Management of HER2-Positive Breast Cancer for a Young Patient with Visceral Crisis—The Adjuvant Role of Lifestyle Changes

The safety profile and effectiveness of existing anti-HER2-targeted therapies have not been evaluated in patients with breast cancer and visceral crisis. We report the case of a 26-year-old woman who was diagnosed with advanced HER2-positive breast cancer and initially treated with curative intent therapy in a neoadjuvant setting, using Trastuzumab and Pertuzumab in combination with Docetaxel; her cancer recurred two years later, with liver metastases and pulmonary lymphangitic carcinomatosis, causing visceral crisis. Furthermore, the patient’s clinical status worsened when she developed respiratory failure, hepatomegaly and a severe hepatocytolysis. Since the patient was free of disease more than six months, we started with Paclitaxel half dose because of the hepatic dysfunction, and we gradually reintroduced Trastuzumab and then Pertuzumab. In the meantime, the patient changed her lifestyle by increasing her consumption of fresh fruits and vegetables and fiber and reducing her intake of processed meat, dairy and sugar. As a result, the patient showed a significant improvement in her respiratory symptoms and liver tests in less than two months. Imaging reevaluation showed partial remission of liver metastases and pulmonary lymphangitic carcinomatosis. She underwent seven months of dual anti-HER2 blockade before relapsing cerebrally. Our results suggest that the sequential combination therapy with Trastuzumab, Pertuzumab and Paclitaxel presented in this study, associated with a healthy lifestyle, may be a good management for recurrent HER2-positive breast cancer with pulmonary visceral crisis and severe liver dysfunction.     

The use of hierarchical models for estimating relative risks of individual genetic variants: an application to a study of melanoma

For major genes known to influence the risk of cancer, an important task is to determine the risks conferred by individual variants, so that one can appropriately counsel carriers of these mutations. This is a challenging task, since new mutations are continually being identified, and there is typically relatively little empirical evidence available about each individual mutation. Hierarchical modeling offers a natural strategy to leverage the collective evidence from these rare variants with sparse data. This can be accomplished when there are available higher-level covariates that characterize the variants in terms of attributes that could distinguish their association with disease. In this article, we explore the use of hierarchical modeling for this purpose using data from a large population-based study of the risks of melanoma conferred by variants in the CDKN2A gene. We employ both a pseudo-likelihood approach and a Bayesian approach using Gibbs sampling. The results indicate that relative risk estimates tend to be primarily influenced by the individual case-control frequencies when several cases and/or controls are observed with the variant under study, but that relative risk estimates for variants with very sparse data are more influenced by the higher-level covariate values, as one would expect. The analysis offers encouragement that we can draw strength from the aggregating power of hierarchical models to provide guidance to medical geneticists when they offer counseling to patients with rare or even hitherto unobserved variants. However, further research is needed to validate the application of asymptotic methods to such sparse data.     

Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling

Current evidence suggests that the genetic risk of breast cancer may be caused primarily by rare variants. However, while classification of protein-truncating mutations as deleterious is relatively straightforward, distinguishing as deleterious or neutral the large number of rare missense variants is a difficult on-going task. In this article, we present one approach to this problem, hierarchical statistical modeling of data observed in a case-control study of contralateral breast cancer (CBC) in which all the participants were genotyped for variants in BRCA1 and BRCA2. Hierarchical modeling permits leverage of information from observed correlations of characteristics of groups of variants with case-control status to infer with greater precision the risks of individual rare variants. A total of 181 distinct rare missense variants were identified among the 705 cases with CBC and the 1,398 controls with unilateral breast cancer. The model identified three bioinformatic hierarchical covariates, align-GV, align-GD, and SIFT scores, each of which was modestly associated with risk. Collectively, the 11 variants that were classified as adverse on the basis of all the three bioinformatic predictors demonstrated a stronger risk signal. This group included five of six missense variants that were classified as deleterious at the outset by conventional criteria. The remaining six variants can be considered as plausibly deleterious, and deserving of further investigation (BRCA1 R866C; BRCA2 G1529R, D2665G, W2626C, E2663V, and R3052W). Hierarchical modeling is a strategy that has promise for interpreting the evidence from future association studies that involve sequencing of known or suspected cancer genes.     

