Proliferation determined by Ki-67 immunohistochemistry has been proposed as a useful prognostic and predictive marker in breast cancer. However, the clinical validity of Ki-67 is questionable. In ...this study, Ki-67 was retrospectively evaluated by three pathologists using two methods: a visual assessment of the entire slide and a quantitative assessment of the tumour margin in 411 early-stage breast cancer patients with a median follow-up of 26.8 years. We found excellent agreement between the three pathologists for both methods. The risk of recurrence for Ki-67 was time-dependent, as the high proliferation group (Ki-67 ≥ 30%) had a higher risk of recurrence initially, but after 4.5 years the risk was higher in the low proliferation group. In estrogen receptor (ER)-positive patients, the intermediate Ki-67 group initially followed the high Ki-67 group, but eventually followed the low Ki-67 group. ER-positive pN0-1 patients with intermediate Ki-67 treated with endocrine therapy alone had a similar outcome to patients treated with chemotherapy. A cut-off value of 20% appeared to be most appropriate for distinguishing between the high and low Ki-67 groups. To summarize, a simple visual whole slide Ki-67 assessment turned out to be a reliable method for clinical decision-making in early breast cancer patients. We confirmed Ki-67 as an important prognostic and predictive biomarker.
High-grade B-cell lymphomas with
and
and/or
rearrangements are known for their aggressive clinical course and so are the ones with MYC and BCL2 protein overexpression. The optimal therapy for these ...lymphomas remains to be elucidated. A retrospective analysis of all diffuse large B-cell lymphomas and high-grade B-cell lymphomas with
and
and/or
rearrangements diagnosed between 2017 and 2021 at the Institute of Oncology Ljubljana, Slovenia, has been performed. Only patients with double-expressor lymphoma (DEL), double-hit lymphoma (DHL), or triple-hit lymphoma (THL) were included. Demographic and clinical parameters were assessed, as well as progression-free survival (PFS) and overall survival (OS). In total, 161 cases out of 309 (161/309; 52,1%) were classified as DEL. Sixteen patients had DHL,
/
rearrangement was observed in eleven patients, and
/
rearrangement was observed in five patients. Five patients were diagnosed with THL. Out of 154 patients (according to inclusion/exclusion criteria) included in further evaluation, one-hundred and thirty-five patients had double-expressor lymphoma (DEL), sixteen patients had DHL, and three patients had THL. In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The median follow-up was 22 months. The 5-year OS for the whole DEL group was 57.1% (95% CI 45.9-68.3%) and the 5-year PFS was 76.5% (95% CI 72.6-80.4%). The log-rank test disclosed no differences in survival between treatment groups (
= 0.712) while the high-risk international prognostic index (IPI) carried a significantly higher risk of death (HR 7.68, 95% CI 2.32-25.49,
= 0.001). The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.
BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer ...syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions,
BAP1
alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline
BAP1
likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in
BAP1
(partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.
Background
High‐grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer, and it is often associated with ascites at presentation. The objective of this study was to ...evaluate the accuracy of cytopathology to identify immunophenotypic features of HGSC and BRCA1/2 mutations from ascites.
Methods
The study included 45 patients with histologically confirmed primary HGSC and malignant ascites. Immunocytochemistry (ICC) staining for PAX8, WT1, P53, P16, and Ki‐67 was performed on cytospins and cytoblocks prepared from ascites. Next‐generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the ascites. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of primary tumor. Cronbach α and χ2 statistics, respectively, were used.
Results
ICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α > 0.75), whereas poor reliability and significant differences were observed for Ki‐67 between ascites and tissue blocks (α < 0.26; p < .001 Kruskal–Wallis). For germline BRCA1/2 mutations, 100% concordance was confirmed, but only 14% concordance was confirmed for somatic mutations.
Conclusions
These results demonstrate that cytopathology is an accurate method for identifying immunophenotypic features of HGSC and detecting germline BRCA1/2 mutations from ascites. However, further investigation is required for assessing the proliferation activity of HGSC in ascites and for detecting somatic BRCA1/2 mutations.
Cytopathological assessment of immunophenotypic features and germline BRCA1/2 mutations of high‐grade serous carcinoma from ascites is comparable to histological assessment of the primary tumor. This approach is valuable when optimal surgical debulking cannot be performed.
Erythroblastic sarcoma (ES) is an extremely rare extramedullary solid tumor of immature erythroid cells, with around a dozen human cases to our knowledge presented so far in the english literature, ...none of the cases presenting as pleural effusion. Here we describe a case of ES in a thoracic wall diagnosed by cytological examination of pleural effusion with histologic correlation in a 53‐year‐old patient with a 10‐month history of myelodysplastic syndrome/myeloproliferative neoplasm with grade III reticulin myelofibrosis.
The aim of the study was to evaluate the independent prognostic role of
activating mutations and an association between
activating mutations and efficacy of adjuvant endocrine therapy (ET) in ...patients with operable invasive lobular carcinoma (ILC).
