Chemotherapy Rechallenge or Reintroduction Compared to Regorafenib or Trifluridine/Tipiracil for Pretreated Metastatic Colorectal Cancer Patients: A Propensity Score Analysis of Treatment Beyond Second Line (Proserpyna Study).

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated. PATIENTS AND METHODS: PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses. RESULTS: Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses. CONCLUSIONS: Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

FMRP expression in primary breast tumor cells correlates with recurrence and specific site of metastasis.

Breast cancer is the most common cancer among women worldwide. Molecular and clinical evidence indicated that Fragile X Messenger Ribonucleoprotein 1 (FMRP) plays a role in different types of cancer, including breast cancer. FMRP is an RNA binding protein that regulates the metabolism of a large group of mRNAs coding for proteins involved in both neural processes and in epithelial-mesenchymal transition, a pivotal mechanism that in cancer is associated to tumor progression, aggressiveness and chemoresistance. Here, we carried out a retrospective case-control study of 127 patients, to study the expression of FMRP and its correlation with metastasis formation in breast cancer. Consistent with previous findings, we found that FMRP levels are high in tumor tissue. Two categories have been analyzed, tumor with no metastases (referred as control tumors, 84 patients) and tumor with distant metastatic repetition, (referred as cases, 43 patients), with a follow-up of 7 years (mean). We found that FMRP levels were lower in both the nuclei and the cytoplasm in the cases compared to control tumors. Next, within the category cases (tumor with metastases) we evaluated FMRP expression in the specific sites of metastasis revealing a nuclear staining of FMRP. In addition, FMRP expression in both the nuclear and cytoplasmic compartment was significantly lower in patients who developed brain and bone metastases and higher in hepatic and pulmonary sites. While further studies are required to explore the underlying molecular mechanisms of FMRP expression and direct or inverse correlation with the secondary metastatic site, our findings suggest that FMRP levels might be considered a prognostic factor for site-specific metastasis.

Association between background parenchymal enhancement and tumor response in patients with breast cancer receiving neoadjuvant chemotherapy.

PURPOSE: To analyze the relationships between background parenchymal enhancement (BPE) of the contralateral healthy breast and tumor response after neoadjuvant chemotherapy (NAC) in women with breast cancer. MATERIALS AND METHODS: A total of 228 women (mean age, 47.6 years±10 [SD]; range: 24-74 years) with invasive breast cancer who underwent NAC were included. All patients underwent breast magnetic resonance imaging (MRI) before and after NAC and 127 patients underwent MRI before, during (after the 4th cycle of NAC) and after NAC. Quantitative semi-automated analysis of BPE of the contralateral healthy breast was performed. Enhancement level on baseline MRI (baseline BPE) and MRI after chemotherapy (final BPE), change in enhancement rate between baseline MRI and final MRI (total BPE change) and between baseline MRI and midline MRI (early BPE change) were recorded. Associations between BPE and tumor response, menopausal status, tumor phenotype, NAC type and tumor stage at diagnosis were searched for. Pathologic complete response (pCR) was defined as the absence of residual invasive cancer cells in the breast and ipsilateral lymph nodes. RESULTS: No differences were found in baseline BPE, final BPE, early and total BPE changes between pCR and non-pCR groups. Early BPE change was higher in non-pCR group in patients with stages 3 and 4 breast cancers (P=0.019) and in human epidermal growth factor receptor 2 (HER2)-negative patients (P=0.020). CONCLUSION: Early reduction of BPE in the contralateral breast during NAC may be an early predictor of loss of tumor response, showing potential as an imaging biomarker of treatment response, especially in women with stages 3 or 4 breast cancers and in HER2 - negative breast cancers.

Antimicrobial properties of the medicinal plant Cardiospermum halicacabum L: new evidence and future perspectives.

The emergence and rapid spread of multidrug-resistance in human pathogenic microorganisms urgently require the development of novel therapeutic strategies for the treatment of infectious diseases. From this perspective, the antimicrobial properties of the natural plant-derived products may represent an important alternative therapeutic option to synthetic drugs. Among medicinal plants, the Cardiospermum halicacabum L. (C. halicacabum), belonging to Sapindaceae family, could be a very promising candidate for its antimicrobial activity against a wide range of microorganisms, including both Gram-positive and Gram-negative bacteria, as well as fungal pathogens. Although the antimicrobial properties of C. halicacabum have been intensively studied, the mechanism/s by which it exerts the inhibitory activity towards the pathogenic microbes have not yet been completely understood. This review focuses on the main antimicrobial activities displayed in vitro by the plant extract, with particular attention on our recent advances. We demonstrated that C. halicacabum is able to exert in vitro a dose-dependent fungistatic effect against Trychophyton rubrum (T. rubrum) through molecular interaction with the fungal heat shock protein (Hsp)-90 chaperone. These findings are supported by a growing body of research indicating the crucial role played by the Hsp90 in the virulence of the pathogenic microorganisms, including fungal pathogens. The possible future use of C. halicacabum for treating a wide range of infectious diseases is also discussed.

Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab.

BACKGROUND: Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) is a rare condition associated with plaque-type psoriasis, generalized pustular psoriasis, palmoplantar pustular psoriasis and pityriasis rubra pilaris. Recently, a new CARD14 -associated phenotype defined as CAPE (CARD14-associated papulosquamous eruption) with clinical features of both psoriasis and pityriasis rubra pilaris was reported. We describe a family carrying a novel heterozygous mutation in CARD14 gene, with childhood-onset erythrodermic psoriasis requiring an unusual extremely high dose (up to 2 mg/kg every 8 weeks) of ustekinumab to achieve disease remission. CASE PRESENTATION: We describe a large family with three pairs of twins presenting a clinical phenotype characterized by childhood-onset erythrodermic psoriasis; in some family members is also reported psoriatic arthritis. The two probands presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, NOD2, PSMB8, PSTPIP1, LPIN2) we approached a new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family. A novel heterozygous mutation (c.446 T > G, leading to the missense amino acid substitution p.L149R) in the exon 4 of the CARD14 gene was identified in all affected members. Increasing dosages (up to 2 mg/kg every 8 weeks) of ustekinumab, a human monoclonal antibody targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), allowed the complete control of the clinical manifestations, with an evident reduction of circulating Th17 and Th22 CD4+ T cell subsets. CONCLUSIONS: We describe the association of mutations of the CARD14 gene with an erythrodermic psoriasis pedigree, underlying the necessity to investigate CARD14 mutations in childhood-onset psoriasis cases and confirming the presence of CARD14 causative mutations also in erythrodermic psoriasis form, as recently reported. Also in pediatric age, ustekinumab represents a powerful therapeutic option for this rare condition, that is usually refractory to other treatments. In young children, high and frequent dosages allowed a complete control of the clinical manifestations without any severe side effects, with a long-term follow-up.

Clusterin silencing restores myoblasts viability and down modulates the inflammatory process in osteoporotic disease.

BACKGROUND: Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition. METHODS: Vastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis. RESULTS: We found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment. CONCLUSIONS: Results obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.

Usefulness of automated breast volume scanner (ABVS) for monitoring tumor response to neoadjuvant treatment in breast cancer patients: preliminary results.

OBJECTIVE: We investigated the accuracy of Automated Breast Volume Scanner (ABVS) compared to handheld ultrasound (HHUS) for monitoring tumor response to neoadjuvant treatment (NAT) in breast cancer (BC). PATIENTS AND METHODS: All the patients submitted to biopsy in our Institution, from January 2017 to May 2017, proven invasive BC and eligible for NAT, were enrolled in this prospective study. The participants underwent ABVS, HHUS, dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) and mammography at the beginning of NAT and ABVS, HHUS and DCE-MRI at the halfway point of therapy and before the surgery. DCE-MRI was considered the standard of reference. Two breast radiologists (R1, R2), with fifteen and five years of experience in breast imaging, independently assigned a visibility score (ordinal 5-point scale) to ABVS, HHUS, and DCE-MRI. Diagnostic performance of ABVS and HHUS as measured by sensitivity, specificity, positive and negative predictive values (PPV and NPV) was calculated. Correlations between ABVS and MRI, and between HHUS and MRI were analyzed using Pearson's correlation test. RESULTS: A total of 21 patients were enrolled. 189 examinations were performed. The comparison between ABVS and DCE-MRI was similar for the both readers: ABVS had a sensitivity of 63,16%, specificity of 83,58%, PPV of 76,60%, NPV of 72,73%, accuracy of 74,19% (R1) and a sensitivity of 54.54%, specificity of 85.51%, PPV of 75%, NPV of 70,24%, accuracy of 71.77% (R2). The comparison between HHUS and DCE-MRI showed that HHUS had a sensitivity of 63,16 %, specificity of 83,58%, PPV of 76,60%, NPV of 72,73%, accuracy of 74,19% (R1) and a sensitivity of 36.84%, specificity of 85.07%, PPV of 67.74%, NPV of 61.29%, accuracy of 62.90% (R2). The calculated Pearson's correlation coefficient r values were 7.8 for HHUS vs. DCE-MRI and 28.5 for ABVS vs. DCE-MRI (R1) and 7.8 for HHUS vs. DCE-MRI and 22.4 for ABVS vs. DCE-MRI (R2). Statistical significance of ABVS and HHUS was p < 0.0001 and 0.005 < p < 0.01, respectively (R1, R2). CONCLUSIONS: DCE-MRI is recommended for the tumor response assessment. ABVS, a product of the biotechnology development, providing reproducible images, in addition to DCE-MRI, can be a potentially useful tool for the monitoring of response to NAT.

