Effect of a multilevel implementation programme on shared decision-making in breast cancer care.

BACKGROUND: Women with newly diagnosed breast cancer face multiple treatment options. Involving them in a shared decision-making (SDM) process is essential. The aim of this study was to evaluate whether a multilevel implementation programme enhanced the level of SDM behaviour of clinicians observed in consultations. METHODS: This before-after study was conducted in six Dutch hospitals. Patients with breast cancer who were facing a decision on surgery or neoadjuvant systemic treatment between April 2016 and September 2017 were included, and provided informed consent. Audio recordings of consultations made before and after implementation were analysed using the five-item Observing Patient Involvement in Decision-Making (OPTION-5) instrument to assess whether clinicians adopted new behaviour needed for applying SDM. Patients scored their perceived level of SDM, using the nine-item Shared Decision-Making Questionnaire (SDM-Q-9). Hospital, duration of the consultation(s), age, and number of consultations per patient that might influence OPTION-5 scores were investigated using linear regression analysis. RESULTS: Consultations of 139 patients were audiotaped, including 80 before and 59 after implementation. Mean (s.d.) OPTION-5 scores, expressed on a 0-100 scale, increased from 38.3 (15.0) at baseline to 53.2 (14.8) 1 year after implementation (mean difference (MD) 14.9, 95 per cent c.i. 9.9 to 19.9). SDM-Q-9 scores of 105 patients (75.5 per cent) (72 before and 33 after implementation) were high and showed no significant changes (91.3 versus 87.6; MD -3.7, -9.3 to 1.9). The implementation programme had an association with OPTION-5 scores (ß = 14.2, P < 0.001), hospital (ß = 2.2, P = 0.002), and consultation time (ß = 0.2, P < 0.001). CONCLUSION: A multilevel implementation programme supporting SDM in breast cancer care increased the adoption of SDM behaviour of clinicians in consultations.

Learning Aspects in Implementing Vitrification Program Using Mouse Blastocysts.

BACKGROUND: Oocyte vitrification is important for fertility preservation. There are debates, however, surrounding the components of the procedure itself. OBJECTIVE: before starting a vitrification program, we decided to (1) determine if blastocysts derived from previously frozen mouse embryos would be suitable to practice vitrification and (2) to analyze the factors that contributed to improving our "learning curve". MATERIALS AND METHODS: 58 expanded blastocysts cultured from commercially available frozen 1-cell mouse embryos (B6D2F1 x B6C3F1) were used. Embryos were vitrified, during 2 separate attempts, in a closed device (Cryopette) and vitrified and warmed using Ethylene Glycol-cryoprotectant vitrification kit (Vitrification Attempt 1 and 2 - VA1 and 2; Warming Attempt 1 and 2 - WA1 and 2). Differences in attempts by more focusing on the reaction of the embryo itself. The survival rate (SR) of embryos was evaluated immediately after warming (T0), then rinsed and cultured for 24 hours in an HTF-like medium (Cleavage Medium - Sage; Cooper Surgical; U.S.A.). Additional evaluations were done at 2 and 24 hours of culture (T2 and T24, respectively). RESULTS: The combined SR for both attempts were 70.6, 60.3 and 34.4% at T0, T2 and T24, respectively. Embryo loss was significantly higher in WA1 compared to WA2 (30.8 versus 10.1%; p=.05). The SR at T0 after VA1 and VA2 were similar (90.9 versus 80.9%) and the SR after VA1+WA1 versus VA1+WA2 was 55.6 vs. 76.9% at T2 and 22.2 vs. 61.5% at T24, respectively (NS). CONCLUSION: Commercially frozen mouse embryos can provide essential information for initiating a Vitrification Program applicable to human embryos and oocytes. Practice is critical, particularly Warming, which can provide the confidence needed to adapt and optimize these protocols before vitrifying limited human tissues or gametes.

Factors associated with frequency of discussion of or referral for counselling about fertility issues in female cancer patients.