A single institution study of patients with early-stage ILC treated between 2003 and 2008 was performed. Clinicopathological parameters, systemic therapy exposure and outcomes (distant metastasis-free survival DMFS and overall survival OS) were collected based on presence or absence of PIK3CA activating mutation in the primary tumor determined using a quantitative polymerase chain reaction (PCR)-based assay. An association between PIK3CA mutation status and prognosis in all patient cohort was analyzed by Kaplan-Meier survival analysis, whereas an association between PIK3CA mutation and ET was analyzed in estrogen receptors (ER) and/or progesterone receptors (PR)-positive group of our patients by the Cox proportional hazards model.
Median age at diagnosis of all patients was 62.8 years and median follow-up time was 10.8 years. Among 365 patients, PIK3CA activating mutations were identified in 45%. PIK3CA activating mutations were not associated with differential DMFS and OS (p = 0.36 and p = 0.42, respectively). In patients with PIK3CA mutation each year of tamoxifen (TAM) or aromatase inhibitor (AI) decreased the risk of death by 27% and 21% in comparison to no ET, respectively. The type and duration of ET did not have significant impact on DMFS, however longer duration of ET had a favourable impact on OS.
PIK3CA activating mutations are not associated with an impact on DMFS and OS in early-stage ILC. Patients with PIK3CA mutation had a statistically significantly decreased risk of death irrespective of whether they received TAM or an AI.
Chronic lymphocytic leukemia (CLL) typically pursues a prolonged course. Its transformation into a more aggressive lymphoma occurs in 2-8% of all patients. Most commonly, diffuse large B-cell ...lymphoma develops. Transformation into a classical Hodgkin's lymphoma (cHL) occurs in <1%. Plasmablastic transformation has been only rarely reported. Cases of synchronous divergent transformation of CLL into a composite lymphoma are exceedingly rare. We describe the unique occurrence of the transformation of a long-standing CLL into a synchronous clonally related cHL as well as plasmablastic lymphoma (PBL) in an 85-year-old female patient. After 10 years of asymptomatic CLL, our patient was treated with a rituximab-chlorambucil scheme in combination with pegfilgrastim for recurrent infections and the development of B symptoms. Five cycles (of six planned) were administrated with no adverse effects. After the fifth cycle, lymphadenopathy with pronounced B symptoms appeared. Histology showed the presence of cHL in the lymph node, while the bone marrow was infiltrated by PBL. Our patient died in sepsis not receiving further specific oncologic treatment due to her poor general condition. Additional cytogenetic and molecular studies showed that this was a case of mutated CLL with trisomies of chromosomes 12, 3, and 18 (a rare specific +12 plus other-non+19 CLL subgroup). The presence of trisomy 12 has also been proved in plasmablasts and in cHL cells.
Background To overcome obstacles within the Slovenian organised cervical cancer screening programme, a randomised pilot study of human papillomavirus (HPV) self-sampling among non-attenders was ...performed, aiming to assess three different screening approaches. Participants and methods Non-attenders aged 30-64 years from two Slovenian regions were randomised to two HPV self-sampling groups-the opt-in (I1, n = 14.400) and the opt-out (I2, n = 9.556), with a control group (P, n = 2.600). Self-collected samples were analysed using the Hybrid Capture 2 assay. HPV-positive women were invited to a colposcopy. The overall and type-specific intention-to-screen response rates and histological outcomes with a positive predictive value (PPV) according to the women's age, the screening approach, the level of protection resulting from previous screening history, and the region of residence were assessed. Results Of the 26.556 women enrolled, 8.972 (33.8%) responded with self-sample for HPV testing and/or traditional cytology within one year of enrolment. Response rates were 37.7%, 34.0% and 18.4% (p < 0.050) for opt-out, opt-in and control groups. Cervical intraepithelial neoplasia (CIN)2+ was diagnosed in 3.9/1.000, 3.4/1.000, and 3.1/1.000 women (p > 0.050), respectively. PPV of the HPV self-sampling was 12.0% and 9.6% for CIN2+ and CIN3+. The highest PPV was obtained in non-attenders in screening programme for more than 10-years and concordant results of HPV testing with 40.8% for CIN2+ and 38.8% for CIN3+. Conclusions The results of our study show that a high response to HPV self-sampling can be achieved also in an opt-in approach, if women are encouraged to choose between self-sampling at home and screening with gynaecologist. In addition, clinically important risk difference for a high-grade cervical lesion exists in the case of a positive result of HPV testing on self-collected samples, depending on the length of the interval since last screening. Stratified management of these women should be strongly considered. Women who were not screened with cytology for at least 10 years should be referred to immediate colposcopy for histology verification instead to delayed re-testing.
For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine ...(5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects.
5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC.
5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27
, resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27
led to G2/M accumulation. Finally, we observed a decrease in MMP-2 levels, a stimulator of HCC cell migration. Aza effects were confirmed in the mouse model; in the zebrafish model, we also demonstrated the downregulation of tumor neo-angiogenesis, and in the orthotopic rat model, we observed impaired N1-S1 grafting in a healthy liver.
We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27
/MMP-2 in HCC.
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