Intestinal Microbiota Increases Cell Proliferation of Colonic Mucosa in Human-Flora-Associated (HFA) Mice.

Intestinal epithelium renewal strictly depends on fine regulation between cell proliferation, differentiation, and apoptosis. While murine intestinal microbiota has been shown to modify some epithelial cell kinetics parameters, less is known about the role of the human intestinal microbiota. Here, we investigated the rate of intestinal cell proliferation in C3H/HeN germ-free mice associated with human flora (HFA, n = 8), and in germ-free (n = 15) and holoxenic mice (n = 16). One hour before sacrifice, all mice were intraperitoneally inoculated with 5-bromodeoxyuridine (BrdU), and the number of BrdU-positive cells/total cells (labelling index, LI), both in the jejunum and the colon, was evaluated by immunohistochemistry. Samples were also observed by scanning electron microscopy (SEM). Moreover, the microbiota composition in the large bowel of the HFA mice was compared to that of of human donor's fecal sample. No differences in LI were found in the small bowels of the HFA, holoxenic, and germ-free mice. Conversely, the LI in the large bowel of the HFA mice was significantly higher than that in the germ-free and holoxenic counterparts (p = 0.017 and p = 0.048, respectively). In the holoxenic and HFA mice, the SEM analysis disclosed different types of bacteria in close contact with the intestinal epithelium. Finally, the colonic microbiota composition of the HFA mice widely overlapped with that of the human donor in terms of dominant populations, although Bifidobacteria and Lactobacilli disappeared. Despite the small sample size analyzed in this study, these preliminary findings suggest that human intestinal microbiota may promote a high proliferation rate of colonic mucosa. In light of the well-known role of uncontrolled proliferation in colorectal carcinogenesis, these results may deserve further investigation in a larger population study.

Expertise is crucial to prolong survival in average risk medulloblastoma: long-term results of a retrospective study.

PURPOSE: Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated. METHODS: Patients included in our study were ⩾16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification. RESULTS: We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5-178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p = 0.05; OS: HR, 0.187, p = 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p = 0.008; OS: HR, 0.295, p = 0.038). CONCLUSIONS: Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy.

Is Molecular Tailored-Therapy Changing the Paradigm for CNS Metastases in Breast Cancer?

Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation.

Molecular alterations in pancreatic tumors.

Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these "inconclusive" specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.

Association between socioeconomic status and survival in glioblastoma: An Italian single-centre prospective observational study.

BACKGROUND: To date, no prospective study has been conducted to investigate the role of socioeconomic status (SES) on clinical outcome of glioblastoma (GBM) in Italy, where there is a National Health Service that provides universal coverage regardless of the patient's economic status. METHODS: We performed a prospective observational study investigating the association between SES and survival in GBM patients at our institution, a hub centre for brain cancer research and treatment. We included GBM patients who underwent medical treatment or chemo-radiation between April 2017 and December 2017. The SES was measured using the income-brackets, attributed by the Italian Ministry of Finance on the basis of the income of the fiscal family unit, referring to the previous year. RESULTS: One hundred and six patients were included in the study. In multivariate analysis, overall survival (OS) correlated significantly with higher-income (HR = 0.623.95% CI 0.467-0.832; p = 0.001) and MGMT methylation status (HR = 0.158.95% CI 0.082-0.304; P < 0.001). When adjusted for age, performance status and extension of surgery, survival benefit remained superior for higher-income HR = 0.641 (95% CI 0.478-0.858; p = 0.003) and MGMT methylated tumours HR = 0.167 (95% CI 0.084-0.331; p < 0.001). CONCLUSIONS: SES is an important determinant of prognosis in GBM even in the Italian National Health Service, which provides universal, largely free and relatively comprehensive healthcare. Despite aspirations to achieve equality in healthcare, socioeconomic differences exist and may impact the clinical outcome.

Treatment of recurrent glioblastoma: state-of-the-art and future perspectives.

