SEOM-GECP-GETTHI Clinical Guidelines for the treatment of patients with thymic epithelial tumours (2021).

Thymic epithelial tumours (TET) represent a heterogeneous group of rare malignancies that include thymomas and thymic carcinoma. Treatment of TET is based on the resectability of the tumour. If this is considered achievable upfront, surgical resection is the cornerstone of treatment. Platinum-based chemotherapy is the standard regimen for advanced TET. Due to the rarity of this disease, treatment decisions should be discussed in specific multidisciplinary tumour boards, and there are few prospective clinical studies with new strategies. However, several pathways involved in TET have been explored as potential targets for new therapies in previously treated patients, such as multi-tyrosine kinase inhibitors with antiangiogenic properties and immune checkpoint inhibitors (ICI). One third of patient with thymoma present an autoimmune disorders, increasing the risk of immune-related adverse events and autoimmune flares under ICIs. In these guidelines, we summarize the current evidence for the therapeutic approach in patients with TET and define levels of evidence for these decisions.

Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations.

Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody-drug conjugates (ADCs) ado-trastuzumab-emtansine and trastuzumab-deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.

Antibiotic-exposed patients with non-small-cell lung cancer preserve efficacy outcomes following first-line chemo-immunotherapy.

BACKGROUND: Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes to chemo-immunotherapy combinations is still unknown. PATIENTS AND METHODS: In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions. RESULTS: Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 [95% confidence interval (CI): 0.91-2.22]; P = 0.1207} and PFS [HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552], compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS [HR = 1.29 (95% CI: 0.91-1.84); P = 0.149] and PFS [HR = 1.20 (95% CI: 0.89-1.63); P = 0.222] when evaluated as time-varying covariate in multivariable analysis. CONCLUSIONS: In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.

SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019).

Small-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15-20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum-etoposide. In stage IIB-IIIC, the recommended treatment is early concurrent chemotherapy with platinum-etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum-etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum-etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary.

Obstetric intra-operative cell salvage and maternal fetal red cell contamination.

BACKGROUND: The significance of fetal red blood cell (RBC) contamination in obstetric intra-operative cell salvage is not fully known. It is unclear if we re-infuse a larger volume of fetal RBCs into the maternal circulation than the amount that occurs secondary to transplacental haemorrhages is unclear. We also do not know if there is a critical volume required to cause alloimmunisation or if larger volumes increase the risk. OBJECTIVES: The aim of this study is to provide data on the level of fetal RBC contamination in the maternal circulation prior to delivery and immediately post-partum and to compare these levels to those found in processed cell-salvaged blood. METHODS: In the first part of this study, we quantified the levels of fetal RBCs circulating in women immediately prior to delivery. This was then repeated with a separate group measuring the levels of fetal RBCs pre- and post-delivery. RESULTS: We found that 37% of women had fetal cells detected in their circulation, median 0·00 mL (IQR 0-0·24; average 0·3 mL, maximum 4·56 mL). Fetal RBCs were present pre-delivery (maximum 0·66 mL) in 16% of women, increasing to 53% post-delivery (median 0·66 mL; IQR 0·22-2·20, maximum 21·20 mL). CONCLUSIONS: We have shown that fetal RBCs are present in the maternal circulation throughout pregnancy and that the volumes are comparable to that obtained from intra-operative salvage, with contamination amounts of up to 19 mL. At the Royal Cornwall Hospital, our experience and evidence supports offering intra-operative salvage to all women, and we have not noted an increase in antibody formation, compared to allogeneic transfusion.

KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer.

