Communication skills training in oncology: it works!

While the previous chapter by L. Fallowfield and V. Jenkins focuses on different communication skills training (CST) concepts currently being utilized, this chapter reviews and comments the scientific evidence of the impact of CST on improving communication skills. The aim of this chapter is not to provide a complete review of the evidence-this has already been done in systematic reviews-but to discuss the scientific evidence and reflect on the available results and relevant topics for further investigations.

Heat shock protein 27 enhances the tumorigenicity of immunogenic rat colon carcinoma cell clones.

The REG and PRO cell clones were obtained from a colon adenocarcinoma induced in a BDIX rat by 1,2-dimethylhydrazine. When injected s.c. into syngeneic hosts, REG cells induce tumors that regress in less than 3 weeks, whereas PRO cells, like parental cells, induce progressive tumors. Here, we show that compared to PRO cells, REG cells are more sensitive to cell death induced by anticancer drugs. The small heat shock protein (HSP) 27 is not expressed or inducible in REG clones, whereas it is abundantly expressed and inducible by heat shock in PRO clones. The expression of HSP27 in REG cells increases their resistance to apoptosis in vitro and dramatically enhances their tumorigenicity when injected s.c. into syngeneic rats. HSP27 expression in REG cells both increases tumor size and delays tumor regression. This increased tumorigenicity is associated with a substantial decrease of in vivo tumor cell apoptosis. We conclude that HSP27 expression in malignant cells increases their tumorigenicity in syngeneic animals. In combination with the role of HSP27 in tumor cell resistance to cytotoxic agents, its contribution to tumorigenicity makes this protein a potential target for antitumoral therapy.

Cancer cell sensitization to fas-mediated apoptosis by sodium butyrate.

Cancer cells often resist Fas-mediated apoptosis even when the Fas receptor is expressed at the cell surface. We show here that human and rat colon cancer cells undergo massive apoptosis when they are exposed to soluble Fas ligand in the presence of sodium butyrate, an agent that induces by itself only a low rate of apoptosis. Sodium butyrate potentiates Fas-dependent apoptosis in seven out of eight colon cancer cell lines. Sodium butyrate does not increase Fas receptor cell surface expression and does not modify cell levels of Bcl-2, Bcl-xL, Bcl-xS and Bax. Sodium butyrate also induces tumor cell sensitization to the apoptotic effect of the combination of TNF-alpha and IFN-gamma, but it does not modify the level of the FADD/Mort1 adaptator molecule, at the connection between Fas- and TNF-dependent apoptosis pathways. Because the clinical toxicity of butyrate is low, its ability to enhance Fas-signal delivery in cancer cells could be of therapeutic interest.

[Case report: Vasa previa diagnosis and management. How to prevent Benckiser's hemorrhage?]. / Cas clinique : diagnostic et prise en charge d'un vasa praevia. Comment prévenir l'hémorragie de Benckiser ?

Benckiser's haemorrhage is a serious obstetrical complication, following a vasa previa rupture. Incidence of vasa previa is estimated between 1/1150 and 1/5000 pregnancies. This case report illustrates the consequences of a suspected vasa previa rupture. There is no French recommendation of how to treat vasa previa. Different methods of prevention are described and examined thanks to a literature review.

Role of ICAM-1 (CD54) in the development of murine cerebral malaria.