Current practices in counselling of female cancer patients with respect to fertility issues need considerable improvement, particularly given the general underuse of fertility preservation options and the negative impact that infertility can have on quality of life. We investigated the relationship between physicians' and physician-related factors and the frequency of physicians discussing fertility issues and referring to a reproductive specialist. We invited 1,832 physicians in the Netherlands who had treated at least five reproductive-age female cancer patients within the past year to complete a questionnaire. Of the 748 respondents, 406 met our inclusion criteria, and 280 participated. Analysis revealed that 79% of the participants usually or always discuss fertility issues. Specialty, confidence in knowledge regarding fertility issues and a lack of reproductive specialists in their region contributed independently to the variance in the frequency of discussing fertility issues. Moreover, 54% either regularly or always refer. Specialty and frequency of discussion contributed independently to the variance in referral. In conclusion, although high, frequency of discussion of fertility issues is not optimal, and referral seems limited. Patients would benefit from more knowledge among physicians regarding fertility issues and referral options, both in terms of informed choice, and more importantly, quality of life.

Practice, attitude and knowledge of Dutch paediatric oncologists regarding female fertility.

BACKGROUND: Chemotherapy and radiotherapy for childhood cancer can result in a decreased reproductive function. It is therefore important that paediatric oncologists discuss the possible impact of treatment on female fertility and available fertility preservation options with their patients. However, it is unknown what Dutch paediatric oncologists know about of the effect of cancer treatment on female fertility, whether or not they address this issue in clinical practice, what their attitudes are towards addressing fertility after cancer treatment and fertility preservation options, and to what extent they require additional information resources. METHODS: In this nationwide quantitative cross-sectional study a survey was sent to all registered paediatric oncologists in the Netherlands (n=64). RESULTS: Thirty-seven paediatric oncologists participated (participation rate 58%). Fertility issues were discussed with patients and/or parents by 97%. Of the paediatric oncologists, 54-76% were aware of possibilities for fertility preservation; however only <25% reported a moderate or high confidence in their knowledge of these techniques. Paediatric oncologists stated that they had little resources to counsel their patients and 92% found educational resources not completely sufficient. CONCLUSION: Paediatric oncologists are well aware of the effect that cancer treatment may have on female fertility and their responsibility to counsel their patients and/or the parents on this issue. They do not (yet) possess the knowledge to sufficiently counsel these patients and, if needed, do not frequently refer them to a fertility specialist.

[Fertility preservation in female oncology patients]. / Fertiliteitspreservatie bij vrouwen met kanker.

Four women were referred to the department ofGynaecology for fertility preservation. A 33-year-old nulliparous woman with breast cancer stage pT1cN0M0 underwent an IVF-ICSI cycle; five embryos were frozen. Pre-implantation genetic diagnosis (PGD) because of BRCA2 gene mutation carriage was not carried out and more recently follow-up oocyte donation options are being considered. A second, 32-year-old nulliparous woman with breast cancer stage pT2N1M0 underwent an IVF cycle; seven embryos were frozen. The third patient was a 14-year-old girl with osteosarcoma of the distal femur, who underwent a laparoscopic unilateral ovariectomy, one day after referral, and cortical tissue was frozen. The fourth patient was a 33-year-old nulliparous woman without partner, with non-Hodgkin lymphoma stage IIA. She underwent laparoscopic ovariectomy and cortical tissue was frozen. Infertility due to cancer treatment and fertility preservation options should be discussed early in treatment planning. Patients' expectations and fertility preservation limitations are important to consider. Fertility preservation options can be conducted in specialised hospitals under institutional review board approval. It still has an experimental status.

[The consequences of postponing pregnancy]. / Gevolgen van uitstel van zwangerschap.

The postponement of childbearing is determined by societal factors and is related to the fact that it is often difficult for women to combine an education, a job or a career with having children and taking care of a family. Especially gynaecologists are increasingly confronted with women who undergo the medical consequences of such postponement. Postponing the first pregnancy is accompanied by an increased risk of unwanted infertility. If women do succeed in becoming pregnant later in life, there is an increased risk of complications during pregnancy and delivery. The child runs a greater risk of chromosomal aberrations and of mental and physical handicaps related to increased numbers of premature births and fertility treatments. All these problems begin to increase after age 30, but especially after age 35. Finally, the risk of breast cancer is also increased if a woman delays the birth of her first child or remains childless.