BACKGROUND: Almost all patients affected by glioblastoma experience recurrence of the disease. AREAS COVERED: Management of recurrent glioblastoma is a clinical challenge, and several elements should be taken into consideration when making treatment choice. Loco-regional treatments may be the best treatment approach in selected cases while systemic therapies or supportive care alone are necessary for other patients. Unfortunately, few drugs have shown clinical in this setting. This lack of effective treatments has made recurrent glioblastoma a disease orphan of an effective approach. EXPERT OPINION: Results of recent clinical trials offer interesting perspectives and may controvert this axiom.

Concordance between RTOG and EORTC prognostic criteria in low-grade gliomas.

Aim: European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) criteria are used to choose treatment in low-grade gliomas. However, no data exist on their concordance. Methods: Low-grade glioma patients treated at our institution from 1998 to 2015 and assessable for both RTOG and EORTC criteria were included to analyze their concordance. Surgery extension, postsurgical treatments, molecular characteristics (IDH mutation, MGMT methylation and 1p/19q codeletion) were recorded. Results: We included 99 patients. The concordance was low (50.5%; K = 0.127; p = 0.021) but for two subgroups: EORTC high-risk patients were also RTOG high-risk patients (concordance: 97.5%) and RTOG low-risk patients were also EORTC low-risk patients (concordance: 90.9%). Conclusion: The concordance between RTOG and EORTC criteria is low. Thus, clinical trials adopting different risk criteria are not comparable.

TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer.

BACKGROUND: FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. METHODS: This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, L-leucovorin 200 mg/m2, 5-fluoruracil 2400 mg/m2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. DISCUSSION: The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. CLINICAL TRIAL INFORMATION: NCT03231722.

Temozolomide rechallenge in recurrent glioblastoma: when is it useful?

AIM: To identify patients with recurrent glioblastoma after temozolomide (TMZ) concurrent with and adjuvant to radiotherapy who could benefit from TMZ rechallenge at the time of disease progression. METHODS: We retrospectively evaluated 106 glioblastoma patients who had nonprogressive disease at first magnetic resonance imaging after completion of TMZ concurrent with and adjuvant to radiotherapy, a treatment-free interval (TFI) of at least 8 weeks and received TMZ rechallenge or a nitrosourea at the time of progression. RESULTS: In patients with TFI ≥5 months, median survival was 17.7 and 11.6 months and median progression-free survival was 8.1 and 5.8 months in the TMZ and nitrosourea group, respectively. Longer TFI was associated with reduced risk for death (p = 0.002) and for disease progression (p = 0.005). CONCLUSION: TFI ≥5 months represents a predictor of retained TMZ sensitivity.

Third-line therapy in recurrent glioblastoma: is it another chance for bevacizumab?

BACKGROUND: Standard glioblastoma therapy is long-lasting. Among second-line therapy, choices could be bevacizumab and nitrosoureas depending on National Agencies approval. There is no consensus on 3rd line therapy or clinical trials specifically designed for this setting. METHODS: We reviewed our institutional database on all consecutive patients who received 3rd line therapy for glioblastoma. RESULTS: Data on 168 out of 1337 (12.6%) glioblastoma patients who underwent 3rd line therapy treatment were collected. Third line treatments were bevacizumab or chemotherapy (nitrosourea, temozolomide or carboplatin plus etoposide). Median progression free survival was 2.9 months and median survival time was 6.6 months from the start of 3rd line therapy. Bevacizumab significantly improved progression-free survival (4.7 vs. 2.6 months, p = .020) and survival from 3rd line start (8.0 vs. 6.0 months, p = .014) in respect to chemotherapy. Toxicity of grade ≥ 3 occurred in 13.7% of patients. In multivariate analysis, survival in 3rd line treatment depends on MGMT methylation (p = .006) and treatment with Bevacizumab (p = .011). CONCLUSIONS: Third line therapy in selected glioblastoma patients may be feasible and well tolerated. Bevacizumab improved outcome in 3rd line in respect to chemotherapy.

The percentage of Epidermal Growth Factor Receptor (EGFR)-mutated neoplastic cells correlates to response to tyrosine kinase inhibitors in lung adenocarcinoma.

