The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.

Cutaneous metastases from gastric carcinoma: an unusual presentation.

We report the case of a 71-year-old gentleman who intially developed cutaneous metastases from gastric carcinoma on his chin and cheek resembling sebaceous cysts.

An exploration of the impact of ethanol diluent on breath alcohol concentration in patients receiving paclitaxel chemotherapy.

PURPOSE: This study aimed to provide a better understanding of the impact of paclitaxel chemotherapy on breath alcohol in an Irish population. METHODS: Patients attending the Oncology Day Unit at Beaumont Hospital were invited to participate on the day of their treatment. The brand of paclitaxel used was Actavis Pharma Inc and contained 6 mg/mL paclitaxel in 50% Ethanol/ 50% Cremophor EL. Breath alcohol concentration was measured using the AlcoSense ™ Breathalyser on three separate visits. The primary end-point was the number of patients who were above the legal threshold for drink driving in Ireland. RESULTS: In total, 50 patients were recruited. 36 (68%) were female. The most common diagnosis was breast cancer (56%). Ten (20%) patients had metastatic disease and 4 (8%) had liver metastases. The mean paclitaxel dose administered was 118 mg. The mean amount of ethanol infused was 7.7 g. 27 patients had a detectable breath alcohol level on at least one visit. The mean breath alcohol concentration was 2 mcg/100 mL or 0.02 mg/L of breath. The maximum concentration of ethanol in exhaled breath was 11 mcg/100 mL or 0.11 mg/L which is 50% of the statutory limit for drink driving in Ireland. A weak correlation was observed between ethanol concentration in exhaled breath and the total amount of ethanol administered. Although no patient exceeded the general limit for drink driving in Ireland, three (6%) participants had a breath alcohol concentration above the threshold for professional, learner or novice drivers. CONCLUSION: Although definitive conclusions are limited by relatively small numbers, it seems unlikely that weekly paclitaxel infusions pose any significant risk to patients driving.

The impact of outpatient systemic anti-cancer treatment on patient costs and work practices.

BACKGROUND: There is extensive focus on the rising costs of healthcare. However, for patients undergoing cancer treatment, there are additional personal costs, which are poorly characterised. AIM: To qualify indirect costs during anti-cancer therapy in a designated Irish cancer centre. METHODS: An anonymous questionnaire collected demographic data, current work practice, and personal expenditure on regular and non-regular indirect costs during treatment. Differences between groups of interest were compared using the Mann-Whitney U test. RESULTS: In total, there were 151 responders of median age 58 years; 60 % were female and 74 % were not working. Breast cancer (29 %) was the most frequent diagnosis. Indirect costs totalled a median of €1138 (range €21.60-€7089.84) per patient, with median monthly outgoings of €354. The greatest median monthly costs were hair accessories (€400), transportation (€65), and complementary therapies (€55). The majority (74 %) of patients used a car and median monthly fuel expenditure was €31 (range €1.44-€463.32). Women spent more money during treatment (€1617) than men (€974, p = 0.00128). In addition, median monthly expenditure was greater for those less than 50 years old (€1621 vs €1105; p = 0.04236), those who lived greater than 25 km away (€2015 vs €1078; p = 0.00008) and those without a medical card (€2023 vs €961; p = 0.00024). CONCLUSION: This study highlights the need for greater awareness of indirect expenditures associated with systemic anti-cancer therapy in Ireland.

Association between paclitaxel and necrotic pancreatitis.

To our knowledge this is the first reported case of paclitaxel associated necrotic pancreatitis requiring a pancreatic necrostomy. This was a near fatal complication associated with paclitaxel with a high resulting morbidity. Although this is a rare association physicians should be wary of the potential to develop severe pancreatitis in patients receiving this therapeautic agent. Monitoring of serum amylase during therapy is therefore warranted.

HIV infection among heroin users and area of residence.

