Patients' experiences following breast cancer treatment: an exploratory survey of personal and work experiences of breast cancer patients from three European countries.

Improved treatments for early breast cancer have led to a significant increase in overall survival. While evidence regarding potential long-term sequelae of adjuvant treatments exists, relatively little research reports patients' own perceptions of change before and after adjuvant chemotherapy (AC). This study aimed to identify key ongoing issues associated with AC in daily life. An online survey developed for this study was completed by 198 women (mean age 49.7 years) in the UK, France and Germany who had AC 1-5 years previously for oestrogen receptor positive, HER2 negative early breast cancer. Women without AC and endocrine therapy, those treated with Trastuzumab or who had recurrent disease were excluded. A third of women who responded were currently unable to perform their former family role. The majority had needed support, particularly with child care, during treatment. While 54% were in full-time employment before diagnosis this had reduced to 32% following AC. Of those women still working, over half reported difficulties with tiredness or concentration. Most (85.8%) were satisfied with healthcare professionals' treatment information, but only 29.7% received information about returning to work. This exploratory survey highlights areas of women's lives affected 1-5 years following AC for early breast cancer. The impact on returning to work and issues surrounding childcare particularly, require further study.

Game changer in cancer treatment in Switzerland.

BACKGROUND: It is time for a game-changer in the cancer pathway in Switzerland and around the world. COVID-19 has made this more evident than ever. The prevalence, complexity, and cost of cancer care are increasing in Switzerland. Losses in efficiency, resources, and inappropriate attribution hinder health outcomes. This study examined opportunities for improvement across the cancer path, with a focus on patient-provider communication, effective policies and approaches to strengthen interprofessional collaboration. METHODS: A qualitative study was undertaken. Key stakeholders, selected on the basis of their expertise in different areas of the cancer pathway, were assessed through interviews. The need to develop and implement innovative strategies to prevent and treat cancer was investigated, and key recommendations were identified for discussion with politicians and policy makers. Inductive content analysis was conducted. RESULTS: There is a prominent need for collaboration and cross-sectoral action in cancer, encompassing clinical disciplines, communication strategies, and professional attitudes. The need and demand for collaboration responds to a highly fragmented cancer landscape in Switzerland, with a hierarchical organization of medical care entities and much competition. COVID-19 made these gaps more visible and highlighted the need to develop a new systematic approach and contingency plan to protect the most vulnerable. CONCLUSION: Pressing developments are occurring in the health care system given the increasing prevalence of some cancers, the demographics of the Swiss population, the growing number of cancer survivors, and the consequences of the COVID-19 pandemic. POLICY SUMMARY: More fundamental solutions and policies should be developed and implemented to meet patient needs and increase health outcomes: are providers and patients taking responsibility for change? Will business interests and the power play boycott policy development? Change must start now, with policymakers, patients, providers and insurers joining forces.

Microdomain-dependent regulation of Lck and Fyn protein-tyrosine kinases in T lymphocyte plasma membranes.

Src family protein-tyrosine kinases are implicated in signaling via glycosylphosphatidylinositol (GPI)-anchored receptors. Both kinds of molecules reside in opposite leaflets of the same sphingolipid-enriched microdomains in the lymphocyte plasma membrane without making direct contact. Under detergent-free conditions, we isolated a GPI-enriched plasma membrane fraction, also containing transmembrane proteins, selectively associated with sphingolipid microdomains. Nonionic detergents released the transmembrane proteins, yielding core sphingolipid microdomains, limited amounts of which could also be obtained by detergent-free subcellular fractionation. Protein-tyrosine kinase activity in membranes containing both GPI-anchored and transmembrane proteins was much lower than in core sphingolipid microdomains but was strongly reactivated by nonionic detergents. The inhibitory mechanism acting on Lck and Fyn kinases in these membranes was independent of the protein-tyrosine phosphatase CD45 and was characterized as a mixed, noncompetitive one. We propose that in lymphocyte plasma membranes, Lck and Fyn kinases exhibit optimal activity when juxtaposed to the GPI- and sphingolipid-enriched core microdomains but encounter inhibitory conditions in surrounding membrane areas that are rich in glycerophospholipids and contain additional transmembrane proteins.

Somatic mutations detected by mini- and microsatellite DNA markers reveal clonal intratumor heterogeneity in gastrointestinal cancers.