BACKGROUND: Epidermal Growth Factor Receptor (EGFR) molecular analysis is performed to assess the responsiveness to Tyrosine Kinase Inhibitors (TKIs) in patients with Non-Small Cell Lung Cancer (NSCLC). The existence of molecular intra-tumoral heterogeneity has been observed in lung cancers. The aim of the present study is to investigate if the percentage of mutated neoplastic cells within the tumor sample might influence the responsiveness to TKIs treatment. MATERIAL AND METHODS: A total of 931 cases of NSCLC were analyzed for EGFR mutational status (exon 18, 19, 20, 21) using Next Generation Sequencer. The percentage of mutated neoplastic cells was calculated after normalizing the percentage of mutated alleles obtained after next generation sequencer analysis with the percentage of neoplastic cells in each tumor. RESULTS: Next generation sequencing revealed an EGFR mutation in 167 samples (17.9%), mainly deletions in exon 19. In 18 patients treated with TKIs and with available follow-up, there was a significant correlation between the percentage of mutated neoplastic cells and the clinical response (P = 0.017). Patients with a percentage of mutated neoplastic cells greater than 56%, have a statistical trend (P = 0.081) for higher Overall Survival (26.3 months) when compared to those with a rate of mutated neoplastic cells lower than 56% (8.2 months). CONCLUSIONS: The percentage of EGFR-mutated neoplastic cells in the tumor is associated with response to TKIs. A "quantitative result" of EGFR mutational status might provide useful information in order to recognize those patients which might have the greatest benefit from TKIs.

New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.

Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

A Randomized Controlled Trial of Tong Len Meditation Practice in Cancer Patients: Evaluation of a Distant Psychological Healing Effect.

CONTEXT: Tong Len meditation is an important therapeutic tool in the Tibetan medicine, and it can be used for self-healing and/or to heal others. Currently, in the West, there is no scientific study concerning the efficacy of a Tong Len distant healing effect on psychological disorders in cancer patients. OBJECTIVES: To evaluate a distant healing effect of Tong Len meditation on stress, anxiety, depression, fatigue, and self-perceived quality of life in cancer patients. These psychological objectives were chosen as a consequence of the limited scientific literature of present day. DESIGN: We performed a double-blind randomized controlled trial on 103 cancer patients with tumors. Overall, 12 meditators used Tong Len in aid of 52 patients randomly selected as experimental group, while the remaining 51 patients constituted the control group. Patients and meditators did not know each other. All patients completed profile of mood states (POMS) and European Quality of Life-5 dimensions (EQ-5D) questionnaires before treatment (T0), after two (T1) and three months of treatment (T2), and one month after treatment cessation (T3). RESULTS: With regard to the parameters related to depression, a statistically significant improvement (P = .003) was observed in the treatment group compared to controls. On the other hand, the vigor/activity parameter saw significant improvements in the control group (P = .009). Both groups exhibited significant improvements in the other factors assessed in the POMS and EQ-5D questionnaires. CONCLUSIONS: This study did not provide sufficient evidence supporting an efficacy of Tong Len meditation in distant psychological healing as compared to a control condition. The research highlighted some psychological improvements through Tong Len distant meditation in a group of patients unknown to meditators. Therefore, the enhancement detected in most parameters in both treatment and control groups raises interest on in-depth analysis and evaluation of distant meditation on cancer patients to mitigate psychological problems caused by the disease.

Maintenance therapy in non-small cell lung cancer.

Several randomized trials have investigated the role of maintenance treatment for patients with advanced non-small cell lung cancer (NSCLC) not progressed after completion of first-line chemotherapy, with good performance score (PS) and no persistent chemotherapy-induced toxicity. Two separate strategies have been developed: the immediate use of non-cross-resistant drug (switch maintenance or early second-line therapy) or the continuation of platinum partner alone (continuation maintenance) or in combination with other drug (combination maintenance). Here we discuss how the benefits demonstrated in these studies may change clinical practice (in terms of potential toxicity and costs) and reflect on factors that may identify subgroups of patients who might benefit from maintenance therapy in general, and which maintenance therapy specifically.

Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis.

UNLABELLED: Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with "sensitive disease" are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome. INTRODUCTION: Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses > 90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide. PATIENTS AND METHODS: Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method. RESULTS: Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs. > 150 days) did not show any statistically significant difference in PFS or OS-R. CONCLUSION: The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

A commentary on interstitial pneumonitis induced by docetaxel: clinical cases and systematic review of the literature.

BACKGROUND: Pulmonary toxicity is a well-known complication observed with several anticancer drugs. Docetaxel, a taxane chemotherapy drug widely used in the treatment of many types of solid tumors including non-small cell lung cancer (NSCLC), rarely causes infiltrative pneumonitis. The exact mechanism by which docetaxel develops this side effect is not well understood; probably it is produced by type I and IV hypersensitivity responses. Here we describe 2 cases of infiltrative pneumonitis induced by docetaxel as second-line chemotherapy in advanced NSCLC. MATERIALS AND METHODS: Two patients with advanced NSCLC were treated with weekly docetaxel as second-line chemotherapy. After 3 courses of chemotherapy, restaging computed tomography (CT) of the chest revealed bilateral diffuse ground-glass opacities with a peribronchial distribution possibly indicative of hypersensitivity pneumonitis. No evidence of pulmonary embolus or pleural effusion was found. Fiberoptic bronchoscopy showed normal bronchi without lymphangitis; biopsies showed interstitial fibrosis without tumor cells. Bronchial tissue laboratory tests for fungi or bacilli were negative. No malignant cells were found at bronchoalveolar lavage. The patients were given high-dose corticosteroid therapy with prednisone 0.7 mg per kilogram per day. RESULTS: After 1 month of therapy, contrast-enhanced chest CT showed complete disappearance of the pulmonary changes in both patients. Spirometry and blood gas analysis revealed complete recovery of pulmonary function. The patients continued their oncological follow-up program. CONCLUSIONS: Pulmonary injury is a rare adverse event during docetaxel chemotherapy. Prompt treatment with high-dose corticosteroids is needed to avoid worsening of respiratory performance.

Third- and further-line therapy in advanced non-small-cell lung cancer patients: an overview.

Non-small-cell lung cancer (NSCLC) treatment has led to improved efficacy and compliance due to individual tailoring of the therapeutic options and the use of strategies based on both clinical characteristics and histological and biological features of the disease. In nonsquamous NSCLC, novel agents, such as pemetrexed and bevacizumab, have improved survival in the first-line setting. Maintenance therapy with pemetrexed and erlotinib resulted in improved progression-free survival compared with second-line therapy at disease progression. In the second-line setting, pemetrexed improves survival in nonsquamous NSCLC compared with docetaxel, and erlotinib has shown a survival benefit compared with best supportive care in patients who did not previously receive an EGF receptor inhibitor. Although the benefit of first- and second-line treatment over best supportive care alone has been firmly established, the role of further-line treatment remains controversial. This article summarizes the state-of-the-art treatments in this setting.

Resistance to antiangiogenic therapies.

Angiogenesis is a key process for tumoral growth, which has become a main target for anticancer treatments. A wide number of agents targeting both VEGF and its receptor have recently become standard treatments for different tumor types. Unfortunately, most of the tumors become resistant to these agents after few months of treatment. Different mechanisms of resistance to antiangiogenic drugs have been proposed and investigated; some agents demonstrated to be able to restore sensitivity to antiangiogenic drugs by blocking pathways or molecules involved in the resistance in preclinical models. Biomarkers for the prediction of response or resistance to antiangiogenic agents are under evaluation.

The role of systemic and targeted therapies in brain metastases.

For many years, brain metastases (BMs) have been considered as the final stage of a disease course and engendered skepticism about the efficacy of treatments. Local treatments, mainly, whole-brain radiotherapy have been the standard of care, whereas chemotherapy has been considered of limited efficacy due to the potential role of blood-brain barrier.