The aim of this study was to develop a hypothesis to explain the link between HIV prevalence and area of residence. The study was conducted in two parts using two existing data sources. In Part 1, the bloodborne viral test status and test results of a sample of clients attending treatment in December 2001 in two areas of Dublin, an inner city area (Dublin 8) and a suburban area (Dublin 24), were extracted from the Bloodborne Viral Status Dataset created by Grogan. In Part 2 the characteristics of heroin users seeking treatment for the first time at treatment services in their respective areas of residence, Dublin 8 or Dublin 24, between 1997 and 2000 were examined, using data from the National Drug Treatment Reporting System. A higher proportion of heroin users in Dublin 8 had HIV and hepatitis C than did their counterparts in Dublin 24. The analysis suggests that heroin users in Dublin 8 were more likely both to have ever used cocaine and to have used heroin daily, than were those who lived in Dublin 24. Also, a higher proportion of injectors living in Dublin 8 used heroin and cocaine concurrently than did their counterparts in Dublin 24. In both samples, heroin users who lived in Dublin 8 were older than those who lived in Dublin 24. The findings led to a hypothesis:'The risk of acquiring HIV is associated with area of residence and may be linked to cocaine use.

Mutations in beta-catenin are uncommon in colorectal cancer occurring in occasional replication error-positive tumors.

Beta-catenin has been identified as an oncogene in colon cancer and melanoma. Phosphorylation of sites in exon 3 of beta-catenin leads to degradation of this protein. These sites are primary targets for activating mutations. The frequency with which oncogenic mutations at these sites are found in colorectal cancer is unknown, as is the frequency of their occurrence in other malignancies. We analyzed 92 colorectal cancers (CRCs) and 57 cancer cell lines (representing a diversity of tumor types) to determine the frequency of activating mutations in this gene. Mutations in exon 3 of beta-catenin were found in 2 of 92 CRCs and in the colorectal cancer cell line HCT 116. Both tumors with beta-catenin mutations exhibited widespread microsatellite instability, which is indicative of a replication error phenotype, a phenotype known to be present in HCT 116. This suggests that mutations in beta-catenin are infrequent in CRC and miscellaneous cancer cell lines and may occur in association with a replication error phenotype.

Bloodborne virus infections among drug users in Ireland: a retrospective cross-sectional survey of screening, prevalence, incidence and hepatitis B immunisation uptake.

BACKGROUND: Injecting drug users are at high-risk of bloodborne virus infections including hepatitis C (HCV), hepatitis B (HBV) and HIV. AIMS: To document screening for and immunisation against bloodborne viruses and to determine the known prevalence and incidence of these infections. METHODS: A cross-sectional survey of clients attending 21 specialist addiction treatment clinics in one health board area in greater Dublin. Data collected on demographic characteristics, serology for HCV, HBV and HIV and immunisation against HBV. RESULTS: A total of 316 (88%) had been tested for anti-HCV antibody, 244 (68%) had been tested for anti hepatitis B core antibody (anti-HBc), 299 (84%) had been tested for hepatitis B surface antigen (HBsAg) and 307 (86%) had been tested for anti-HIV antibody. The prevalence of anti-HCV, anti-HBc, HBsAg, and anti-HIV were: 66%, 17%, 2% and 11% respectively. The incidence of HCV, HBV and HIV infections were: 24.5, 9.0 and 3.4 per hundred person years respectively. Eighty-one per cent of those in whom it was indicated, had started a targeted HBV immunisation programme in the clinics. CONCLUSION: The proportion of clients screened for HCV, HBV and HIV infection has increased since the introduction of a screening protocol in 1998. Targeted vaccination for opiate users against hepatitis B is more successful than previously shown in Ireland. The prevalence and incidence of bloodborne viruses remains high among opiate users attending addiction treatment services, despite an increase in availability of harm reduction interventions.

The "comparative growth assay": examining the interplay of anti-cancer agents with cells carrying single gene alterations.