We investigated clonal intratumor heterogeneity by comparing different areas of each tumor in 20 gastrointestinal cancers from female patients (1 esophageal cancer, 5 stomach cancers, and 14 colorectal cancers). In all 19 cases informative for X-inactivation analysis with the M27 beta and/or the phosphoglycerate kinase probes, the tumors were clonal. Separate areas from a given tumor showed identical X-inactivation patterns, providing evidence for its single-cell origin. Of 20 cancers, 11 showed p53 gene mutations (base pair insertions, point mutations, and one case of a base pair deletion) in exons 5-8. A particular p53 gene mutation was identical in all tumor areas investigated per case. The minisatellite probes detected loss of heterozygosity or new mutant alleles at 1p33, 1q21, 5q35, 17p13, or 18q21. In seven cases mutations at particular loci were restricted to one or two areas per tumor, while in another seven cases they were common to all tumor areas. Loss of heterozygosity or new alleles detected at the microsatellite loci D2S123, D3S1611, D5S107, D17S261, or D18S34 [(CA)n repeats] were common to all tumor areas in 7 of 19 cases. In another seven cases, however, microsatellite mutations at these loci were restricted to one to three areas per tumor. Tracing clonal intratumor heterogeneity would permit one to study the hierarchy of mutational events in cancers where no premalignant lesions can be harvested. Most important, our study indicates that clonal intratumor heterogeneity might lead to sampling errors in the molecular diagnosis of cancer biopsy specimens when using mini- or microsatellite markers.

Aberrant FHIT mRNA transcripts are present in malignant and normal haematopoiesis, but absence of FHIT protein is restricted to leukaemia.

Aberrant FHIT mRNA transcripts are present in malignant and normal haematopoiesis, but absence of FHIT protein is restricted to leukaemia Alterations of the recently cloned fragile histidine triad (FHIT) gene at chromosome 3p14.2 are frequent in a variety of solid tumours and cancer cell lines. Based on these findings, FHIT has been proposed as a putative tumour-suppressor gene. We evaluated the mRNA expression of the FHIT gene in samples from 55 patients with various haematological malignancies (21 AML, 8 CML, 10 CLL, seven low-grade and nine high-grade Non-Hodgkin's lymphomas), in a panel of 16 leukaemia cell lines, in normal mature haematopoietic cells of both myeloid and lymphoid lineage, as well as in CD34+ haematopoietic progenitor cells. Aberrant FHIT mRNA transcripts were observed in 14/16 (88%) leukaemia cell lines, 43/55 (78%) primary haematological neoplasms, but also in 17/22 (77%) normal controls. 1/16 (6%) cell lines and 7/55 (13%) neoplasms did not express any FHIT mRNA. cDNA sequencing revealed exonic deletions, small DNA insertions and combinations of both. Analysis of genomic DNA showed gene deletions in two myeloid leukaemia cell lines. In contrast to all normal types of haematopoietic cells, FHIT protein was clearly reduced or absent in 8/18 (44%) neoplastic samples tested. Our data indicate that whilst aberrant FHIT mRNA transcripts are seen both in normal and malignant cells, lack of FHIT protein is restricted to leukaemia. Absent FHIT protein expression might contribute to leukaemogenesis.

Parathyroid localization.

Twenty-nine consecutive patients with suspected primary hyperparathyroidism were examined preoperatively using ultrasound, sonographically guided fine needle aspiration, and aspirate immunostaining for PTH. In 25 patients, localization of enlarged parathyroid glands was successful. In 2 patients, the tumors were located retrosternally and, thus, could not be detected by ultrasound. One patient had a multinodular goiter which impeded localization. In 1 patient with renal osteodystrophy, 2 enlarged parathyroid glands in the neck were not visualized preoperatively. Cytology was not diagnostic, although some cytological features were suggestive of parathyroid cells. Immunostaining of the aspirated smears for PTH, however, correctly diagnosed all preoperatively localized lesions. Ultrasound should be the routine procedure of choice for preoperative localization of abnormal parathyroid glands in primary hyperparathyroidism. Fine needle aspiration and immunocytochemistry can supply confirmation, if necessary.

Cerebral vasculitis during FK 506 treatment in a liver transplant patient.

The immunosuppressive agent FK 506 is widely used in liver transplant patients. Neurotoxicity is a major complication of its use. We report progressive and irreversible neurologic complications occurring in a 39-year-old woman who underwent liver transplantation and was treated with FK 506. Neuropathologic examination revealed multiple vasculitic lesions. The possibility of an FK 506-mediated toxic effect on the cerebral vessels is suggested.

A multicenter study of treatment of primary CNS lymphoma.

