observed between the two groups, with median overall survival (OS) of 27.0 months (95% confidence interval [CI] 24.6-29.5 months) and 30.6 months (95% CI 27.8-33.4 months) for FOLFOX/bevacizumab and XELOX/bevacizumab, respectively (p = 0.281). Median progression-free survival (PFS) was 11.4 months (95% CI 10.7-12.1 months) for FOLFOX/bevacizumab and 11.5 months (95% CI 10.8-12.3 months) for XELOX/bevacizumab (p = 0.337). The number of metastatic sites was identified as the most significant predictor of PFS and, together with the presence/absence of metastatic disease at diagnosis, also for OS. CONCLUSIONS: According to this large registry-based analysis, XELOX and FOLFOX regimens have similar effectiveness for use in combination with bevacizumab in the first-line treatment of mCRC. Multiple metastatic sites and the presence of metastatic disease at diagnosis were the strongest negative predictors of OS regardless of backbone chemotherapy regimen.

[Testicular malignit tumors - are we in the end of the road?]. / Testikulární zhoubné nádory - jsme snad u konce cesty?

Testicular germ cell tumors are currently the most curable cancer in adults. The 5-year survival is 95 %. In spite of this many patients come to physician in advanced stage of disease. The early diagnosis is an only way to improve outcomes in accordance to standardization, successfulness of complex diagnostic and therapy algorithm. Misdiag-nosis and errors of physicians are very rare nowadays however knowledge and oncology awareness of our young male population is inadequate. Health education targeted at young male population at risk has up to day large reserves.Key words: cisplatin - germ cell tumors - incidence - mortality - NSGCT - prevalence - seminoma.

Clinical outcomes of patients with nonseminomatous germ cell tumours and negative postchemotherapy positron emission tomography.

Univariate and multivariate analyses were carried out to identify factors associated with the failure of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to correctly predict relapse-free survival in patients with nonseminomatous germ cell tumours. Ninety-three patients with negative postchemotherapy FDG-PET scan were analyzed in the retrospective study. The FDG-PET result was validated by long-term follow-up and, in some patients, by resection of the residual tumour mass. The negative predictive value of FDG-PET was 81.7%. Higher tumour marker levels and nodal stage at diagnosis, presence of residual mass, and teratoma or teratocarcinoma in the primary histology were associated with FDG-PET failure.

Detection of second malignancies during long-term follow-up of testicular cancer survivors.

BACKGROUND: Second cancers are an important cause of mortality and morbidity in long-term survivors of testicular germ cell tumors (TGCTs). Studies on the impact of follow-up for the first tumor on the outcome of second malignancies are lacking. The aim of this study was to study the details of diagnosis of second cancers and the role of focused oncology follow-up. METHODS: Medical records and the electronic database of a tertiary referral center for germ cell neoplasms were searched for second cancers diagnosed in TGCT survivors. In a database of 1057 patients, 63 cases of metachronous second malignancies (26 contralateral testicular cancers and 37 nontesticular cancers) were found in 57 patients. Long-term oncology follow-up consisted of yearly history, physical examination, germ cell tumor markers, and imaging including abdominal computed tomography (CT) scans and chest x-ray. RESULTS: The second malignancies occurred after a medium follow-up of 9.9 years (range, 1.1-33 years) after the diagnosis of the first tumor. Only 17 (27%) of the 63 second tumors were detected by oncology follow-up investigations, and a further 12 (29%) were detected by nononcology physicians during a preplanned clinical visit. In 34 (54%) cases, patients themselves or their relatives initiated a clinical appointment because of symptoms. Follow-up investigations all had low yields for the detection of second malignancies, although CT imaging did detect several cases of cancer at an early stage. CONCLUSIONS: In this retrospective study, most second cancers occurring in long-term TGCT survivors were missed by regular oncology follow-up that included yearly physical examination, tumor marker, and imaging.

Systematic COronary Risk Evaluation (SCORE) and 20-year risk of cardiovascular mortality and cancer.

BACKGROUND: Cardiovascular disease (CVD) followed by cancer are the two leading causes of death worldwide. SCORE charts have been recommended in Europe to identify individuals at increased CVD risk. However, the SCORE ability to identify individuals at increased risk of cancer has not yet been evaluated. The aim of this study was to determine the SCORE chart calibration in a country with changing CVD epidemiology, and its discrimination ability to identify individuals at increased risk of cancer over 20-years. METHODS: The present analysis includes data from two cross-sectional independent surveys within the Czech post-MONICA study (randomly selected representative population samples of the Czech Republic, aged 25-64 years); 3209 individuals in 1997/98 and 3612 in 2006-2009. RESULTS: The SCORE had reasonable discrimination to predict 10-year CVD mortality, but significantly overestimated the risk across all risk categories. During the 20-year follow up, high and very high-risk categories were associated with an increased risk of cancer morbidity (in particular colorectal, other gastrointestinal, lung and malignant skin) and cancer mortality, as compared to low risk category. CONCLUSIONS: The present study shows that periodical calibration testing of SCORE charts is needed in countries with changing CVD epidemiology. Furthermore, we show that in middle-aged individuals, identified by SCORE charts as being at high or very high risk for CVD, cancer morbidity and cancer mortality is increased. Rigorous cancer screening may be appropriate in this group, especially in countries with falling CVD mortality, where relative proportion of cancer mortality is increasing.