Association of allele-specific HLA expression and histopathologic progression of cervical carcinoma.

Immunohistochemical studies have shown that loss of HLA expression is observed in cervical carcinomas but not in premalignant CIN lesions, indicating that downregulation of HLA is linked to tumor progression. The present study was performed to investigate whether the degree of HLA expression in cervical cancer correlates with more advanced disease as defined by histopathological features. Frozen tissue sections from 49 patients with squamous carcinoma of the cervix FIGO stage IB to IIB were stained with HLA class I monomorphic, locus- and allele-specific monoclonal antibodies. Histological data indicative of local disease, i.e., depth of invasion, tumor size, stage, and systemic spread of the disease, such as tumor-positive lymph nodes, were collected by reviewing the histological slides. Univariate analysis revealed that loss of HLA-A locus and A2-allele expression showed a positive, significant correlation with both presence of tumor-positive lymph nodes (P = 0.04 and 0.02, respectively) and the number of lymph nodes involved (both P = 0.04). These results strongly support the idea that, specifically in an immunogenic cancer type such as cervical cancer, tumor cells escape immunosurveillance and gain growth advantage by allele-specific downregulation of the HLA-A2 molecule. In view of the development of immunotherapeutical interventions in cancer, upregulation of HLA class I molecules may prove to be a useful additional tool in the combat against immunogenic tumors.

HLA expression and tumor-infiltrating immune cells in uveal melanoma.

BACKGROUND: In uveal melanoma, both the amount of tumor-infiltrating cells and the level of expression of HLA antigens are quite variable. We hypothesized that low levels of HLA expression lead to a lack of antigen presentation, which might prevent proper immunologic recognition of the tumor. This lack of recognition might subsequently lead to low levels of tumor-infiltrating cells. METHODS: To test this hypothesis, we determined the type and number of tumor-infiltrating cells in tumor sections from 24 uveal melanomas. We applied monoclonal antibodies directed against different types of immune cells and compared the results with the expression of HLA class I and class II antigens on the tumor cells. RESULTS: Infiltrating immune cells were observed in all uveal melanomas (although in small amounts), with a predominance of T lymphocytes. Significant positive correlations were observed between the number of CD3+ cells (T lymphocytes) and monomorphic HLA class I expression, allele-specific HLA-A2 and Bw4 expression, and HLA class II expression. Furthermore, the number of CD4+ cells (T helper cells, monocytes/ macrophages) and of CD11b+ cells (monocytes/macrophages) was significantly correlated with the level of monomorphic HLA class I expression. CONCLUSION: These data support our hypothesis that low levels of HLA expression (and therefore a lack of presentation of tumor-specific antigens) may lead to a low level of tumor infiltrate.

Differential expression of HLA-A and B-alleles on uveal melanoma as determined by immuno-histology.

HLA molecules play an important role in the presentation of antigens to the immune system, including tumor-specific antigens. Uveal melanomas vary in the level of expression of monomorphic HLA molecules. However, since the HLA system is polymorphic and since antigen-presentation may be linked to the expression of specific HLA alleles, the authors wondered whether allelic differences in expression existed on uveal melanomas. In order to test this, tissue sections from 23 uveal melanomas were stained in an indirect immunoperoxidase technique with monoclonal antibodies against monomorphic and polymorphic determinants of HLA molecules. All uveal melanomas showed a high level of expression of the monomorphic determinants of HLA-Class I. The polymorphic HLA-Class I molecules A2, A3, Bw4 and Bw6 varied in expression, with a higher expression of HLA-A than of HLA-B. A low level of expression of both ß2-microglobulin and HLA-B locus products was associated with a large tumor diameter. Expression of HLA-Class II molecules was low (0 to 35%). The observation that expression of the HLA-A allelic products was higher than of the HLA-B subtypes may have implications for the search of tumorspecific peptides for immunotherapeutic use: it may be worthwile to select peptides that specifically bind to HLA-A and not to HLA-B.