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation.

BACKGROUND: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. METHODS: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m-2 per day on days 1-5 every 28 days. RESULTS: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. CONCLUSIONS: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Biological and predictive role of ERCC1 polymorphisms in cancer.

Excision repair cross-complementation group 1 (ERCC1) is a key component in DNA repair mechanisms and may influence the tumor DNA-targeting effect of the chemotherapeutic agent oxaliplatin. Germline ERCC1 polymorphisms may alter the protein expression and published data on their predictive and prognostic value have so far been contradictory. In the present article we review available evidence on the clinical role and utility of ERCC1 polymorphisms and, in the absence of a 'perfect' trial, what we call the 'sliding doors' trial, we present the data of ERCC1 genotyping in our local patient population. We found a useful predictive value for oxaliplatin-induced risk of anemia.

Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report.

Human adenoviruses (HAdVs) cause a wide spectrum of clinical syndromes, depending on species and types, from mild respiratory infections to deadly pneumonia: in particular, severe infections occur in immunocompromised patients. In this report, we describe the case of a 36 years-old woman admitted to our intensive care unit (ICU) with severe respiratory distress syndrome caused by adenovirus pneumonia, that required invasive respiratory support (mechanical ventilation and extracorporeal membrane oxygenation). Molecular assays detected the virus in respiratory and plasma specimen and sequencing procedure identified HAdV type 4. Patient improved after cidofovir administration. Leukopenia and subsequent bacterial infection occurred, but the patient recovered completely and was discharged from the hospital after 54days.

Elemental analysis of histological specimens: a method to unmask nano asbestos fibers.

There is recent mounting evidence that nanoparticles may have enhanced toxicological potential in comparison to the same material in the bulk form. The aim of this study was to develop a new method for unmask asbestos nanofibers from Formalin-Fixed, Paraffin-Embedded tissue. There is an increasing amount of evidence that nanoparticles may enhance toxicological potential in comparison to the same material in the bulk form. The aim of this study was to develop a new method to unmask asbestos nanofibers from Formalin-Fixed Paraffin-Embedded (FFPE) tissue. For the first time, in this study we applied Energy Dispersive X-ray (EDX) microanalysis through transmission electron microscopy to demonstrate the presence of asbestos nanofibers in histological specimens of patients with possible occupational exposure to asbestos. The diagnostic protocol was applied to 10 randomly selected lung cancer patients with no history of previous asbestos exposure. We detected asbestos nanofibers in close contact with lung cancer cells in two lung cancer patients with previous possible occupational exposure to asbestos. We were also able to identify the specific asbestos iso-type, which in one of the cases was the same rare variety used in the workplace of the affected patient. By contrast, asbestos nanofibers were not detected in lung cancer patients with no history of occupational asbestos exposure. The proposed technique can represent a potential useful tool for linking the disease to previous workplace exposure in uncertain cases. Furthermore, Formalin-Fixed Paraffin-Embedded (FFPE) tissues stored in the pathology departments might be re-evaluated for possible etiological attribution to asbestos in the case of plausible exposure. Since diseases acquired through occupational exposure to asbestos are generally covered by workers' insurance in most countries, the application of the protocol used in this study may have also relevant social and economic implications.

Gemcitabine versus FOLFIRINOX in patients with advanced pancreatic adenocarcinoma hENT1-positive: everything was not too bad back when everything seemed worse.

PURPOSE: hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available. METHODS: 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS. RESULTS: The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OS and PFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3-2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM-treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients. CONCLUSIONS: In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer.

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis.

BACKGROUND: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. RESULTS: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. CONCLUSION: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.

Trastuzumab-induced corneal ulceration: successful no-drug treatment of a "blind" side effect in a case report.

BACKGROUND: We report the first successful treatment of limbal lesions and corneal erosion experienced by a breast cancer patient undergoing trastuzumab treatment. CASE PRESENTATION: A 49-year-old Caucasian woman with early stage breast cancer was treated with adjuvant trastuzumab and subsequently showed persistent bilateral corneal marginal infiltrates resistant to topical steroid and antibiotic treatment. Autologous serum was applied in the conjunctival sac as an experimental treatment to antagonize the inhibitory effect of the HER2 receptor antibody on the corneal epithelial cells. Topical application of autologous serum led to rapid improvement of the ulcerative keratitis, with complete healing of the corneal defect after 7 days. Continued administration of the serum allowed the resumption of trastuzumab therapy without any further side effects. CONCLUSIONS: Persistent bilateral corneal marginal infiltrates may occasionally arise as a side effect of trastuzumab treatment. Topical medication with autologous serum may be an effective therapeutic option for the ocular side effects of trastuzumab therapy.