In susceptible mouse strains, infection of mice with Plasmodium berghei ANKA (PbA) results in a lethal complication, cerebral malaria. Cerebral malaria is due to the immune response induced by the parasite, which results in an increased production of TNF, known to increase the expression of adhesion molecules on the endothelia. To investigate the role of the adhesion molecule ICAM-1 (CD54), we infected wild-type (+/+) and ICAM-1-deficient (-/-) mice with PbA. While +/+ mice died 6-8 days after infection, -/- mice survived > 15 days. Parasitaemia was similar in +/+ and -/- mice. Serum TNF concentration was increased by the infection and was significantly higher in infected +/+ than in -/- mice. However, TNF mRNA levels in spleen, lungs, and brain were elevated in both infected +/+ and -/- mice. For IFN-gamma, serum levels were similar in both groups. A breakdown of the blood-brain barrier was evident in infected +/+ mice only. Interestingly, thrombocytopenia was profound in infected +/+, but practically absent in -/- mice. Moreover, macrophage sequestration was evident in brain venules and lung capillaries of +/+ mice and was significantly less important in the alveolar capillaries of infected -/- mice. In contrast, neutrophil sequestration in the lung was similar in both +/+ and -/- mice. Sequestration of parasitized red blood cells was significantly greater in the alveolar capillaries from +/+ than -/- mice. These results indicate that while the immune response is similar in both +/+ and ICAM-1(-/-) mice, the absence of mortality in ICAM(-/-) mice correlates with a decrease of macrophage and parasitized RBC trapping and a less severe thrombocytopenia.

Use of the CTL44 cell line, a derivative of CTL/L cells, to identify and quantify mouse interleukin-4 by bioassay.

The isolation and characterization of a new and excellent indicator cell line for murine interleukin-4 (IL-4) bioassays, CTL44, is described. CTL44, a subline of CTL/L cells, is vigorously responsive to murine IL-4, but hyporesponsive to IL-2, requiring > 6 ng/ml (approximately 120 U/ml) of human IL-2 or > 80 U/ml of mouse IL-2 to induce IL-2 dependent proliferation. In CTL44 both IL-4 receptor mRNA accumulation and cell surface expression are detected, whereas IL-2 receptor expression appears to be absent. CTL44 cells maintained in IL-4 containing medium grow rapidly in a non-adherent fashion, and can be stored frozen in liquid nitrogen without loss of function.

Comparison of cytokine measurements using ELISA, ELISPOT and semi-quantitative RT-PCR.

We have investigated the correlation between results obtained by three different methods (semi-quantitative RT-PCR, ELISA and ELISPOT) used to measure cytokine expression by mouse leukocytes. The production of the cytokines tumour necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) and interleukin-4 (IL-4), was analysed with all three methods. In a simple experimental murine in vivo model of leukocyte stimulation, consisting of a single intravenous injection of anti-CD3 antibodies followed by a short incubation in vitro, the results obtained with spleen cells for each of the three cytokines differed greatly, depending on the method used. For TNF alpha, a significant increase in RNA was observed upon stimulation, whereas the number of spot-forming cells did not increase and the protein was not detectable in serum or in cell culture supernatants by ELISA. In vitro cultured splenocytes showed a strong correlation between all three methods for IFN gamma. Upon stimulation, the amount of RNA for IL-4 increased in parallel with the secretion of the cytokine and the number of spot-forming cells. However, high numbers of spot forming cells were observed in controls. We conclude that, depending on the specific aim of an investigation, combinations of different methods have to be chosen carefully in order to detect activation of leukocytes for cytokine expression.

[Pediatric outcome after selective feticide for 30 complicated monochorionic twin pregnancies]. / Suivi pédiatrique de 30 grossesses gémellaires monochoriales consécutives traitées par fœticide sélectif.

OBJECTIVES: To describe perinatal and pediatric outcome after selective feticide for complicated monochorionic twin pregnancy. PATIENTS AND METHODS: We reviewed all consecutive cases of umbilical cord occlusion performed for complicated monochorionic twin pregnancy over a 16-year period. Pediatric follow-up was based on medical records and updated by phone calls to the parents. RESULTS: Thirty procedures were performed. Indications were: twin-to-twin transfusion syndrome (TTTS) progressing despite serial amniodrainage (n=12) ; twin reversed arterial perfusion (n=9) ; selective growth restriction (n=5) ; severe discordant structural anomalies (n=4). Mean gestational age at procedure was 21.8±3.1gestational weeks (GW) and 31.8±4.8 GW at birth. Overall survival rate was 87%, i.e. 83%, 100%, 60% and 100% for each indication, respectively. Mean pediatric follow-up was 5years (range: 6months to 15years). Medical charts and parents declared normal development in 88% of surviving children, i.e. 67%, 100%, 100%, and 100% for each indication. Cross-comparison between the four groups revealed that in the TTTS group, gestational age at procedure was more advanced (P=0.01) while delivery was slightly earlier (P=0.1), and pediatric development was poorer (P=0.02). DISCUSSION AND CONCLUSION: Pediatric outcome after selective feticide appeared to be poorer for TTTS progressing despite serial amniodrainage than for other indications.

