Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Pan-European Study on the Prevalence of the Feline Leukaemia Virus Infection - Reported by the European Advisory Board on Cat Diseases (ABCD Europe).

Feline leukaemia virus (FeLV) is a retrovirus associated with fatal disease in progressively infected cats. While testing/removal and vaccination led to a decreased prevalence of FeLV, recently, this decrease has reportedly stagnated in some countries. This study aimed to prospectively determine the prevalence of FeLV viraemia in cats taken to veterinary facilities in 32 European countries. FeLV viral RNA was semiquantitatively detected in saliva, using RT-qPCR as a measure of viraemia. Risk and protective factors were assessed using an online questionnaire to report geographic, demographic, husbandry, FeLV vaccination, and clinical data. The overall prevalence of FeLV viraemia in cats visiting a veterinary facility, of which 10.4% were shelter and rescue cats, was 2.3% (141/6005; 95% CI: 2.0%-2.8%) with the highest prevalences in Portugal, Hungary, and Italy/Malta (5.7%-8.8%). Using multivariate analysis, seven risk factors (Southern Europe, male intact, 1-6 years of age, indoor and outdoor or outdoor-only living, living in a group of ≥5 cats, illness), and three protective factors (Northern Europe, Western Europe, pedigree cats) were identified. Using classification and regression tree (CART) analysis, the origin of cats in Europe, pedigree, and access to outdoors were important predictors of FeLV status. FeLV-infected sick cats shed more viral RNA than FeLV-infected healthy cats, and they suffered more frequently from anaemia, anorexia, and gingivitis/stomatitis than uninfected sick cats. Most cats had never been FeLV-vaccinated; vaccination rates were indirectly associated with the gross domestic product (GDP) per capita. In conclusion, we identified countries where FeLV was undetectable, demonstrating that the infection can be eradicated and highlighting those regions where awareness and prevention should be increased.

Basal and bevacizumab-based therapy-induced changes of lactate dehydrogenases and fibrinogen levels and clinical outcome of previously untreated metastatic colorectal cancer patients: a multicentric retrospective analysis.

BACKGROUND: To assess the predictive role of lactate dehydrogenases (LDH) and fibrinogen (FBG) serum levels in metastatic colorectal cancer (mCRC) patients receiving a first-line bevacizumab-based therapy. OBJECTIVES: The aim of the present analysis was to retrospectively evaluate the role of basal and post-treatment LDH and FBG serum levels in predicting the clinical outcome of 139 mCRC patients receiving first-line chemotherapy in combination with bevacizumab. RESULTS: A statistically significant association between high pre-treatment LDH and FBG levels and progressive disease was observed with respect to low basal LDH and FBG patients. Furthermore, median progression-free survival was 7.3 versus 10.8 months and 7.3 versus 9.4 months for high and low LDH and FBG levels, respectively. Within the high LDH group, we observed a statistically significant reduction of LDH mean value compared with pre-treatment values in patients with objective response rate and stable disease. CONCLUSIONS: High LDH and FBG levels correlated with prognosis. A significant correlation between bevacizumab-based chemotherapy-induced reduction in LDH serum levels and response to treatment was observed within the high LDH group. These results, if confirmed in larger prospective studies, could be helpful for early identification of patients responsive to bevacizumab-based chemotherapy or candidate to more aggressive treatments.

Pharmacogenomics of cetuximab in metastatic colorectal carcinoma.

Cetuximab is a chimeric monoclonal antibody that has revolutionized the treatment of metastatic colorectal cancer. Knowledge of the mechanisms that underlie its effectiveness, as well as the primary and secondary resistance mechanisms, have led to important developments in the understanding of cetuximab biology. In light of knowledge gained from recent trials, the efficacy of cetuximab has been clearly demonstrated to depend upon RAS mutational status, moreover cetuximab should only be used in a subset of patients who may benefit. In this article, we critically review clinical and pharmacogenetic issues of cetuximab, focusing on the cost-effectiveness involved with the use of the drug.

CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen.