Experiences, knowledge, and opinions on palliative care among Romanian general practitioners

Aim

To assess experience, knowledge, and opinions of Romanian general practitioners (GPs) on palliative health care in Romania.

Methods

A questionnaire survey was performed among 1283 GPs in five districts of Romania in 2004. The data were collected on the GPs’ self-assessed experience in, knowledge of, and opinion on palliative care, entered into a database, and analyzed. The GPs were also asked to indicate if they needed to improve their knowledge about palliative care.

Results

The response rate was 71%. GPs mostly reported having limited experience in providing palliative care, with 24% reporting to have provided palliative care frequently, and 55% reporting to have it provided sometimes. Significant correlations were found between the GPs’ experience in palliative care provision and their age, sex, and place of work. The majority of Romanian GPs reported that their medical knowledge was inadequate for the provision of care to terminal patients at home. Over 80% of GPs agreed to develop palliative care services and to participate in a training program.

Conclusion

GPs in Romania reported to recognize the need for improvement of palliative care delivery in their country. They expressed the need for better knowledge of palliative care and agreed that multidisciplinary teams to provide palliative care at home would be the best form of delivering this type of health care.Palliative care is a relatively new form of health care provision in Central-Eastern European (CEE) countries unlike in Western Europe, where it has been an established health care specialty for decades (1,2). The most widely used model of palliative care provision in CEE countries is the hospice model. However, the number and availability of hospices and financial means allocated to these institutions have been insufficient, and the population in need of palliative care has been increasing. Palliative care professionals are less focused on the needs of patients and possible development of a new model for palliative care provision than they are on the “vested interests” of the model, ie, preventing the hospices in which they work from being closed down.With aging of the population, the morbidity profile in CEE countries has changed and so have the health care needs. The need for nursing and care, including palliative care, is increasing and largely uneven distribution of medical care facilities between urban and rural areas only aggravates the problem. All these factors bring the palliative care issues to focus (3).Until recently, palliative care in Romania and many CEE countries was primarily associated with terminal care of patients with cancer and the hospice movement (4,5). In the last few years, however, the hospice model as a preferred model of palliative care has been reevaluated and questioned by many (3). Because of the over-institutionalization of health care and the decrease in the number of hospital beds, health care policymakers are increasingly thinking about promoting palliative care at home, which would be supported by a palliative care team (1). Furthermore, people in most CEE countries prefer to die at home, as there is still a strong tradition of family care (6).The expectation of the Romanian primary health care system, which includes general practitioners (GPs) and nurses, to play an important role in palliative care at home is relatively far from realization. Not only that this aspect of health care provision is new and partly unknown to great majority of GPs, but the complementary services and expertise in home care and pain management are not well developed either. This problem is also present in Croatia, Hungary, and Slovakia (1), where various initiatives are being taken to develop palliative care as the need for it increases. As Doyle et al (7) have stated, palliative care at home is dependent on the attitudes and perceptions of family physicians and wider socio-cultural attitudes. Also, the lack of information on the latest techniques and developments in palliative care may prohibit the development of that health care area (8).The first hospices in Romania were established in Oradea and Brasov (9); by 2004, five hospices had been opened. Although a government policy from 1998 tried to strengthen the role of the GP in the health care delivery system (10), no systematic attention had been given to palliative care in general practice or hospitals until 2002 (4). Thereafter, family physicians have increasingly started to provide palliative care, but they have not been reimbursed for the service. Thus, it may be said that the efforts to develop a system of palliative care provision in Romania are still not organized.We asked GPs in five districts in Romania to self-assess their experience in palliative care provision, their knowledge and need for better education in palliative care, and their opinion on the best way to deliver this type of care.     

Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months’ follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months’ follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02399085","term_id":"NCT02399085"}}NCT02399085.