Extreme hypofractionated proton radiotherapy for prostate cancer using pencil beam scanning: Dosimetry, acute toxicity and preliminary results.

INTRODUCTION: Extreme hypofractionated radiotherapy for prostate cancer is a common modality in photon therapy. Pencil beam scanning (PBS) in similar fractionation allows better dose distribution and makes proton therapy more available for such patients. The purpose of this study is the feasibility of extreme proton hypofractionated radiotherapy and publication of early clinical results. METHODS: Two hundred patients with early-stage prostate cancer were treated with IMPT (intensity-modulated proton therapy), extreme hypofractionated schedule (36.25 GyE in five fractions) between February 2013 and December 2015. Mean age of the patients was 64.3 years, and the mean value of prostate-specific antigen (PSA) before treatment was 6.83 µg/L (0.6-17.3 µg/L). Ninety-three patients (46.5%) were in the low-risk group. One hundred and seven patients (53.5%) were in the intermediate-risk group. Twenty-nine patients (14.5%) had neoadjuvant hormonal therapy, and no patients had adjuvant hormonal therapy. Acute toxicity, late toxicity and short-term results were evaluated. RESULTS: All patients finished radiotherapy without interruptions. The median follow-up time was 36 months. The mean treatment time was 9.5 days (median 9 days). Acute toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 was (gastrointestinal toxicity) GI (grade) G1-17%, G2-3.5%; (genitourinary toxicity) GU G1-40%, G2-19%; and no G3 toxicity was observed. Late toxicity was GI G1-19%, G2-5.5%; GU G1-17%, G2-4%; and no G3 toxicity was observed. PSA relapse was observed in one patient (1.08%) in the low-risk group (pelvic lymph node involvement was detected) and in seven patients (6.5%) in the intermediate-risk group (three lymph node metastases, two lymph node and bone metastases, two PSA relapses). No patient died of prostate cancer, and three patients died from other reasons. No local recurrence of cancer in the prostate was observed. CONCLUSIONS: Proton beam radiotherapy for prostate cancer is feasible with a low rate of acute toxicity and promising late toxicity and effectivity.

Locally advanced breast cancer in elderly patients.

BACKGROUND: Although locally advanced breast cancer (LABC) is more common in the elderly population, there is little data on the clinical characteristics and survival of these patients. The aim of the present study was to compare different factors affecting survival in elderly patients with LABC. METHODS: Retrospective analysis was carried out on a cohort of 80 patients aged 70 to 96 years, diagnosed with LABC defined as T3 N1, T4 N0, any N2 or N3, and M0. The prognostic impact of selected clinical parameters including age, comorbidities, tumour grade, HER2 status, tumour stage, local therapies, and systemic treatments was studied. RESULTS: The median age of the patients was 79 years. The majority (n=53; 66%) had at least one significant comorbidity according to the Charlson score evaluation. The median overall survival was 50.6 months. As expected, hormonal therapy was the dominant mode of systemic treatment, but 24% also received at least one line of chemotherapy. Local therapies including surgery and/or radiotherapy were applied in 58% of patients. CONCLUSIONS: The diagnosis of LABC in the elderly is associated with poor prognosis. Age and serious comorbidities were negative prognostic factors.

Molecular biology of testicular germ cell tumors: unique features awaiting clinical application.

Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men characterized by distinct biologic features and clinical behavior. Both genetic predispositions and environmental factors probably play a substantial role in their etiology. TGTCs arise from a malignant transformation of primordial germ cells in a process that starts prenatally, is often associated with a certain degree of gonadal dysgenesis, and involves the acquirement of several specific aberrations, including activation of SCF-CKIT, amplification of 12p with up-regulation of stem cell genes, and subsequent genetic and epigenetic alterations. Their embryonic and germ origin determines the unique sensitivity of TGCTs to platinum-based chemotherapy. Contrary to the vast majority of other malignancies, no molecular prognostic/predictive factors nor targeted therapy is available for patients with these tumors. This review summarizes the principal molecular characteristics of TGCTs that could represent a potential basis for development of novel diagnostic and treatment approaches.

Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000-2008.