PURPOSE: Several angiogenic prognostic markers are under investigation because of their potential clinical utility, aiming to improve patient outcomes. We hypothesized that genetic variant in the VEGF pathway could be used as prognostic markers of survival in non-small cell lung cancer (NSCLC) patients undergoing pulmonary resection. METHODS: We evaluated the relationship between genetic variants in the VEGF pathway and relapse-free survival (RFS, main endpoint) and overall survival (OS, secondary endpoint) among 131 patients with stage I-III NSCLC treated with surgical resection from 2009 to 2013. Clinical, pathological and surgical data were prospectively collected. Twenty-five variants in sixteen relevant genes were selected and genotyped in tumor samples by real time PCR. The Kaplan-Meier method with the log-rank test and Cox's regression models were used for RFS and OS analyses. RESULTS: With a median follow-up of 36 (min = 2.8; max = 67.4) months, there were 31 (24%) relapses and 31 (24%) deaths. Overall, median RFS was not reached and median OS was 65 [95% confidence interval (CI) 56-75] months. The KRAS rs1137282 and PIK3C2A rs4356203 variants were significantly associated with RFS. For KRAS rs1137282, the 3-year RFS was 76% [95% CI 64-84%] in patients harboring an A/A genotype compared to 53% [95% CI 37-69%] in patients harboring an A/G or G/G genotype (p = 0.02). For PIK3C2A rs4356203, patients with an A/A or an A/G genotype had a 3-year RFS of 72% [95% CI 58-76%], whereas in patients with a G/G genotype was 49% [95% CI 28-70%] (p = 0.02). These associations remained statistically significant after adjusting for all the relevant clinical parameters in the multivariable analysis. CONCLUSION: Genetic variants in VEGF pathway may be associated with recurrence in stage I-III NSCLC. Specifically, the KRAS rs1137282 could be considered as a prognostic factor for recurrence in resectable NSCLC patients. Although PIK3C2A rs4356203 was associated with RFS, further analyses are necessary to confirm these data.

Is cell salvaged vaginal blood loss suitable for re-infusion?

BACKGROUND: Haemorrhage is one of the commonest causes of maternal critical care admission. Cell salvage used during caesarean section can contribute to a reduction in allogeneic blood consumption. This study sought to provide a practical method to salvage blood lost after vaginal delivery and a description of the constituents before and after washing. METHODS: Blood lost after vaginal delivery was collected from 50 women and washed in a cell salvage machine. No blood was re-infused to any patient in this study. The following measurements were made pre- and post-wash: haemoglobin (haematocrit), alpha-fetoprotein, albumin, lactate dehydrogenase, plasma free haemoglobin, heparin concentration, fetal red cells and identification of bacterial species and colony-forming units (cfu). RESULTS: Median haemoglobin concentration post-wash was 15.4 g/dL. Alpha-fetoprotein, lactate dehydrogenase and albumin concentrations were significantly reduced post-wash (<1 KU/L, 183 IU/L, 0.011 g/L, respectively; P <0.001). Median fetal red cell level post-wash was 0.15 mL [range 0-19 mL]. Median bacterial contamination concentration post-wash was 2 cfu/mL, with a median total count of 303 cfu. CONCLUSIONS: Vaginal blood can be collected efficiently with little disruption to patient management. The amounts of haemolysis and washout of non-red cell blood components are consistent with results in our cell salvage quality assurance programme for caesarean section and non-obstetric surgery. Although bacteria are detectable in all the post-wash and post-filter samples, the median residual contamination is similar to that found with cell salvage in caesarean section, and if re-infused would result in a circulating bacteraemia of <1 cfu/mL; this is similar to that seen with dental procedures (0.3-4.0 cfu/mL) and is thought to be clinically insignificant.

Is there a limit for the laparoscopic approach of a retroperitoneal residual mass postchemotherapy?

OBJECTIVES: Rescue lymphadenectomy for testicular cancer is a complex surgery, with a high number of complications. The laparoscopic approach appears to offer faster recovery and improved quality of life compared with open surgery. The aim of our study is to report on our experience and to define whether there is a limit (oncological, anatomical or technical) for laparoscopic management. MATERIAL AND METHODS: A retrospective study was conducted of 15 patients who underwent laparoscopic retroperitoneal lymphadenectomy after chemotherapy. In addition to epidemiological and oncologic variables, we analyzed the mean surgical time, intraoperative and postoperative complications, the mean hospital stay and the mean follow-up time. RESULTS: The mean surgical time was 294 minutes (range, 180-240). There were 4 large-vessel vascular lesions, all of which were large-volume retroperitoneal masses, with diameters >7 cm. The rate of postoperative complications was 33%; there was only 1 case of Clavien >III. The mean hospital stay was 5.38 days (range, 2-9), and the mean patient follow-up was 28.9 months (range, 1-79). There was no recurrence in any of the cases. CONCLUSIONS: The laparoscopic approach is an oncologically safe option for the rescue treatment of testicular cancer. The complex location of these masses entails the onset of severe intraoperative complications. We have observed a clear relationship between vascular complications and large masses (>7 cm). We therefore believe that it would be appropriate to establish a limit on the size for laparoscopic treatment.

EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer.

Epidermal growth factor receptor (EGFR) activation by radiation leads to increased cell proliferation and acts as a radioresistance mechanism. Neoadjuvant chemoradiation is the standard of care for locally advanced rectal cancer, and to date, no biomarkers of response have been found. We analyzed polymorphisms in the EGFR and its ligands, DNA repair genes and the thymidylate synthase in 84 stages II and III rectal cancer patients treated with neoadjuvant capecitabine plus radiotherapy. The rs11942466 polymorphism in the amphiregulin (AREG) gene region was associated with a pathological complete response (ypCR) (odds ratio: 0.26; 95% confidence interval: 0.06-0.79; P=0.014). The rs11615 C>T polymorphism in the ERCC1 gene also correlated with the ypCR as no patients with a C/C genotype achieved ypCR; P=0.023. This is the first work to propose variants within the AREG and the ERCC1 genes as promising predictive biomarkers of ypCR in rectal cancer.

Assessment of intra-operative cell salvage haemolysis in the obstetric and orthopaedic clinical setting, in comparison with allogeneic blood.

OBJECTIVES/BACKGROUND: Haemolysis is still a re-occurring theme in intra-operative cell salvage (ICS) with further haemolysis possibly caused by suction pressure, washing/centrifuging process and aspiration method. Previous investigations, along with manufacturer's reports, state that between 75 and 95% of free haemoglobin (Hb) is removed by the washing and centrifugation process; however, if these results are above the expected levels, excess free Hb may remain after washing. The aim of this article was to quantify haemolysis levels whilst employing different aspiration methods from skimmed (orthopaedics) and pooled (obstetrics) surgery types and comparing this to allogeneic blood. METHODS/MATERIALS: Samples obtained from 50 allogeneic units and 50 ICS cases (25 obstetric and 25 orthopaedic) were tested for plasma free Hb levels. RESULTS: Free Hb testing as a marker of haemolysis was greatest in orthopaedic 17·2 g L(-1) (range: 1·7-57·0 g L(-1) ), obstetric 2·8 g L(-1) (range: 1·0-13·5 g L(-1) ) and allogeneic 0·95 g L(-1) (range: 0·2-4·8 g L(-1) ) cases. CONCLUSION: ICS involving skimming collection techniques (orthopaedics) had significantly more haemolysis than pooled collections (obstetrics) (P < 0·001). Further analysis of orthopaedic data highlighted a difference between the three machines used with the Haemonetics OrthoPat (Haemonetics Ltd., Watford, UK) significantly higher with a free Hb of 29·8 g L(-1) compared with the other two machines 6·7 g L(-1) (P < 0·001). On comparison of ICS blood to allogeneic blood, free Hb levels obtained from ICS were significantly higher (P < 0·001).

Exposure to the common food additive carrageenan leads to glucose intolerance, insulin resistance and inhibition of insulin signalling in HepG2 cells and C57BL/6J mice.

AIMS/HYPOTHESIS: The aim of this study was to determine the impact of the common food additive carrageenan (E407) on glucose tolerance, insulin sensitivity and insulin signalling in a mouse model and human hepatic cells, since carrageenan is known to cause inflammation through interaction with toll-like receptor (TLR)4, which is associated with inflammation in diabetes. METHODS: Male C57BL/6J mice were given carrageenan (10 mg/l) in their drinking water, and underwent a glucose tolerance test (GTT), an insulin tolerance test (ITT) and an ante-mortem intraperitoneal insulin injection. HepG2 cells were exposed to carrageenan (1 mg/l × 24 h) and insulin. Levels of phospho(Ser473)-protein kinase B (Akt), phospho(Ser307)-IRS1, phosphoinositide 3-kinase (PI3K) activity and phospho(Ser32)-inhibitor of κB (IκBα) were determined by western blotting and ELISA. RESULTS: Glucose tolerance was significantly impaired in carrageenan-treated 12-week-old mice compared with untreated controls at all time points (n = 12; p < 0.0001). Baseline insulin and insulin levels at 30 min after taking glucose during the GTT were significantly higher following carrageenan treatment. During the ITT, glucose levels declined by more than 80% in controls, but not in carrageenan-treated mice. Carrageenan exposure completely inhibited insulin-induced increases in phospho-(Ser473)-Akt and PI3K activity in vivo in mouse liver and in human HepG2 cells. Carrageenan increased phospho(Ser307)-IRS1 levels, and this was blocked when carrageenan-induced inflammation was inhibited. CONCLUSION: This is the first report of the impact of carrageenan on glucose tolerance and indicates that carrageenan impairs glucose tolerance, increases insulin resistance and inhibits insulin signalling in vivo in mouse liver and human HepG2 cells. These effects may result from carrageenan-induced inflammation. The results demonstrate extra-colonic manifestations of ingested carrageenan and suggest that carrageenan in the human diet may contribute to the development of diabetes.

