Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research

Sub-Lethal Irradiation of Human Colorectal Tumor Cells Imparts Enhanced and Sustained Susceptibility to Multiple Death Receptor Signaling Pathways

Background: Death receptors (DR) of the TNF family function as anti-tumor immune effector molecules. Tumor cells, however, often exhibit DR-signaling resistance. Previous studies indicate that radiation can modify gene expression within tumor cells and increase tumor cell sensitivity to immune attack. The aim of this study is to investigate the synergistic effect of sub-lethal doses of ionizing radiation in sensitizing colorectal carcinoma cells to death receptor-mediated apoptosis. Methodology/Principal Findings: The ability of radiation to modulate the expression of multiple death receptors (Fas/ CD95, TRAILR1/DR4, TRAILR2/DR5, TNF-R1 and LTbR) was examined in colorectal tumor cells. The functional significance of sub-lethal doses of radiation in enhancing tumor cell susceptibility to DR-induced apoptosis was determined by in vitro functional sensitivity assays. The longevity of these changes and the underlying molecular mechanism of irradiation in sensitizing diverse colorectal carcinoma cells to death receptor-mediated apoptosis were also examined. We found that radiation increased surface expression of Fas, DR4 and DR5 but not LTbR or TNF-R1 in these cells. Increased expression of DRs was observed 2 days post-irradiation and remained elevated 7-days post irradiation. Sub-lethal tumor cell irradiation alone exhibited minimal cell death, but effectively sensitized three of three colorectal carcinoma cells to both TRAIL and Fasinduced apoptosis, but not LTbR-induced death. Furthermore, radiation-enhanced Fas and TRAIL-induced cell death lasted as long as 5-days post-irradiation. Specific analysis of intracellular sensitizers to apoptosis indicated that while radiation di

Perianal Paget's disease: a case report and Literature Review

Perianal Paget's disease is a rare condition characterized by an intraepidermal growth of neoplastic cells with apocrine glandular differentiation (Paget's cells), often associated with an underlying malignancy. Fewer than 200 cases have been reported in the literature over the past 20 years. Here we discuss the clinical case of a young woman who was referred to our institution for this rare disorder and briefly review the literature

Perianal Paget's disease: a case report and Literature Review

Perianal Paget's disease is a rare condition characterized by an intraepidermal growth of neoplastic cells with apocrine glandular differentiation (Paget's cells), often associated with an underlying malignancy. Fewer than 200 cases have been reported in the literature over the past 20 years. Here we discuss the clinical case of a young woman who was referred to our institution for this rare disorder and briefly review the literature

Role of PARP, NF-kB and telomerase in necrosis induced by selective methylation of N3-adenine.

Selective methylation of N3-adenine represents a novel pharmacological strategy for the treatment of mismatch repair-deficient tumors, which are tolerant to O6-methylguanine, the main cytotoxic lesion induced by methylating agents of clinical interest such as temozolomide. However, the biochemical pathways involved in cell death induced by N3-methyladenine have not been clarified, yet. In the present study we show that MeOSO2(CH2)2-lexitropsin (Me-Lex), a compound generating almost exclusively N3-methyladenine, provoked poly(ADP-ribosylation), loss of mitochondrial membrane potential, and increase of ROS production in leukemia cell lines with intact or defective mismatch repair system. These events were followed by a marked reduction of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and Nuclear Factor-kB (NF-kB) activity. Moreover, treatment with Me-Lex induced a profound decrease of telomerase in the cytosol that was accompanied by a transient up-regulation of activity in the nucleus. PARP-1 inhibition blocked ADP-ribose polymer formation, preserved mitochondrial membrane integrity and counteracted the reduction of NF-kB activity thus preventing the appearance of necrosis. On the other hand, the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis due to disruption of base excision repair process. In conclusion, the results underline the central and paradoxical role of PARP-1 in cell death induced by N3-methyladenine: effector of necrosis and co-ordinator of methylpurine repair. Supported by: FIRB 2001, PRIN 2003 and NIH grant RO1 CA29088 projects to GG, LT and BG, respectively

Role of PARP, NF-kB and telomerase in necrosis induced by selective methylation of N3-adenine.

Selective methylation of N3-adenine represents a novel pharmacological strategy for the treatment of mismatch repair-deficient tumors, which are tolerant to O6-methylguanine, the main cytotoxic lesion induced by methylating agents of clinical interest such as temozolomide. However, the biochemical pathways involved in cell death induced by N3-methyladenine have not been clarified, yet. In the present study we show that MeOSO2(CH2)2-lexitropsin (Me-Lex), a compound generating almost exclusively N3-methyladenine, provoked poly(ADP-ribosylation), loss of mitochondrial membrane potential, and increase of ROS production in leukemia cell lines with intact or defective mismatch repair system. These events were followed by a marked reduction of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and Nuclear Factor-kB (NF-kB) activity. Moreover, treatment with Me-Lex induced a profound decrease of telomerase in the cytosol that was accompanied by a transient up-regulation of activity in the nucleus. PARP-1 inhibition blocked ADP-ribose polymer formation, preserved mitochondrial membrane integrity and counteracted the reduction of NF-kB activity thus preventing the appearance of necrosis. On the other hand, the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis due to disruption of base excision repair process. In conclusion, the results underline the central and paradoxical role of PARP-1 in cell death induced by N3-methyladenine: effector of necrosis and co-ordinator of methylpurine repair. Supported by: FIRB 2001, PRIN 2003 and NIH grant RO1 CA29088 projects to GG, LT and BG, respectively

Valproic acid increases the stimulatory effect of estrogens on proliferation of human endometrial adenocarcinoma cells

Long-term use of valproic acid (VA), a well-tolerated anticonvulsant agent widely used for treating epilepsia, has been recently shown to inhibit histone deacetylases, which in turn are involved in the regulation of the expression of estrogen receptor alpha (ERalpha) by suppressing gene transcription. Because estrogens are known to increase cell proliferation of human endometrial tumors, in this study we investigated whether treatment with VA may increase the proliferative response of human endometrial adenocarcinoma cells to 17-beta-estradiol through induction of ERalpha. The results clearly show that VA, at concentrations of clinical interest, significantly enhanced the proliferative activity exerted by 17-beta-estradiol in the endometrial adenocarcinoma Ishikawa cell line. Moreover, in these cells treatment with VA resulted in increased ERalpha gene expression. Similar effects of VA on cell proliferation were also observed in an ERalpha-positive breast cancer cell line (MCF7). These findings indicate that VA might favor proliferation of estrogen-dependent human tumors