[Uterine lipoma: A case report probably due to a surgical traumatism]. / Lipome utérin : à propos d'un cas possiblement lié à un traumatisme chirurgical.

Uterine lipomas are uncommon. Several histology hypotheses are described. Ultrasound is firstly performed but diagnosis is sometimes difficult. Magnetic resonance imaging is more specific and helpful to make a differential diagnosis with a dermoid ovarian cyst. Despite those imaging exams we detail a case of a patient where a laparoscopic hysterectomy with bilateral salpingo-oophorectomy and preliminary adhesiolysis has been necessary to establish diagnosis. Among her medical history some previous abdominal surgeries could be the cause of this lesion.

[Importance of bile acids for intra-hepatic cholestasis of pregnancy]. / Intérêt des acides biliaires dans la cholestase gravidique.

Intrahepatic cholestasis during pregnancy is a risk factor for prematurity, respiratory distress, fetal death in utero and exposure to meconium stained liquor. Treatment is based on ursodeoxycholic acid, which allows the pregnancy to continue until term. There is no consensus for labor induction criteria or for extraction of the fetus. We report a series of 10 patients who presented cholestasis during pregnancy and for whom we monitored the bile acid levels. These assays provided the means of confirming the diagnosis in patients suffering from pruritus. The threshold of 40 micromoles/L could be a way of defining a group at risk of complications. Proper management for monitoring this pathology has not yet been properly established, but assay of the bile acids is an important element.

Immunization of mice with phosphatidylcholine drastically reduces the parasitaemia of subsequent Plasmodium chabaudi chabaudi blood-stage infections.

It has been suggested that phospholipids and antibodies directed against phospholipids are important in the pathology of malaria. We have investigated the influence of immunizations with phospholipids on the course of subsequent blood-stage Plasmodium chabaudi chabaudi infections in ICR inbred mice. We observed a significant reduction in the parasitaemia following immunization with phosphatidylcholine (PC), but not with phosphatidylethanolamine (PE) immunization. At the peak of the infection, PC-immunized mice displayed a T-helper 2 (Th2)-type cytokine production pattern, whereas PE-immunized or non-treated controls displayed a cytokine production pattern of the T-helper 1 (Th1) type. Serum immunoglobulin transfer from PC-immunized mice protected naive mice in a similar fashion to PC-immunization, demonstrating that the observed reduction of parasitaemia was caused by the presence of PC-specific antibodies.

Malaria toxins: effects on murine spleen and bone marrow cell proliferation and cytokine production in vitro.

The ability of deproteinated malaria exoantigens from Plasmodium falciparum (Pf-MT) and P. berghei ANKA (PbA-MT) to activate murine haematopoietic cells was analysed in vitro. Malaria toxins (MT) of both plasmodium species induced cell proliferation and the production of IFN-gamma in overnight and long-term (5 days) spleen and bone marrow cultures and a reduction of the number of TNF-alpha spot forming cells (SFC). When added to cells of malaria-experienced animals, MT decreased the number of IL-4 SPC and increased the number of IL-5 SPC. However, the same proliferative and IFN-gamma induction properties as in naive cells were observed. Simultaneous addition of IL-2 and PbA-MT to spleen cells inhibited the proliferation but increased the IFN-gamma production usually induced by IL-2. Flow cytometric analysis revealed that the addition of MT triggered an expansion of CD3+ and GR1+ cell populations. Our results suggest that malaria toxins of different species can induce an immediate and strong proliferation and a TH1-type cytokine release by murine cells, independently of previous in vivo priming.

The development of murine cerebral malaria does not require nitric oxide production.