A modified thrombin clotting time test as a quality control marker for heparin contamination in obstetric intraoperative cell salvage.

OBJECTIVE: To assess if a modified thrombin clotting time test could be used as a simple quality control (QC) method to screen for unfractionated heparin in the product obtained from obstetric intraoperative cell salvage cases before re-infusion. BACKGROUND: A national QC scheme has recently been piloted to monitor the quality of autologous blood being returned to the patient. Laboratory tests include full blood count and microalbumin. Unfractionated heparin testing should be performed to ensure that there is no gross contamination of heparin in the final product; however, presently, there is no quick cheap test available suitable for heparin detection. MATERIALS AND METHODS: Samples were collected into plain non-anticoagulated tubes and centrifuged at 2500 × g for 5 min. Supernatant was mixed with commercially available coagulated normal plasma and a thrombin clotting time test performed. RESULTS: Calibration runs demonstrated that our system was sensitive up to 0 · 14 IU mL(-1) heparin, linear between 0 · 08 and 0 · 14 IU mL(-1). CONCLUSION: We have shown that the thrombin clotting time test can be modified and used as a cheap and reliable marker for heparin contamination. We have successfully incorporated this modified test into our hospital's obstetric QC scheme.

Intraoperative cell salvaged blood as part of a blood conservation strategy in Caesarean section: is fetal red cell contamination important?

BACKGROUND: Cell salvage is used in obstetric surgery as part of a blood conservation strategy in our Trust. This carries a theoretical risk of amniotic fluid embolism and also a risk of fetal red cells being present in the re-infusion, resulting in alloimmunization. In this study, we attempted to quantify the risk of antibody formation from re-infusion of autologous blood after Caesarean section. METHODS: Women presenting for elective Caesarean section were routinely requested to consent for collection of blood by cell salvage, using one suction device. If an adequate volume of blood was collected, it was processed and, if clinically appropriate, re-infused via a leucodepletion filter. Women who received a re-infusion were followed up to test for antibody formation. RESULTS: Seventy women consented for re-infusion and follow-up. The median volume re-infused was 324 ml (range 118-1690 ml). The median fetal red cell contamination was 0.8 ml (range 0.2-12.9 ml). All re-infusions were given without adverse clinical signs. No antibodies were detected in 48 follow-up samples. One positive anti-S antibody was detected. CONCLUSIONS: The implementation of a blood conservation strategy which includes the use of intraoperative cell salvage appears safe and can contribute to a reduction in the number of blood transfusions to the obstetric population. We remain uncertain of the significance of fetal red cell contamination.

Use of cardiac markers to assess the toxic effects of anthracyclines given to children with cancer: a systematic review.

AIM: To evaluate the effectiveness of cardiac markers to quantify anthracycline-induced cardiotoxicity in children with cancer. METHODS: Systematic review using a priori methods. RESULTS: Seven studies, all with methodological limitations, were identified. One RCT suggests that cardiac troponin can be used to assess the effectiveness of the cardio-protective agent dexrazoxane. Cohort studies suggest that atrial natriuretic peptide and brain (B-type) natriuretic peptide are elevated in some subgroups of patients compared with healthy children; NT-pro-BNP levels are significantly elevated in children with cardiac dysfunction compared with those without; serum lipid peroxide is higher in children who have received doxorubicin compared with children not receiving doxorubicin; there are no differences in carnitine levels between children treated with doxorubicin and a healthy control group. CONCLUSIONS: The limited evidence makes conclusions difficult. Research is needed to fill this important evidence gap and link short-term changes in cardiac markers to longer-term cardiac damage.

Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

OBJECTIVES: To evaluate the technologies used to reduce anthracycline-induced cardiotoxicity in children. Also to evaluate cardiac markers to quantify cardiotoxicity, and identify cost-effectiveness studies and future research priorities. DATA SOURCES: Eight electronic databases were searched from inception to January 2006. Bibliographies of related papers were assessed for relevant studies and experts contacted to identify additional published references. REVIEW METHODS: A systematic review of the evidence was undertaken using a priori methods. RESULTS: Four randomised controlled trials (RCTs) met the inclusion criteria of the review, each considering a different cardioprotective intervention; all trials included children with acute lymphoblastic leukaemia, and one also included children with non-Hodgkin's lymphoma. However, all had methodological limitations. No cost-effectiveness studies were identified. One RCT and six cohort studies on the use of cardiac markers met the inclusion criteria of the review, but also had methodological limitations. Of the two RCTs that considered continuous infusion versus bolus (rapid) infusion, one found that continuous infusion of doxorubicin did not offer any cardioprotection over bolus; the other suggested that continuous infusion of daunorubicin had less cardiotoxicity than bolus. Two studies considered cardioprotective agents, one concluded that dexrazoxane prevents or reduces cardiac injury without compromising the antileukaemic efficacy of doxorubicin and the other reported a protective effect of coenzyme Q10 on cardiac function during anthracycline therapy. One RCT suggested that cardiac troponin T can be used to assess the effectiveness of the cardioprotective agent dexrazoxane. Two cohort studies considering atrial natriuretic peptide and two considering brain (B-type) natriuretic peptide suggested that these chemicals are elevated in some subgroups of children treated with anthracyclines for cancer. N-terminal B-type natriuretic peptide levels were significantly elevated in children treated with anthracyclines who had cardiac dysfunction. One cohort study found that serum lipid peroxide was higher in younger children treated with doxorubicin than correspondingly aged children not receiving doxorubicin. No differences in carnitine levels were found in children treated with doxorubicin and a group of healthy children in one cohort study. CONCLUSIONS: It is difficult to draw conclusions about the effectiveness of technologies for reducing or preventing cardiotoxicity and about the use of cardiac markers in children as the evidence is limited in quantity and quality. The lack of standardisation for monitoring and reporting cardiac performance is problematic. Not all studies report effectiveness in terms of cardiac outcomes and event-free survival with supporting statistical analyses. Studies are mostly small and of short duration, making generalisation difficult. Increasing numbers of survivors of childhood cancer treated with anthracyclines will experience cardiac damage and require long-term surveillance and management. This will have an impact on cardiac services and costs. Diverse medical problems and other late sequelae that affect cardiac outcome will have an impact on other specialist services. Mechanisms to reduce or prevent cardiotoxicity from anthracycline therapy and cardiac markers to improve monitoring could alter the extent of this impact on service provision. RCTs of the different methods for reducing or preventing cardiotoxicity in children treated with anthracyclines for cancer with long-term follow-up are needed to determine whether the technologies influence the development of cardiac damage. Cost-effectiveness research is also required.

T-regulatory cells are relatively deficient in squamous carcinomas undergoing regression in mice immunized with a squamous carcinoma vaccine enriched for immunotherapeutic cells.

In a prior report (Int J Cancer 2006; 119: 339-348), we described a new vaccination strategy for squamous cell carcinoma (SCC). The vaccine was prepared by transfer of unfractionated DNA-fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 origin; H-2(d)) into LM cells, a highly immunogenic mouse fibroblast cell line (C3H/He origin; (H-2(k))). As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying antigens associated with the squamous carcinoma cells, we devised a novel strategy to enrich the vaccine for immunotherapeutic cells. Enhanced immunity to squamous carcinoma was induced in tumor-bearing mice treated solely by immunization with the enriched vaccine, which translated into prolonged survival without toxicity. Here, we describe the characteristics of the cell populations infiltrating established squamous carcinomas undergoing regression in mice immunized with vaccines enriched for immunotherapeutic cells. The results indicated that CD8+ T cells were predominant and that T-regulatory cells (FoxP3+, CD4/CD25+, CD4/CD62L(high), CD4/CTLA-4e) were relatively deficient in the regressing tumors. Inflammatory infiltrates were not detected in various organs and tissues of mice immunized with the DNA-based vaccine.