We have developed a "comparative growth assay" that complements current assays of drug effects based on cytotoxicity. A co-culture of two cell lines, one of which is fluorescently labeled, is exposed to a cytotoxic agent and the proportion of fluorescent cells is compared with that of a baseline unexposed co-culture. For demonstration purposes, two HCT116 cell lines (an hMLH1 homozygous and an hMLH1 heterozygous mutant), altered by insertion of vector alone or the same vector carrying an insert for the expression of enhanced green fluorescent protein (EGFP), were exposed to numerous "anti-cancer" agents. The assay was further validated in a system of two cell lines differing only in the expression of the breast cancer resistance protein (BRCP). The assay allowed the estimation of the duration of action of a particular agent. Assessment of the agent's differential activity over a given time in culture could be expressed as a selection rate, which we chose to describe on an "average selection per day" basis. We conclude that this assay: 1) provides insight into the differential dynamic effects of chemotherapeutic agents or radiation; and 2) allows, through the use of matched cell lines, the investigation of critical physiologic features that govern cell sensitivity.

Preclinical and clinical aspects of biomodulation of 5-fluorouracil.

Although single agent 5-FU has for many years been the standard therapy for advanced colorectal malignancies, a number of recent clinical trials show higher response rates with biomodulation of 5-FU by several different agents. In general, trials of leucovorin, methotrexate, interferon, and PALA given in biomodulatory doses and sequences with 5-FU have demonstrated comparable response rates over a broad range. However, in the absence of controlled direct comparative phase III trials, final judgement on clinical superiority of a particular regimen must be reserved. Nevertheless, on the basis of current data, certain approaches appear promising and warrant further investigation. Compared to single agent 5-FU, survival benefit has been demonstrated with both low and high dose leucovorin/5-FU regimens and response rates in the 20-50% range appear reproducibly higher than those of 5-FU alone. Low dose and either continuous infusion or repetitive dosing of leucovorin, as well as the effect of treatment sequence and intervals between drugs, require additional investigation. When given 20-24 h before 5-FU, methotrexate achieves response rates similar to leucovorin modulated 5-FU, but the potential role of rescue leucovorin used in many of the trials makes definitive interpretation difficult. Interferon/5-FU regimens attaining response rates of 30-40% are promising but need to be carefully and rationally designed. Low dose PALA with effective doses of 5-FU achieving responses in 35-45% of patients represent a marked improvement in earlier trials of high dose PALA, but additional studies with higher doses not compromising 5-FU dose intensity should be considered. Certainly, the concomitant use of multiple modulating agents also needs further investigation. While many such trials already performed attained results no better than single agent biomodulation, the preliminary results obtained by Grem and colleagues with IFN/LV/5-FU in untreated patients, and by Conti et al. using TMTX/LV/5-FU in previously treated patients are encouraging. Further understanding of the mechanisms of action and interaction of modulating agents should allow additional rational combinations to be explored clinically. Cisplatin biomodulation of 5-FU has been studied in gastrointestinal and head and neck malignancies achieving excellent results in the latter group. Preclinical evidence exists which suggests, however, that 5-FU modulation of cisplatin may be more effective, especially when 5-FU is administered 24 h or more before cisplatin. Clinical investigation of this sequence is currently lacking. Data to support the clinical promise of AZT, IdUrd, uridine, and the benzylacyclouridines are not yet available, although preclinical and preliminary clinical studies are promising.

Genetic Testing for Cancer Risk Assessment: A Review.

Both environmental factors and an inherited predisposition influence carcinogenesis. The direct role of inheritance in the development of cancer is evident in familial cancer syndromes. These syndromes predispose to cancer through the inheritance of a mutation in a single gene in affected carriers. While many inherited cancer syndromes are rare, an inherited predisposition is directly responsible for 5%-10% of all colon and breast cancers. Complex multigenic inheritance plays an important role in cancer predisposition for the population at large. The identification of genes responsible for an inherited predisposition to colon and breast cancer syndromes has directed public attention to genetic testing for susceptibility to cancer. Assays are currently available to determine individual susceptibility to specific cancers. Cancer genetic testing is currently a time-consuming and complex procedure which requires expertise in its application, interpretation, and follow-up strategic planning. This review discusses cancer genetics and its application to individual and family cancer risk assessment with particular emphasis on breast and colon cancer.

Oral etoposide in small cell lung cancer.