Altered HLA expression by metastatic cervical carcinoma cells as a factor in impaired immune surveillance.

The altered expression of histocompatibility leukocyte antigens (HLA) in the development to cervical carcinoma suggests that tumor progression may be related to impaired recognition by host immune defense mechanisms. To investigate whether this phenomenon plays a role in the process of metastasis of cervical cancer, we analyzed and compared the HLA expression with the number of infiltrating immune cells in primary cervical carcinoma and related autologous metastases (n = 30) by staining serial paraffin and corresponding frozen sections with a panel of monoclonal antibodies. In 60% of the cervical metastases, compared to 21% of the primary tumors, a downregulation of monomorphic HLA class I antigens was observed, with frequent allele-specific alterations. In 50% the HLA class II expression was slightly increased on the metastatic tumor cells in comparison to the primary tumor. In addition, variability of alterations in HLA expression was observed between different metastases in the same patient. A minor infiltration of immune cells was present in cervical metastases compared to the primary tumors, especially in the HLA class I-downregulated metastases. Furthermore, loss of HLA class I expression on the metastatic tumor cells resulted in a significant decrease of tumor-infiltrating CD8+ T lymphocytes. These findings suggest that in cervical carcinoma loss of HLA class I expression plays a decisive role in the escape from immune surveillance leading to a greater metastatic potential of tumor cells.

Isolation and characterization of tumor-infiltrating lymphocytes from cervical carcinoma.

The evidence that virus-induced tumors generally elicit T-cell responses prompts the notion that HPV-related cervical carcinoma would be amenable to treatment by T-cell-mediated adoptive therapy. Therefore, we cultured and cloned tumor-infiltrating lymphocytes (TIL) from a patient with cervical carcinoma and studied the in vitro characteristics of these TIL by using the established autologous tumor-cell line. After stimulation of bulk TIL cultures with 1,000 Units/ml recombinant interleukin 2 (rIL-2), followed by limiting dilution, T-cell clones were generated in the presence of 20 U/ml rIL-2 and irradiated autologous tumor cells, PBLs and EBV-transformed B-cell lines. Phenotypically, all clones were CD3/CD8-positive with a heterogeneous CD56 expression. All expressed preferential cytolytic activity against autologous tumor cells, did not lyse autologous lymphoblasts, and were cytotoxic against the NK-sensitive cell line K562. A minor lytic capacity was detectable on allogeneic cervical tumor-cell lines or tumor-cell lines of other histologic types. Cytotoxicity against the autologous tumor could be inhibited by anti-CD3, anti-CD8 and anti-ICAM1 but not by anti-HLA class-1 (W6/32, B9.12.1), anti-allele-specific HLA determinants and anti-LFA-3 antibodies. We demonstrate a highly specific autologous lytic activity of cervical carcinoma TIL, in which a CD3-associated surface antigen recognition is involved. These results may prove useful in further studies on adoptive immunotherapy of cervical cancer patients.

The expression of histocompatibility-related leukocyte antigens in the pathway to cervical carcinoma.

The major histocompatibility complex probably plays a crucial role in the efficacy of the cellular immune response against virally infected cervical diseases. Therefore, the allele-specific histocompatibility-related leukocyte antigens (HLA) class I and II expression on normal (n = 10), premalignant (n = 25), and malignant cervical tissue (n = 30) was investigated. No alterations in monomorphic or locus/allele-specific HLA class I or II expression were observed in normal and premalignant epithelial tissue. In cervical carcinomas, however, a reduced expression of HLA class I antigens was present in 70% of the cases, comprising a monomorphic class I loss in 20%, and an allele-specific loss in 50% of HLA-A2-, 66% of A3-, 56% of Bw4-, and 37% of Bw6-positive patients. De novo expression of class II antigens was observed in 80% of the cervical carcinomas, with the sublocus products being expressed in the order HLA-DR > HLA-DQ > HLA-DP. The authors' results show that alteration in HLA expression is a process confined to malignant cells, which may allow tumors to evade immune surveillance. In addition, these findings have to be considered as new strategies of immunotherapy using cytotoxic T lymphocytes are developed.