OBJECTIVE: To characterize the therapeutic variables correlated to outcome in 370 patients with primary CNS lymphoma. METHODS: Planned treatment was radiotherapy (RT) in 98 patients, chemotherapy (CHT) in 32, RT followed by CHT in 36, and CHT followed by RT in 197 patients. High-dose methotrexate (HD-MTX; 1 to 8 g/m2) was used in 169 patients and intrathecal CHT in 109. RESULTS: One hundred sixteen patients are alive (median follow-up 24 months), with a 2-year overall survival of 37%. Patients treated with CHT followed by RT had improved survival with respect to patients treated with RT alone. Patients receiving HD-MTX-based primary CHT survived longer than those treated with other drugs. HD-MTX associated with other cytostatics, in particular HD-cytarabine, produced better results than HD-MTX alone. No correlation between MTX dose and survival was found. In patients receiving HD-MTX, consolidation RT or intrathecal CHT did not improve survival. Age, performance status, lactate dehydrogenase serum level, CSF protein level, site of disease, and use of HD-MTX were all predictors of survival. CONCLUSIONS: Combination CHT-RT is superior to RT alone. Patients treated with primary CHT containing HD-MTX exhibited improved survival. In these patients, the addition of HD-cytarabine was associated with a better survival, whereas intrathecal CHT was not correlated to outcome. RT may be unnecessary in patients achieving complete remission after receiving HD-MTX-based primary CHT.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Protothecosis in an HIV-positive patient.

This is the first report of localized tendosynovial human protothecosis in an HIV-positive host. The lesion appeared as a nodule in the extensor face of the thumb. A simple excision was performed, and histology confirmed numerous granulomas, some with central fibrinoid necrosis. Enormous numbers of prototheca were found in periodic acid-Schiff and Gömöri methenamine silver strains, evidencing endosporulation with diagnostic morula- or daisy-like sporangia. The presence of prototheca species was confirmed by direct immunofluorescence with the specific conjugate. The cellular response estimated by the relative number of polymorphonuclear leukocytes, lymphocytes, and plasma cells was minimal, although granuloma formation was unaffected. The infective agents were found either extracellular or harbored by macrophages and giant cells.

Recurrent cutaneous anaplastic large cell (CD30+) lymphoma associated with Epstein-Barr virus. A case report with 9-year follow-up.

CD30-positive large cell cutaneous T-cell lymphomas are known to be associated with the human T-cell leukemia/lymphoma virus type I. We present a case of anaplastic large cell lymphoma that recurred three times during 9 years at different sites. Molecular studies [polymerase chain reaction (PCR), in situ hybridization] showed Epstein-Barr virus (EBV) genome in biopsy samples of this first reported case of EBV-associated cutaneous anaplastic large cell lymphoma. This case was human T-lymphotropic virus-1 and -2 negative by PCR. The results add some evidence to the hypothesis that EBV may be a factor in the pathogenesis of cutaneous lymphoproliferative lesions.

Primary hepatic diffuse large B-cell lymphoma in a patient with chronic hepatitis C.

Epidemiological and experimental data suggest that the hepatitis C virus infection might be associated with the development of distinct types of non-Hodgkin's lymphomas. Here, we report a case of a patient with chronic hepatitis C and type II mixed cryoglobulinemia, who developed a primary hepatic non-Hodgkin's B-cell lymphoma. A diffuse, large B-cell lymphoma was diagnosed based on morphological, immunophenotypical and molecular genetic findings. Hepatitis C virus replication, as evaluated by strand-specific reverse transcriptase-polymerase chain reaction, was detected in the nonneoplastic liver, but not in the lymphomatous tissue. High grade non-Hodgkin's lymphomas, although rare complications, have to be considered as part of the spectrum of hepatitis C virus-related hepatic lesions.

Traumatic neuroma with biliary duct obstruction after orthotopic liver transplantation.

BACKGROUND: Traumatic neuromas may develop after injury to nerve fibers encased in Schwann cells. The incidence of symptomatic neural tumors appears to be low after orthotopic liver transplantation (OLT). Only two cases of biliary stricture caused by infiltrating traumatic neuroma have been described previously. METHODS: We report two new cases of biliary tract obstruction after OLT that failed to respond to percutaneous balloon dilatation and were corrected by a resection of the bile duct stricture followed by biliary reconstruction with a Roux-en-Y jejunal loop. RESULTS: The first patient (17 months after OLT) had a traumatic neuroma appearing as a distinct mass with nerve bundles confirmed histologically; the traumatic neuroma in the second patient (5 months after OLT) was a nerve stump with infiltration of nervous elements in the bile duct. Both patients recovered without complications. CONCLUSIONS: Traumatic neuromas should be considered in the differential diagnosis of late biliary stricture after OLT, in particular when not responding to percutaneous dilatation or stenting.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase immunohistochemical expression in lymphoid tissue and lymphoid malignancies.