New strategy for the identification of squamous carcinoma antigens that induce therapeutic immune responses in tumor-bearing mice.

This study describes a new strategy for the identification of squamous carcinoma antigens tumor-associated antigens (TAA). The antigens were discovered by comparing microarrays of squamous carcinoma vaccines highly enriched for immunotherapeutic cells with non-enriched vaccines. The vaccines were prepared by transferring sheared genomic DNA fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 mouse origin (H-2(d)) into LM fibroblasts (C3H/He origin, H-2(k)). The transferred tumor DNA segments integrate spontaneously into the genome of the recipient cells, replicate as the cells divide and are expressed. As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying TAA (the vast majority specify normal cellular constituents), a novel strategy was employed to enrich the vaccine for TAA-positive cells. Microarrays were used to compare genes expressed by enriched and non-enriched vaccines. Seventy-five genes were overexpressed in cells from the enriched vaccine. One, the gene for Cytochrome P450 (family 2, subfamily e, polypeptide 1) (Cyp2e1), was overexpressed in the enriched but not the non-enriched vaccine. A vaccine for squamous carcinoma was prepared by transfer of a 357 bp fragment of the gene for Cyp2e1 into the fibroblast cell line. Robust immunity, sufficient to result in indefinite survival, was induced in tumor-bearing mice immunized with cells transfected with this gene fragment.

Clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

This review systematically assessed the evidence on the clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children with cancer. We searched eight electronic databases, including Medline and the Cochrane Library, from inception to January 2006 for systematic reviews and randomised controlled trials that reported death, heart failure, arrhythmias or measures of cardiac performance associated with cardioprotective technologies compared with standard treatment in children treated for cancer with anthracyclines. Economic evaluations were also sought. Inclusion criteria, data extraction and quality assessment were undertaken by standard methodology. Four randomised controlled trials met the inclusion criteria of the review; each had methodological limitations. No economic evaluations were identified. Studies were combined through narrative synthesis. One trial found that continuous infusion of doxorubicin did not offer any cardioprotection over rapid infusion. One suggested that continuous infusion of daunorubicin provoked less cardiotoxicity than rapid infusion. One concluded that dexrazoxane reduces cardiac injury during doxorubicin therapy and one reported a protective effect of coenzyme Q(10) on cardiac function during anthracycline therapy. The evidence on the effectiveness of cardioprotective technologies in children is limited in quality and quantity thus making conclusions difficult. This is surprising given the importance of anthracycline use in children with cancer. Further long-term research, which includes relevant outcome measures, is needed to determine whether technologies influence the development of cardiac damage without limiting the antitumour efficacy of anthracyclines.

Outcome after preterm delivery of infants antenatally diagnosed with congenital heart disease.

OBJECTIVE: To determine outcome of delivery before 36 weeks gestation in babies diagnosed antenatally with serious congenital heart disease (CHD). STUDY DESIGN: A retrospective database review at 2 tertiary care fetal cardiology centers. Details of neonatal course and outcome were obtained for those antenatally diagnosed with serious CHD who were live born before 36 weeks gestation. RESULTS: Between January 1998 and December 2002, 9918 women were referred for fetal echocardiography. Serious CHD was diagnosed in 1191 fetuses (12%), of which 46 (4%) delivered prematurely. Median gestation was 33 (range 24-35) weeks, and median birth weight 1.56 (0.50-3.59) kg. Extracardiac/karyotypic anomalies occurred in 23 (50%). Twenty-six babies (57%) underwent neonatal surgery: 16 a cardiac procedure, 5 a general surgical procedure, and 5 both. Eight died during or after operation (31%). Two babies underwent interventional heart catheterization; both died. The overall mortality rate was 72%. Extracardiac/karyotypic anomalies increased the relative risk of death by a factor of 1.36. Mean hospital stay for those surviving to initial discharge was 46 (2-137) days. CONCLUSIONS: There is a very high morbidity and mortality rate in this group, particularly for those with extracardiac/karyotypic anomalies. This should be reflected in decisions over elective preterm delivery and when counseling parents.