Sperm mitochondria dysfunction in response to testicular cancer.

Testicular cancer is the most common form of cancer in young men of reproductive age and its incidence is increasing globally. With the currently successful treatment and 95% survival rate, there is a need for deeper understanding of testicular cancer-related infertility. Most patients with testicular cancer experience semen abnormalities prior to cancer therapy. However, the exact mechanism of the effect of testicular cancer on sperm anomalies is not known. Mitochondria are organelles that play a crucial role in both tumorigenesis and spermatogenesis and their malfunction may be an important factor resulting in sperm abnormalities in testicular cancer patients. Within the scope of this review, we will discuss current knowledge of testicular cancer-related alterations in the ATP production pathway, a possible pathophysiological switch from oxidative phosphorylation (OXPHOS) to glycolysis, as well as the role of oxidative stress promoting sperm dysfunction. In this regard, the review provides a summary of the impact of testicular cancer on sperm quality as a possible consequence of impaired mitochondrial function including the energy metabolic pathways that are known to be altered in the sperm of testicular cancer patients.

Total neoadjuvant therapy in rectal cancer: the evidence and expectations.

Current management of locally advanced rectal cancer achieves high cure rates, distant metastatic spread being the main cause of patients' death. Total neoadjuvant therapy (TNT) employs (chemo)radiotherapy and combined chemotherapy prior to surgery to improve the treatment outcomes. TNT has been shown to reduce significantly distant metastases, increase disease-free survival by 5 - 10% in 3 years, and finally also overall survival (≈ 5% in 7 years). It proved to double the rate of pathologic complete responses, making it an attractive strategy for non-operative management to avoid permanent colostomy in patients with distal tumors. In addition, it endorses adherence to the therapy due to better tolerance and, potentially, shortens its overall duration. A number of questions related to TNT remain currently unresolved including the indications, preferred radiotherapy and chemotherapy regimens, their sequence, timing of surgery, and role of adjuvant therapy. A stratified approach may be the optimal way to go.

Insomnia in patients treated with checkpoint inhibitors for cancer: A meta-analysis.

Purpose: Insomnia in cancer patients is a common symptom contributing to poor quality of life and poor functioning. Sleep disturbances have been associated with inflammatory activity, and systemic cancer therapies chemotherapy, hormonal therapy, and immunotherapy may cause insomnia. We have carried out a meta-analysis to estimate the occurrence of insomnia in patients with solid cancer treated with immunotherapy using checkpoint inhibitors (CPI). Methods: PubMed and ClinicalTrials.gov were searched for phase 3 studies in solid tumours where treatment included a checkpoint inhibitor in the experimental arm. Data on the incidence of insomnia were acquired from the adverse events tables available from clinicaltrials.gov and/or from the full texts. Random effect logistic model was used to compare pooled data. Heterogeneity between studies was assessed using Cochrane Q statistics and I2 statistics. Results: A total of 54 studies (including six three-arm studies) involving 37,352 patients were included in the analysis. Insomnia was reported in 8.3% of subjects (95% confidence interval [CI] 8.0%-8.7%) treated with immunotherapy. Insomnia was significantly more common in patients receiving immunotherapy compared to those enrolled in study arms with inactive treatment (odds ratio [OR] 1.49, 95% CI 1.13-1.96). The odds for insomnia were similar between the arms for studies comparing CPI versus chemotherapy and CPI versus non-immunologic targeted therapies (OR 1.07, 95% CI 0.94-1.22 and OR 1.40, 95% CI 0.90-2.18, respectively). The OR for insomnia was higher for cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor inhibitors compared to the inhibitors of programmed death-1 (PD-1) receptor (OR 1.36, 95% CI 1.06 - 1.74). Conclusion: Cancer immunotherapy using CPI is associated with insomnia but the odds of developing the symptom are not greater with immunotherapy than with other systemic modalities including chemotherapy and non-immunologic targeted therapies.

The clinical value of circulating free tumor DNA in testicular germ cell tumor patients.

BACKGROUND: Testicular germ cell tumors (TGCT) are unique malignancies of young adult men; their biology is, however, underexplored and there has not been much progress in their treatment for decades. Circulating free tumor DNA (cfDNA) analysis represents a promising way of discovering novel diagnostic and treatment options. OBJECTIVE: The study evaluates the clinical value of cfDNA detection in TGCT patients. DESIGN AND METHODS: Total cfDNA concentration and ratio of its 2 main fragments (180 and 360 bp) were evaluated by spectrophotometry, capillary electrophoresis and qPCR in peripheral blood plasma of 96 TGCT patients (173 samples) and 31 normal controls. Non-parametric tests were used for statistical analyses. RESULTS: The total cfDNA concentration was significantly higher in TGCT than in controls (P < 0.0001), with the highest levels at disease progression, but with no clear threshold between malignant and normal samples. Patients with positive tumor markers had higher cfDNA concentrations than those with negative markers (P = 0.01). Longer 360 bp cfDNA fragments were found in 58% of TGCT patients including almost all samples from relapse or disease progression but no normal controls (P < 0.0001). CONCLUSION: Total cfDNA levels are significantly increased in TGCT patients but without a clear threshold separating normal and tumor samples, thus total cfDNA amount itself is not a sensitive enough marker to identify or monitor TGCT. Longer cfDNA fragments have been found exclusively in a proportion of tumors and predominantly at disease progression, representing a novel potential marker for TGCT monitoring that would deserve further exploration.

