Metronomic Capecitabine Effectively Blocks Leptomeningeal Carcinomatosis From Breast Cancer: A Case Report and Literature Review.

BACKGROUND Meningeal carcinomatosis is a rare complication in breast cancer patients. At present, there are no defined guidelines for its management. The efficacy of systemic treatment seems to depend on its ability to cross the blood-brain-barrier and its interaction with tumor vasculature. Metronomic chemotherapy is a known modality of drug administration able to inhibit tumor angiogenesis. CASE REPORT We present a case of symptomatic leptomeningeal carcinomatosis from breast cancer successfully treated with capecitabine. Based on the hypothesis that angiogenesis contributes to neoplastic meningitis, the patient was treated with a metronomic schedule that provided long-term clinical benefit with a very low toxicity profile. CONCLUSIONS To assess the real impact of metronomic chemotherapy in patients with meninges involvement, a phase II study will be starting soon in our institution. A review of the literature concerning the management of meningeal carcinomatosis is also presented

Pazopanib-Induced Heart Failure In A Metastastic Sarcoma Patient: Between Reversible Side Effect and Efficacy

Introduction: Pazopanib, a multi-target tyrosine-kinase inhibitor (TKI), is a relatively novel anticancer agent registered for advanced renal cell carcinoma recently emerged in the setting of advanced soft-tissue sarcoma (STS). In the early clinical trials pazopanib has been very marginally linked to left ventricular ejection fraction (LVEF) dysfunction as, on contrary, reported for other anti-angiogenesis TKIs, such as Sunitinib and Sorafenib. Presentation of Case: We here present a case of severe, but reversible, congestive cardiac failure in a 37-year old Caucasian man affected by soft-tissue sarcoma during an efficacious treatment with pazopanib. Conclusion: Cardiac damage from novel TKI treatments is still an underestimated phenomenon. In our patient, pazopanib was the only treatment ensuring stability of disease and its discontinuation meant disease progression. Post-approval monitoring of novel TKIs should be taken into account by clinicians including a careful monitoring of LVEF and all symptoms suggestive of cardiac dysfunction, in particular for drugs potentially capable to change the natural history of still uncurable cancer

Pazopanib-Induced Heart Failure in a Metastatic Sarcoma Patient: between Reversible Side Effect and Efficacy

 Introduction: Pazopanib, a multi-target tyrosine-kinase inhibitor (TKI), is a relatively novel anticancer agent registered for advanced renal cell carcinoma recently emerged in the setting of advanced soft-tissue sarcoma (STS). In the early clinical trials pazopanib has been very marginally linked to left ventricular ejection fraction (LVEF) dysfunction as, on contrary, reported for other anti-angiogenesis TKIs, such as Sunitinib and Sorafenib. Presentation of Case: We here present a case of severe, but reversible, congestive cardiac failure in a 37-year old Caucasian man affected by soft-tissue sarcoma during an efficacious treatment with pazopanib. Conclusion: Cardiac damage from novel TKI treatments is still an underestimated phenomenon. In our patient, pazopanib was the only treatment ensuring stability of disease and its discontinuation meant disease progression. Post-approval monitoring of novel TKIs should be taken into account by clinicians including a careful monitoring of LVEF and all symptoms suggestive of cardiac dysfunction, in particular for drugs potentially capable to change the natural history of still uncurable cancer.

Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature

SIMPLE SUMMARY: Breast cancer is a leading cause of female cancer-related death worldwide. Anti-HER2-targeted therapies dramatically improved prognosis for HER2-positive breast cancer patients. Despite that, growing drug resistance due to the pressure of therapy is relatively frequent. For that reason, it is necessary to find biomarkers able to predict treatment sensitivity and survival outcomes. Increasing research has shown how miRNAs, secreted by tumor cells, are strongly involved in cancer development. In this review, we will discuss the recent evidence on the predictive and prognostic value of miRNAs involved in HER2-positive early breast cancer progression. ABSTRACT: MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value

Impressive response to dose-dense chemotherapy in a patient with NUT midline carcinoma