The catabolic enzyme thymidine phosphorylase (TP) plays a crucial role in nucleic acid metabolism by regulating the availability of thymidine. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that was recently shown to be TP. The angiogenic properties of PD-ECGF/TP are attributable to a reduction of thymidine levels that results in a promotion of endothelial cell proliferation. Early studies showed a higher concentration of TP in macrophages than in parenchymal cells and in neoplastic than in nonneoplastic tissues. We examined the immunohistochemical expression of PD-ECGF/TP in reactive lymphoid tissues (lymph node and tonsil), as well as in a series of 20 cases of Hodgkin's disease and 31 cases of non-Hodgkin's lymphomas. Macrophages, sinus lining cells, and cells with dendritic morphology, of both follicular dendritic and interdigitating reticular cell type, presented a prominent nuclear and cytoplasmic positivity in reactive lymphoid tissue and in malignant lymphomas. Small lymphocytes and the neoplastic population were always negative, whereas endothelial staining was variable and showed no correlation to the type or grade of the lymphomas. In Hodgkin's disease (with the exception of the nodular lymphocyte predominance type) and some cases of high-grade non-Hodgkin's lymphomas, the positive dendritic cells formed a dense meshwork closely surrounding the neoplastic population. Our results suggest that the reported upregulation of PD-ECGF/TP activity in lymphoid malignancies is attributable to the nonneoplastic population, especially to cells of dendritic morphology.

Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin.

Primary cutaneous B-cell lymphomas have been associated with Borrelia burgdorferi, the spirochete responsible for Lyme disease. Recently, cutaneous marginal zone B-cell lymphoma has been proposed as a distinct clinical-pathological entity. We report a case of primary cutaneous marginal zone lymphoma, associated with B burgdorferi infection. Polymerase chain reaction (PCR) amplification of the third complementarity determining region (CDR3) of the immunoglobulin heavy chain gene showed the presence of a monoclonal lymphoproliferation, therefore strengthening the histological diagnosis of a malignant process. B burgdorfer-specific hbb gene sequences were detected by PCR in the lymphoma tissue at diagnosis but not after antibiotic treatment. A nearly complete clinical and histological regression was observed after B burgdorferi eradication, with immunohistochemistry studies showing disappearance of plasma cell differentiation and a marked decline in the number of CD3+ T cells and Ki-67+ cells. Our case confirms the link between B burgdorferi and some cutaneous lymphomas. The disappearance of the microorganism accompanied by the unequivocal decrease of most indicators of active T- and B-cell immune response strongly supported a pathogenetic role for B burgdorferi in sustaining an antigen-driven development and growth of this cutaneous marginal zone lymphoma. Antibiotic therapy (analogous to Helicobacter pylori infection in gastric MALT lymphoma) might be helpful with the aim of averting or at least deferring the indication for more aggressive treatment.

Epstein-Barr virus-associated anaplastic large cell lymphoma in renal transplant patients.

A novel association, Epstein-Barr virus-positive Ki-1+/CD30+ anaplastic large cell non-Hodgkin's lymphoma of B-cell phenotype in immunosuppressed renal transplant recipients is reported. Case 1 involved an aggressive clinical evolution, whereas case 2 followed a more "benign" clinical course. Both lymphomas were Epstein-Barr virus-positive as assessed by in situ hybridization, Southern blot, polymerase chain reaction, and immunohistochemical analysis. Both lymphomas contained a single clonal Epstein-Barr virus terminal-repeat fragment. In case 1, clonality was confirmed by the detection of bi-allelic immunoglobulin (Ig) heavy chain gene rearrangement. Case 2 showed germline Ig genes at presentation and oligoclonal Ig heavy chain gene rearrangements at relapse. These results are consistent with the notion that anaplastic large cell lymphoma might arise in a B cell transformed by Epstein-Barr virus at a very early stage, before Ig gene rearrangement. The latter may occur later in the course of clonal evolution, thus permitting investigators to trace intermediate and late stages within a process of multistep lymphomagenesis and/or tumor progression.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Consistency of staining and reporting of oestrogen receptor immunocytochemistry within the European Union--an inter-laboratory study.

To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.