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

BACKGROUND: Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed. RESULTS: The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001). CONCLUSIONS: This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

Third-line trabectedin for a metastatic desmoplastic small round cell tumour treated with multimodal therapy.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare and aggressive cancer that usually develops in the peritoneal cavity of young males. Its prognosis is dismal, with current treatment options including the combination of multi-agent chemotherapy, aggressive surgery, radiation therapy, and autologous stem cell transplantation. Hyperthermic intraperitoneal chemotherapy (HIPEC) may also be an option. CASE REPORT: Herein we report the administration of the marine-derived multi-target antineoplastic agent, trabectedin, in a patient with DSRCT, heavily pre-treated with conventional multi-agent chemotherapy, HIPEC, and surgery. RESULTS: The patient achieved a prolonged partial response and an extended period of stable disease with third-line trabectedin, following disease progression after conventional multi-agent chemotherapy, HIPEC, and surgery. CONCLUSION: Trabectedin may be a treatment option in multimodal therapy for the management of DSRCT and warrants further research to explore the impact of trabectedin in the treatment of this disease.

Predictive factors to targeted treatment in gastrointestinal carcinomas.

Most cancers are traditionally treated with either chemotherapeutic agents, radiotherapy, or both. Identification of specific molecular characteristics of tumors and the advent of molecular-targeted drugs not only enhance the efficacy but also decrease the toxicity of treatment. These new therapies may target pathways critical to tumor development or specific driver mutations in cancer cells. This understanding of the molecular pathways of cancer cells has led to the ability to predict cancer development, behaviour and prognosis, as well as response or resistance to current therapeutic agents. As a result, pathologic analyses play a vital role in the detection of cancer biomarkers, which are important not only in the diagnosis of cancers but also in the selection of appropriate therapeutic agents and in the development of new targeted therapies.

The prognostic value of the Na⁺/ H⁺ exchanger regulatory factor 1 (NHERF1) protein in cancer.

NHERF1 (Na⁺/H⁺ exchanger regulatory factor) is a scaffolding protein, consists of two tandem PDZ domains linked to a carboxyl-terminal ezrin-binding region. NHERF1 recruits macromolecular complexes at the apical membrane of epithelial cells in many epithelial tissues. It is involved in trafficking and regulation of transmembrane ion transporters and G protein-coupled receptors. Further, NHERF1 also linked other molecules involved in cell growth and cancer progression, such as PDGFR, PTEN, ß-catenin, EGFR and HER2/neu. In this review, we focus on the role of NHERF1 during cancer development. Evidences of its involvement in cancer development are present in hepatocellular carcinoma, schwannoma, glioblastoma, colorectal cancer and particularly in breast cancer. Recent findings obtained from our laboratory show that cytoplasmic NHERF1 expression increases gradually in breast cancer during carcinogenesis, and its overexpression is associated with aggressive clinical parameters, unfavourable prognosis, and increased tumor hypoxia. Interestingly, also nuclear NHERF1 expression seems to play a role both in carcinogenesis and progression of colorectal cancer. These data suggest that NHERF1 could be a new biomarker of advanced malignancies.

PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression.

To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid hormone-related protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that PTHrP and its receptor (PTH-R1) are highly expressed, and that PTHrP is secreted both as a full-length molecule and as small subunits. Among these subunits, the mid-region, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTH-R1 in MM cells. PTH-R1's selective activation by the full-length PTHrP molecule or the NH2 -terminal fragment resulted in a significant increase of intracellular Ca(2+) influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF-κB ligand (RANKL) and monocyte chemoattractant protein-1 (MCP-1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in stress conditions and by autocrine or paracrine stimulation of PTH-R1, which in turn reinforces the production of osteoclastogenic factors. © 2014 American Society for Bone and Mineral Research.