Nitric oxide (NO) production has been suggested to be required for the development of cerebral malaria. However, the importance of this molecule for the appearance of this pathology is debated. To assess whether murine cerebral malaria is NO dependent, we investigated the course of blood-stage Plasmodium berghei ANKA (PbA) infections in inducible nitric oxide synthase (iNOS)-deficient mice. Parasitaemia, haematological alterations, survival and development of cerebral malaria were not affected by the lack of iNOS. To exclude a role of NO produced by other NOS, controls included NO suppression by oral administration of aminoguanidine (AG), a NOS inhibitor. As in iNOS-deficient mice, no difference in the parasitaemia course, survival and haematological values was observed after AG treatment. Our results indicate that NO production is not a crucial factor for the development of murine cerebral malaria.

Parasite killing in murine malaria does not require nitric oxide production.

Nitric oxide (NO) production has been suggested to play a role as effector molecule in the control of the malarial infections. However, the roles of this molecule are debated. To assess whether blood-stage parasite killing is NO dependent, we investigated the course of blood-stage Plasmodium chabaudi chabaudi (Pcc) infections in inducible nictric oxide synthase (iNOS)-deficient mice. Parasitaemia, haematological alterations, and survival were not affected by the lack of iNOS. To exclude a role of NO produced by other NOS, controls included NO suppression by oral administration of aminoguanidine (AG), a NOS inhibitor. As in iNOS-deficient mice, no difference in the parasitaemia course, survival and haematological values was observed after AG treatment. Our results indicate that NO production is not required for protection against malaria in our murine experimental model. However, C57BL/6 mice treated with AG lost their resistance to Pcc infections, suggesting that the requirement for NO production for parasite killing in murine blood-stage malaria might be strain dependent.

Interferon-gamma is essential for the development of cerebral malaria.

Infection with Plasmodium berghei ANKA (PbA) causes fatal cerebral malaria (CM). While a pathogenic role for tumor necrosis factor (TNF) has been established, we asked whether a disruption of interferon-gamma (IFN-gamma) signaling would modulate CM. We demonstrate here that IFN-gammaR-deficient mice are completely protected from CM. PbA-induced release of TNF and up-regulation of endothelial intercellular adhesion molecule (ICAM)-1 expression, recruitment of mononuclear cells, and cerebral microvascular damage with vascular leakage occur only in wild-type mice. Protected mice die at a later time of severe anemia and overwhelming parasitemia. Resistance to CM in IFN-gammaR-deficient mice is associated with reduced serum TNF levels, reduced interleukin-12 expression in the brain and increased T-helper 2 cytokines. In conclusion, IFN-gamma is apparently required for PbA-induced endothelial ICAM-1 up-regulation and subsequent microvascular pathology, resulting in fatal CM. In the absence of IFN-gamma signaling, ICAM-1 and TNF up-regulation is reduced; hence, PbA infection fails to cause fatal CM.

Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats.

Tumors are tolerated by the immune system notwithstanding the expression of tumor-associated antigens. PROb tumor cells, derived from a rat colon carcinoma, are rejected by tumor-immune hosts but give rise to progressive tumors in naive hosts. Paradoxically, these tumors are heavily infiltrated by dendritic cells that express MHC class II and ICAM-1. These tumor-infiltrating dendritic cells (TiDCs) could be expected to process and present to T cells the antigens released by the adjacent tumor cells. Indeed, we report here that TiDCs, compared with splenic dendritic cells, are poor stimulators of primary allogeneic T-cell proliferation and cytokine [interleukin-2 (IL-2) and interferon-gamma] production. Most of them (89-97%) do not express B7, an essential co-stimulatory signal for T cells, even after a culture period allowing B7 up-regulation on epidermal Langerhans cells. GM-CSF in association with tumor necrosis factor-alpha or IL-4, or cell-associated CD40-ligand, all known to be potent stimulators of B7 expression on other dendritic cells, did not restore B7 expression by TiDCs. After a first exposure to TiDCs, allogeneic T-cell response to a second challenge to splenic dendritic cells was decreased. The failure of most dendritic cells infiltrating PROb tumors to express B7, even after stimulation, may contribute to their poor capacity to stimulate T cells and could play a role in the immune tolerance allowing tumor growth.