A paired comparison between glioblastoma “stem cells” and differentiated cells

Cancer stem cells (CSC) have been postulated to be responsible for the key features of a malignancy and its maintenances, as well as therapy resistance, while differentiated cells are believed to make up the rapidly growing tumour bulk. It is therefore important to understand the characteristics of those two distinct cell populations in order to devise treatment strategies which effectively target both cohorts, in particular with respect to cancers, such as glioblastoma. Glioblastoma is the most common primary brain tumour in adults, with a mean patient survival of 12–15 months. Importantly, therapeutic improvements have not been forthcoming in the last decade. In this study we compare key features of three pairs of glioblastoma cell populations, each pair consisting of stem cell‐like and differentiated cells derived from an individual patient. Our data suggest that while growth rates and expression of key survival‐ and apoptosis‐mediating proteins are more similar according to differentiation status than genetic similarity, we found no intrinsic differences in response to standard therapeutic interventions, namely exposure to radiation or the alkylating agent temozolomide. Interestingly, we could demonstrate that both stem cell‐like and differentiated cells possess the ability to form stem cell‐containing tumours in immunocompromised mice and that differentiated cells could potentially be dedifferentiated to potential stem cells. Taken together our data suggest that the differences between tumour stem cell and differentiated cell are particular fluent in glioblastoma.     

“Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: Implications for immunotherapy

The ability of cancer cells to escape from the natural or immunotherapy‐induced antitumor immune response is often associated with alterations in the tumor cell surface expression of Major Histocompatibility Complex (MHC) Class I antigens. Considerable knowledge has been gained on the prevalence of various patterns of MHC Class I defects and the underlying molecular mechanisms in different types of cancer. In contrast, few data are available on the changes in MHC Class I expression happening during the course of cancer immunotherapy. We have recently proposed that the progression or regression of a tumor lesion in cancer patients undergoing immunotherapy could be predetermined by the molecular mechanism responsible for the MHC Class I alteration and not by the type of immunotherapy used, i.e., interleukin‐2 (IL‐2), Bacillus Calmette‐Guèrin (BCG), interferon‐alpha (IFN‐α), peptides alone, dendritic cells loaded with peptides, protein‐bound polysaccharide etc. If the molecular alteration responsible for the changes in MHC Class I expression is reversible by cytokines (“soft” lesion), the MHC Class I expression will be upregulated, the specific T cell–mediated response will increase and the lesion will regress. However, if the molecular defect is structural (“hard” lesion), the MHC Class I expression will remain low, the escape mechanism will prevail and the primary tumor or the metastatic lesion will progress. According to this idea, the nature of the preexisting MHC Class I lesion in the cancer cell has a crucial impact determining the final outcome of cancer immunotherapy. In this article, we discuss the importance of these two types of molecular mechanisms of MHC Class I–altered expression.     

Colorectal cancer—prognostic signs in “local disease”

This detailed review of the clinical and pathologic signs which effect the prognosis of patients with colorectal cancer. The following are reviewed: (1) the degree of cellular anaplasia, (2) local penetration of the bowel wall, (3) lymph-node spread, (4) venous invasion, (5) perineural invasion, (6) obstruction and perforation, and (7) the number of cm the lesion is located from the anal verge.     

Differential Chemotherapeutic Sensitivity for Breast Tumors With “BRCAness”: A Review

BRCA1 or BRCA2 mutations predispose to cancer development, primarily through their loss of role in the repair of DNA double‐strand breaks. They play a key role in homologous recombination repair, which is a conservative, error‐free DNA repair mechanism. When mutated, other alternative, error‐prone mechanisms for DNA repair take over, leading to genomic instability. Somatic mutations are rare in sporadic breast tumors, but expression of BRCA1 and BRCA2 genes can be downregulated in other mechanistic ways. These tumors have similar features in terms of their phenotypic and genotypic profiles, which are normally regulated by these genes, and mutations lead to defective DNA repair capacity, called “BRCAness.” Attempts have been made to exploit this differentially expressed feature between tumors and normal tissues by treatment with DNA‐damaging chemotherapy agents. Cells with this functional BRCA deficiency should be selectively susceptible to DNA‐damaging drugs. Preclinical and early clinical (primarily retrospective) evidence supports this approach. In contrast, there is emerging evidence of relative resistance of tumors containing BRCA1 or BRCA2 mutations (or BRCAness) to taxanes. In this review, we summarize the data supporting differential chemotherapeutic sensitivity on the basis of defective DNA repair. If confirmed with available, clinically applicable techniques, this differential chemosensitivity could lead to treatment choices in breast cancer that have a more individualized biologic basis.     

“The Displaced Pineal?” A Case Report

A large subdural haematoma caused displacement of the choroid plexus. This was interpreted on the plain skull X-rays as displaced pineal and localised to the wrong side of the head.     

Adjuvant chemotherapy for the “oldest old” ovarian cancer patients

BACKGROUND:

Patients aged ≥80 years who are diagnosed with advanced ovarian cancer (OC) have been reported to have a poor prognosis. In the current study, chemotherapy?related toxicity data were evaluated between patients aged ≥80 years and those aged <80 years.

METHODS:

Patients with OC who underwent cytoreductive surgery with chemotherapy were included. Self‐reported toxicity data were obtained from National Cancer Institute Common Toxicity Criteria (CTC) forms. Objective indicators of status including albumin level, weight, and creatinine clearance were abstracted both before and after therapy. Data were compared between patients by decade of age.