Target therapies in pancreatic carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early locoregional spread and distant metastases at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapy provides only modest benefit to patients with PDAC. Identification of different molecular pathways, overexpressed in pancreatic cancer cells, has provided the opportunity to develop targeted therapies (monoclonal antibodies and small-molecule inhibitors) and peculiar new class of taxanes with a crucial therapeutic role in this cancer setting. A phase III trial has shown that erlotinib in combination with gemcitabine was clinically irrelevant and skin toxicity can be a positive prognostic factor. Moreover, the combination of cetuximab or erlotinib with radiotherapy in advanced pancreatic cancer has shown to be synergistic and a reversal of radio-resistance has been suggested by inhibition of VEGF/EGFR pathway. To overcome EGFR-inhibition therapy resistance several alternative pathways targets are under investigation (IGF- 1R, MMPs, Hedgehog proteins, m-TOR, MEK, COX-2) and provide the rationale for clinical use in phase II/III studies. Also nab-paclitaxel, a new taxanes class, uses high pancreatic albumin-binding protein SPARC levels to act in cancer cells with a less toxic and more effective dose with respect to classic taxanes. Understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. However, many promising data in preclinic and phase I/II trials did not yield promise in phase III trials, suggesting that identification of predictive biomarkers for these new agents is mandatory. The knowledge of biologic and molecular aspects of pancreatic cancer can be the basis for future therapeutic developments.

Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey.

BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. PATIENTS AND METHODS: Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 8 months (CI 95%, 6.125-9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). CONCLUSIONS: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients.

Carcinogenesis of pancreatic adenocarcinoma: precursor lesions.

Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.

Expression and prognostic value of VEGFR-2, PDGFR-ß, and c-Met in advanced hepatocellular carcinoma.

BACKGROUND: We explore the clinical and prognostic significance of expression of vascular endothelial growth factor receptor (VEGFR)-2, platelet-derived growth factor receptor (PDGFR)-ß, and c-Met in patients with hepatocellular carcinoma (HCC). METHODS: The expression of VEGFR-2, PDGFR-ß, and c-Met were determined by immunohistochemical examination of the tissues of 93 HCC patients. The relationships of these markers with clinicopathological factors and prognosis were then analyzed. RESULTS: High expression of VEGFR-2, PDGFR-ß, and c-Met was found in 86%, 19.4%, and 80.6% of patients, respectively. Expression of VEGFR-2 correlated with gender (P = 0.044), hepatitis B surface antigen positivity (P = 0.024), degree of tumor differentiation (P = 0.023), and hepatic cirrhosis (P = 0.026). Expression of PDGFR-ß correlated with alpha-fetoprotein level (P = 0.029), tumor size (P = 0.033), and hepatic cirrhosis (P = 0.023). No significant correlations were identified between expression of c-Met and clinicopathological factors. Expression of PDGFR-ß correlated with overall survival (P = 0.046) and expression of c-Met correlated with progression-free survival (P = 0.01). CONCLUSIONS: We found that in patients with HCC, high expression of VEGFR-2 correlates with chronic hepatitis B virus infection and hepatic cirrhosis. High expression of PDGFR-ß is a predictor of poor prognosis. High expression of C-Met may predict therapeutic effectiveness of sorafenib in HCC patients.

Complete response to second line Paclitaxel every 2 weeks of eyelid kaposi sarcoma: a case report.

A 77-year-old male patient presented to our attention with violaceous nodular lesions on the skin of his hands and lower extremities. Clinical and histologic examination supported the diagnosis of Kaposi sarcoma. A first-line systemic chemotherapy based on liposomal doxorubicin at a dosage of 40 mg/m2 every 3 weeks for 5 cycles was carried out, resulting in partial resolution of skin lesions. However, 1 year later, a relapse of the disease in the lower limbs and a new lesion of the left eyelid were found, therefore the patient began a second-line therapy with 100 mg/m2 paclitaxel every 2 weeks. After 8 cycles of therapy, we observed a complete remission of eyelid tumor and a partial response of lower limbs lesions up to 6 months of follow up. In conclusion, eyelid Kaposi sarcoma was successfully treated with paclitaxel every 2 weeks, obtaining a complete response.

Raman probes based on optically-poled double-clad fiber and coupler.

Two fiber Raman probes are presented, one based on an optically-poled double-clad fiber and the second based on an optically-poled double-clad fiber coupler respectively. Optical poling of the core of the fiber allows for the generation of enough 532nm light to perform Raman spectroscopy of a sample of dimethyl sulfoxide (DMSO), when illuminating the waveguide with 1064nm laser light. The Raman signal is collected in the inner cladding, from which it is retrieved with either a bulk dichroic mirror or a double-clad fiber coupler. The coupler allows for a substantial reduction of the fiber spectral background signal conveyed to the spectrometer.