Regorafenib for Metastatic Colorectal Cancer: An Analysis of a Registry-Based Cohort of 555 Patients.

PURPOSE: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry. METHODS: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified. RESULTS: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0-23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2-3.7 months) and 9.3 months (95% CI 8.3-10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4-72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS. CONCLUSION: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.

Treatment of Malignant Peritoneal Mesothelioma.

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleura of the thoracic cavity, followed by the peritoneum, pericardium, or tinea vaginalis testis. Malignant peritoneal mesothelioma (MPM) accounts for 10-15% of all mesotheliomas. The most significant risk factor for MPM is exposure to asbestos. There is no specific symptomatology, and imaging (computed tomography) and histopathology are crucial for diagnosis. There are no generally accepted guidelines for radical treatment of MPM. Previously, the prognosis of MPM patients was poor, with survival of up to 1 year. However, median survival of patients who are suitable candidates for radical therapy is currently 3-5 years. A combination of cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) is recommended in selected patients, while chemotherapy alone has insufficient efficacy. Systemic chemotherapy remains the only treatment option for patients who are unsuitable for CRS and HIPEC. In selected patients scheduled for or currently undergoing CRS and HIPEC, surgery may be performed in combination with systemic chemotherapy in the neoadjuvant or adjuvant setting; however, the benefit is unclear. There are no recommendations for follow-up of MPM patients after radical surgery. Existing guidelines for the pleural form (e.g., those issued by the European Society for Medical Oncology) do not specify the frequency or method of investigation. In the absence of specific serum markers, only CA 125 and mesothelin are generally available. Imaging methods include ultrasonography, computed tomography, and magnetic resonance imaging.

Molecular Basis of Cisplatin Resistance in Testicular Germ Cell Tumors.

The emergence of cisplatin (CDDP) resistance is the main cause of treatment failure and death in patients with testicular germ cell tumors (TGCT), but its biologic background is poorly understood. To study the molecular basis of CDDP resistance in TGCT we prepared and sequenced CDDP-exposed TGCT cell lines as well as 31 primary patients' samples. Long-term exposure to CDDP increased the CDDP resistance 10 times in the NCCIT cell line, while no major resistance was achieved in Tera-2. Development of CDDP resistance was accompanied by changes in the cell cycle (increase in G1 and decrease in S-fraction), increased number of acquired mutations, of which 3 were present within ATRX gene, as well as changes in gene expression pattern. Copy number variation analysis showed, apart from obligatory gain of 12p, several other large-scale gains (chr 1, 17, 20, 21) and losses (chr X), with additional more CNVs found in CDDP-resistant cells (e.g., further losses on chr 1, 4, 18, and gain on chr 8). In the patients' samples, those who developed CDDP resistance and died of TGCT (2/31) showed high numbers of acquired aberrations, both SNPs and CNVs, and harbored mutations in genes potentially relevant to TGCT development (e.g., TRERF1, TFAP2C in one patient, MAP2K1 and NSD1 in another one). Among all primary tumor samples, the most commonly mutated gene was NSD1, affected in 9/31 patients. This gene encoding histone methyl transferase was also downregulated and identified among the 50 most differentially expressed genes in CDDP-resistant NCCIT cell line. Interestingly, 2/31 TGCT patients harbored mutations in the ATRX gene encoding a chromatin modifier that has been shown to have a critical function in sexual differentiation. Our research newly highlights its probable involvement also in testicular tumors. Both findings support the emerging role of altered epigenetic gene regulation in TGCT and CDDP resistance development.

Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis.

BACKGROUND: The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results. OBJECTIVE: To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens. PATIENTS AND METHODS: Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle. RESULTS: Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9-13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6-39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5-14.3) and 30.6 months (95% CI 25.2-36.1) for cohort A, 9.7 (95% CI 9.1-10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8-13.2) and 37.9 months (95% CI 28.6-47.3) for cohort C, respectively. CONCLUSIONS: Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

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.

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.

Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches.

In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93.38%), and a combined use of both approaches allowed a multi time-point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0.01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0.04), >0.01% at the end of induction (P = 0.02), >0.01% at the end of consolidation (P = 0.01), >0.01% prior to the first delayed intensification (P = 0.01), and >0.1% prior to the second delayed intensification and continued maintenance (P = 0.001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P = 0.0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.