RESULTS:

A total of 246 patients were included. A presenting Karnofsky performance status >2 was recorded in 17% of patients aged ≥80 years versus 0% to 4% of patients aged <80 years (P = .002). Platinum‐based chemotherapy was used in all patients. For patients aged <80 years, combination chemotherapy was used in >90% versus 69% in those aged ≥80 years (P < .0001). Standard?dose combination therapy was used in 72% to 86% of patients aged <80 years versus 28% of patients aged ≥80 years (P < .0001). Patients aged ≥80 years completed ≥6 cycles of therapy approximately 57% of the time versus 84% to 97% of the time for those aged <80 years (P = .0001). CTC forms identified no self‐reported toxicities to be more common among patients aged ≥80 years. Multivariate logistic regression identified creatinine clearance <65 mL/minute (odds ratio [OR] of 4.6), 5% weight loss (OR of 2.5), prechemotherapy albumin level of <2 g/dL (OR of 3.65), and initiation of therapy with a single agent (OR of 3.9) as independent predictors of failure to complete chemotherapy.

CONCLUSIONS:

Despite initial treatment modifications as well as toxicity assessment, only 57% of patients aged ≥80 years completed planned chemotherapy. It was confirmed that further studies into the pharmacokinetics of chemotherapy in the elderly and more sensitive assessment of therapy?related toxicity are required. Cancer 2009. © 2009 American Cancer Society.     

The primary care provider (PCP)‐cancer specialist relationship: A systematic review and mixed‐methods meta‐synthesis

Although they are critical to models of coordinated care, the relationship and communication between primary care providers (PCPs) and cancer specialists throughout the cancer continuum are poorly understood. By using predefined search terms, the authors conducted a systematic review of the literature in 3 databases to examine the relationship and communication between PCPs and cancer specialists. Among 301 articles identified, 35 met all inclusion criteria and were reviewed in‐depth. Findings from qualitative, quantitative, and disaggregated mixed‐methods studies were integrated using meta‐synthesis. Six themes were identified and incorporated into a preliminary conceptual model of the PCP‐cancer specialist relationship: 1) poor and delayed communication between PCPs and cancer specialists, 2) cancer specialists' endorsement of a specialist‐based model of care, 3) PCPs' belief that they play an important role in the cancer continuum, 4) PCPs' willingness to participate in the cancer continuum, 5) cancer specialists' and PCPs' uncertainty regarding the PCP's oncology knowledge/experience, and 6) discrepancies between PCPs and cancer specialists regarding roles. These data indicate a pervasive need for improved communication, delineation, and coordination of responsibilities between PCPs and cancer specialists. Future interventions aimed at these deficiencies may improve patient and physician satisfaction and cancer care coordination. CA Cancer J Clin 2017;67:156–169. © 2016 American Cancer Society.     

Responsiveness to endocrine manipulations in breast cancer after “prophylactic” castration

Two hundred and one cases of premenopausal women with breast cancer who underwent prophylactic castration with subsequent recurrence were reviewed to ascertain the degree of responsiveness of these patients to subsequent endocrine manipulation. We show that the standard endocrine manipulations, particularly the major ablations, retain a fair degree of activity in this group. There is a suggestion that the longer the castration-recurrence interval, the higher the chance of a response, but the difference is significant only for osseous-dominant disease. As in other patient groups, responders to subsequent endocrine manipulations live longer than nonresponders.     

“The median isn't the message”: How to communicate the uncertainties of survival prognoses to cancer patients in a realistic and hopeful way

This study investigated how doctors communicate the uncertainties of survival prognoses to patients recently diagnosed with life‐threatening cancer, and suggests ways to improve this communication. Two hundred thirty‐eight Norwegian oncologists and general practitioners (GPs) participated in Study 1. The study included both a scenario and a survey. The scenario asked participants to respond to a hypothetical patient who wanted to know how long (s)he could be expected to live. There were marked differences in responses within both groups, but few differences between the GPs and oncologists. There was a strong reluctance among doctors to provide patients with a prognosis. Even when they were presented with a statistically well‐founded right‐skewed survival curve, only a small minority provided hope by communicating the variation in survival time. In Study 2, 177 healthy students rated their preferences for different ways of receiving information regarding the uncertainty of a survival prognosis. Participants who received an explicitly described right‐skewed survival curve believed that they would feel more hopeful. These participants also obtained a more realistic understanding of the variation in survival than those who did not receive this information. Based on the findings of the two studies and on extant psychological research, the author suggests much‐needed guidelines for communicating survival prognoses in a realistic and optimistic way to patients recently diagnosed with life‐threatening cancer. In particular, the guidelines emphasise that the doctor explains the often strongly right‐skewed variation in survival time, and thereby providing the patient with realistic hope.     

Platelets in cancer metastasis: To help the “villain” to do evil

Cancer progress is accompanied by platelet activation and thrombotic complications. Platelets are a dangerous alliance of cancer cells, and are a close engager in multiple processes of cancer metastasis. Platelet adhesion to cancer cells forms a protective cloak that helps cancer cells to escape immune surveillance and natural killer cell‐mediated cytolysis. Platelets facilitate tethering and arrest of disseminated cancer cells in the vasculature, enhance invasive potentials and thus extravasation of cancer cells. Moreover, platelets recruit monocytes and granulocytes to the sites of cancer cell arrest, and collaborate with them to establish a pro‐metastatic microenvironment and metastatic niches. Platelets also secret a number of growth factors to stimulate cancer cell proliferation, release various angiogenic regulators to regulate tumor angiogenesis and subsequently promote cancer growth and progress. Albeit platelets are helping the “villain” cancer to do evil, the close engagements of platelets in cancer metastasis and progress can be used as the intervention targets for new anti‐cancer therapeutic developments. Platelet‐targeted anti‐cancer strategy may bring in novel anti‐cancer treatments that can synergize the therapeutic effects of chemotherapies and surgical treatments of cancer.