BACKGROUND: The objective of this study was to assess trends in overall and in stage-specific 5-year relative survival rates of the Czech cancer patients between periods 2000-2004 and 2005-2008. METHODS: All Czech cancer patients diagnosed between 1995 and 2008 were included in the analysis. Period analysis was employed to calculate 5-year relative survival for 21 cancers. RESULTS: Significant improvements in crude 5-year relative survival for 14 of 21 assessed types of cancer, including the most frequent diagnoses, such as, colorectal, prostate, breast, lung, kidney, pancreatic, and bladder cancer and melanoma, were identified. Moreover, in case of colorectal, lung, and prostate cancer, improvement in stage-specific 5-year relative survival was confirmed as statistically significant for all clinical stages. No diagnosis showed significant decrease in the 5-year relative survival. However, the 5-year relative survival remained poor in patients with metastatic cancers at diagnosis, particularly in case of liver, pancreatic, lung, and oesophageal cancer. CONCLUSIONS: The cancer-specific outcomes in the Czech Republic are improving. Nevertheless, despite the overall significant improvement in 5-year relative survival of most of the cancer diagnoses, the high proportion of patients primarily diagnosed with metastatic cancer still represents a substantial challenge for prevention and early detection.

Nontuberculous mycobacterial infection after therapy with temsirolimus for metastatic renal cell carcinoma.

We describe the case of a patient with metastatic renal cell carcinoma (mRCC) who developed a nontuberculous mycobacteria (NTM)-related pulmonary nodule during therapy with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus. After discontinuation of temsirolimus treatment, a small pulmonary nodule with increased glucose uptake was detected on a positron emission tomography (PET) scan. A lung resection carried out to confirm and treat the suspected solitary metastasis of RCC yielded the surprising finding of a caseating granuloma containing NTM. A single PET-positive nodule presents a significant differential diagnostic dilemma in the setting of mRCC treated with mTOR inhibitors. Although the treatment of mRCC with temsirolimus can lead to immunosuppression and opportunistic infections, there is no report to our knowledge on the occurrence of NTM infections in mRCC patients treated with mTOR inhibitors. These infections should be included in the differential diagnosis of lung nodules. Interestingly, there is strong preclinical evidence pointing to direct and indirect antimycobacterial activity of mTOR inhibitors. We therefore hypothesize that while the seeding of NTM can occur during temsirolimus therapy due to T-lymphocyte suppression, the infection may only become active after the discontinuation of mTOR inhibitor treatment.

Objective response and time to progression on sequential treatment with sunitinib and sorafenib in metastatic renal cell carcinoma.

Patients with metastatic renal cell carcinoma (mRCC) are often treated sequentially with targeted agents, although the optimal strategy is not known. A retrospective, registry-based study has been carried out to assess correlation between clinical response and progression-free survival in patients with mRCC treated sequentially with tyrosine-kinase inhibitors (TKIs) sunitinib and sorafenib. Data on 218 mRCC patients treated with sunitinib and sorafenib who completed therapy with both TKIs were obtained from a database of mRCC patients. Standard nonparametric methods were used to assess correlation between response, PFS and length of treatment on the two agents. A strong correlation between responses to first- versus second TKI was observed (p < 0.001). No significant association was noted between the duration of therapy with the two TKIs (p = 0.056), although there was a weak statistically significant correlation between progression-free survival times in the subgroup patients who discontinued treatment because of disease progression. In conclusion, the duration of response on first TKI is of limited value in selecting mRCC patients for sequential TKI therapy. There is a strong correlation between the types of tumour response on the first- versus the second TKI.

Current standards in the treatment of metastatic breast cancer with focus on Lapatinib: a review by a Central European Consensus Panel.

In breast cancer, early detection as well as new developments in therapeutic options has resulted in less patients presenting with metastatic disease. However, about one-third of women with early stage breast cancer will eventually develop metastatic disease. Furthermore, approximately 20-30% of patients with breast cancer have tumors that overexpress human epidermal growth factor receptor (HER-2), which is associated with an aggressive tumor phenotype and poor prognosis. The identification of the HER-2 protein led to the development of highly effective therapeutics directed at this receptor. Trastuzumab, a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER-2 protein, has shown significant clinical benefit in metastatic and early-stage HER-2-positive breast cancer. Since the cancer recurs after adjuvant therapy in some women, and metastatic breast cancer eventually develops resistance to trastuzumab, there is a need for alternative treatment modalities to block HER-2 signaling. One of these treatment options is lapatinib, an orally active small molecule that inhibits the tyrosine kinases of HER-2 and the epidermal growth factor receptor type 1 (EGFR). In this consensus statement current treatment options in metastatic and locally advanced disease are discussed with a special focus on lapatinib.