Association between HLA-expression and infiltration of immune cells in cervical carcinoma.

BACKGROUND: To determine the degree of specificity of the cellular immune response in cervical carcinoma, that is known to be human papillomavirus-related, we investigated the exact relationship between in situ tumor-infiltrating immune cells and the monomorphic/allele-specific HLA expression on the tumor cells. EXPERIMENTAL DESIGN: Attention was focussed on the type, location and number of in situ immunocompetent cells in malignant cervical tissue (N = 30). Immune cell distribution was quantitatively assessed by morphometry for stromal and tumor tissue separately. These results were related to the degree of expression of monomorphic- and allele-specific HLA I and II antigens on the cervical tumor cells. RESULTS: In monomorphic HLA class I downregulated cervical tumors, a significant decrease in tumor-infiltrating CD8+ T cells was observed. However, allele-specific downregulation of respectively HLA-A2, HLA-A3, HLA-Bw4, and HLA-Bw6, did not correlate significantly with a decrease in tumor-infiltrating immune cells. For HLA class II-positive cervical tumors, HLA-DR expression significantly correlated with an increase in the presence of tumor-infiltrating CD3+/CD4+/CD8+ T cells, CD56+ natural killer cells and CD16+ macrophages. No significant correlations were found between alterations in HLA class I or II expression on the tumor cells and stromal infiltrating immune cells. CONCLUSIONS: Our observations provide in situ immunomorphologic evidence that in cervical carcinoma, de novo expression of HLA class II antigens on the tumor cells resulted in an increase of tumor-infiltrating immune cells. In addition, the tumor-infiltrating CD8+ T lymphocytes correlated with monomorphic HLA class I expression on the tumor cells, which stresses the existence of a HLA-restricted immune response of T lymphocytes in cervical carcinoma. These findings might have implications for the biologic behavior of this disease and have to be taken into account in strategies concerning immunotherapy of cervical carcinoma.

Tinnitus suppression by intravenous lidocaine in relation to its plasma concentration.

In a double-blind controlled trial in nine patients with tinnitus we measured the lidocaine plasma concentrations during and after intravenous administration of lidocaine or placebo and scored the level of tinnitus on a visual analog scale. No patient showed any effect during the placebo infusion. Administration of lidocaine resulted in total suppression or suppression to a non-annoying level of tinnitus in five patients, slight suppression but still annoying tinnitus in two patients, and worsening tinnitus in one patient. No effect of lidocaine was observed in one patient. Most relief was obtained at plasma concentrations between 1.5 and 2.5 micrograms/ml. In this concentration range a significant (p < 0.05) effect of lidocaine on tinnitus was observed. However, notable side effects were observed at plasma concentrations greater than 2.0 micrograms/ml. The effect persisted until plasma levels of about 0.5 microgram/ml were reached. A large variability in the effects existed because of variations in lidocaine kinetics and because of the presumed psychologic components of tinnitus.

Vestibular investigations in acoustic neuroma.

Forty-eight patients with surgically proven acoustic neuroma were examined preoperatively with a comprehensive battery of vestibular tests. In 87% of the patients, reduced caloric responses were measured on the side of the lesion. In 60% of the patients a non-responsive labyrinth was found. Spontaneous nystagmus was observed in 29% of the patients. A significant correlation with the size of the tumour was found in the occurrence of abnormal saccades in the calibration test, pathological smooth pursuit movements and the occurrence of gaze nystagmus, respectively. There was no correlation between the magnitude of the caloric response reduction and the mean hearing loss, which suggests that the hearing loss and the vestibular function loss do not occur synchronously. This study shows that in most cases of acoustic neuroma, the peripheral part of the vestibular system is severely disturbed. Abnormalities in the central and peripheral part of the vestibular system are more easily recognized with increasing tumour size. We conclude that a complete battery of vestibular tests is essential in combination with audiometric, neurologic and radiologic analysis for the early clinical diagnosis of acoustic neuroma.