Objective: Rare disease Background: NUT midline carcinoma (NMC) is a rare, highly lethal malignancy that results from a chromosome translocation and mostly arises in the midline organs. To date, no treatment has been established. Most patients receive combinations of chemotherapy regimens and radiation, and occasionally subsequent resection; nevertheless, patients have an average survival hardly exceeding 7 months. Case Report: A 21-year-old patient was admitted to our division with a large mediastinal mass with lung nodules, multiple vertebral metastases, and massive nodal involvement. In a few days, the patient developed a superior vena cava syndrome and an acute respiratory failure. Due to the rapid course of the disease, based on preliminary histology of poorly differentiated carcinoma, a dose-dense biweekly chemotherapy with paclitaxel, ifosfamide, and cisplatin was started. In the meantime, the diagnosis of NMC was confirmed. A surprising clinical benefit was obtained after the first cycle of chemotherapy, and after 6 cycles a PET-CT scan showed a very good response. At this point, radiotherapy was started but the disease progressed outside of the radiation field. The patient entered into a compassionate use protocol with Romidepsin, but a PET/CT scan after the first course showed disease progression with peritoneal and retroperitoneal carcinosis. A treatment with Pemetrexed was then started but the patient eventually died with rapid progressive disease. Conclusions: Our case history adds some interesting findings to available knowledge: NMC can be chemosensitive and radiosensitive. This opens the possibility to study more aggressive treatments, including high-dose consolidation chemotherapy and to evaluate the role of biological agents as maintenance treatments

Quality of life and anxious-depressive symptoms in cancer patients undergoing mindfulness-based interventions: Feasibility and preliminary outcomes on prospective single-centre case-control study (MIND4ME St.)

Background Mindfulness based interventions (MBIs) have shown efficacy in improving psychological symptoms including depression and anxiety in cancer patients (pts). The study aimed to explore feasibility and reproducibility of MBIs in an Italian Cancer Centre measuring biochemical and psychological parameters. Methods In this pilot prospective case-control study, we recruited newly diagnosed pts receiving adjuvant chemotherapy (CT). A MBIs program was designed consisting of 2.5 hours weekly for 8 weeks and, including meditation, yoga and body scan. Material for 45 minutes (mn) home daily practice was provided. Primary endpoint was to evaluate feasibility. Secondary endpoints were assessment of quality of life (QoL), psychological and biochemical outcomes of stress, tested at baseline (W0), W4, W8, W24, W48. PSS (Perceived Stress Reduction), POMS (profile of mood states scores), EuroQoL (EQ-5D-3L) were administered. Results Ten pts underwent MBIs program arm. We present preliminary results, while data of control arm are being collected. All pts were female, two pts (20%) dropped out. Median age was 56 years. All received adjuvant CT, 5/8 received radiotherapy and hormone therapy. Mean of sessions attending was 6.8 (76%). Median daily practice was 30 mn. EQ-5D item for depression and anxiety showed decreasing trend in mean score from moderate to light (P = 0.15) and significant improvement of auto-perceived QoL was observed comparing W0 and W8 (P = 0.02) Conclusions In a sensitive setting such as start CT, we found high pts compliance to MBIs. Improvement in self-perceived QoL after starting program was found and comparing anxious-depressive symptoms outcomes with control arm is still needed

ceritinib plus nivolumab in patients with advanced alk rearranged non small cell lung cancer results of an open label multicenter phase 1b study

Abstract Introduction Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. Methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. Results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. Conclusion Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent

Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer

Lessons Learned Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy. Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition. Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy. Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising. Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels. Background. Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity. Methods. Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3–60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results. A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected. Conclusion. Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested

Predictive value of biologic parameters for primary chemotherapy in operable breast cancer

Primary chemotherapy represents an ideal model to evaluate the relationships between treatments and the prognostic and predictive parameters provided by the new technologies. First- and second-generation trials have shown that primary chemotherapy significantly improves the rate of breast conservation without increasing the risk of ipsilateral recurrence and while assuring survival rates comparable with those achieved with postoperative chemotherapy. Moreover, patients who exhibited a pathologic complete response (pCR) showed better progression-free survival and overall survival. The third-generation trials were aimed at improving the percentage of pCR, identifying and validating gene and protein biomarkers of chemotherapy sensitivity, and better defining the individual risk of relapse. Several parameters, such as index of proliferation and apoptosis, expression of proteins (eg, p53 and Bcl-2), and hormone receptor and epidermal growth factor family receptors, have been related to response to primary chemotherapy. Negative hormone receptors and greater proliferative activity seem to be the only parameters more consistently associated with greater chemotherapy sensitivity. However, the strength of this association is not sufficient to differentiate patients at different degrees of risk and does not allow for an individualized therapeutic choice. Newer technologies offer the possibility of evaluating thousands of genes and identifying clusters of gene expression associated with significantly different risks of relapse and patterns of sensitivity/resistance to specific drugs. The primary chemotherapy model is the ideal clinical setting in which to validate the relationship between tumor molecular profiling and treatment outcomes and to design tailored therapies based on observed effects on individual tumors

Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma

.....T his is the first case of PRES during ipilimumab therapy. Increasing awareness of PRES is needed in patients who undergo anti–CTLA-4 therapies and develop irAEs such as hypophysitis in our patient. Autoimmune disorders are associated with an increased risk of PRES; autoimmune hypophysitis, however, does not seem to be implicated in the development of PRES. Further inves- tigations on the mechanisms of toxicity and risk factors for PRES are necessar