Small cell lung cancer (SCLC) accounts for 25% of all cases of lung cancer diagnosed in the United States. The sensitivity of SCLC to chemotherapy offers good prospects for prolonged remission and long-term survival. Over the last decade, however, the overall response rate and median survival in SCLC patients have remained essentially unchanged. Single-agent intravenous (IV) etoposide has proven to be among the most active drugs for the treatment of SCLC. Oral or oral plus intravenous etoposide has been used in many combination chemotherapies. Studies demonstrating the schedule dependency of etoposide suggest that optimum results would be achieved if the total were administered over a minimum of 5 days. Given in such a schedule, oral etoposide has been shown to be effective in unfit or elderly (> 70 years of age) patients with SCLC, who represent 25% to 30% of the total SCLC population. Prolonged etoposide administration has achieved efficacy comparable with that attained in 5-day schedules, but with notable toxicity. Moreover, the value of dose intensity in single-agent and combination regimens employing etoposide has recently been questioned. New therapeutic strategies are clearly needed to increase the response rate, to prolong survival, and to improve quality of life in SCLC patients.

Single-agent oral etoposide for elderly small cell lung cancer patients.

Among new patients with small cell lung cancer (SCLC), 20% to 25% are over 70 years of age and account for 8,000 cases annually in the United States. For such patients, intensive, aggressive, cytotoxic, combination chemotherapy is not often used because of its association with unacceptable morbidity and mortality rates. However, treatment of these patients is often indicated, if not demanded. Etoposide is among the most active agents for the treatment of SCLC; both oral (PO) and intravenous preparations are available. The bioavailability of etoposide PO ranges from 15% to 75%. We carried out a phase II trial of etoposide PO in elderly patients (greater than or equal to 70 years of age) with a confirmed histologic diagnosis of SCLC. Patients were treated with etoposide capsules 800 mg/m2, with the total dose divided over 5 consecutive days. Cycles were repeated every 3 to 4 weeks for a total of six cycles. All treatment was administered on an outpatient basis. Staging procedures were confined to physical examination, chest x-ray, and laboratory investigations. Further staging procedures were carried out only if clinically indicated. In September 1985, 53 patients (35 male, 18 female) with a median age of 73 years (range, 70 to 95) were treated. After staging, 24 patients (45%) had limited disease (LD); the remaining 29 patients had extensive disease (ED). Overall response was 79% (complete response [CR], 17%; partial response, 62%). CRs were seen in 8 of 24 patients (33%) with LD and in 1 of 29 patients (3%) with ED. Median survival of all patients was 9.5 months (range, 1 to 22+) with 20 patients still alive; the toxicity rate was acceptable. Total alopecia developed in all patients, whereas significant neutropenia (8%) and thrombocytopenia (6%) were rare. There were no treatment-related deaths or hospital admissions. In this study, we showed activity of etoposide PO in patients with SCLC; these results were comparable with those reported for more intensive combination regimens. For elderly patients, etoposide PO provides excellent palliative treatment, with a high response rate and significant prolongation of survival. In addition, therapy is associated with minimal toxicity and can be administered entirely on an outpatient basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Physical interaction between p53 and primary response gene Egr-1.

The tumor suppressor p53 and primary response gene Egr-1 are nuclear transcription factors with regulatory roles in signal transduction pathways mediating cellular proliferation and growth arrest as well as the complex genetic programs controlling differentiation and programmed cell death. We identified a physical association between these regulatory proteins in vitro and in vivo. Recombinant p53 and Egr-1 fusion proteins complexed with in vitro translates of Egr-1 or p53, respectively, or with these respective proteins in cell lysates. This protein-protein interaction was detected in vivo by immunoprecipitation and Western blot analysis of serum-activated cellular lysates with high levels of induced Egr-1 and of human lung cancer cell lines with constitutive overexpression of Egr-1 and mutant p53. A p53 mutant at codon 154 did not bind Egr-1, while p53 proteins with point mutations at residues 156, 246, 247, and 273 associated with this zinc finger transcription factor. p53 bound full-length Egr-1 and an Egr-1 mutant with a deletion of the 5' transactivation region but did not associate with Egr-1 protein lacking an internal segment that included the first two zinc finger domains, suggesting that binding may require the presence of intact zinc finger motifs. A variant-sized Egr-1 protein expressed by lung fibroblast cell line MRC-9 was also bound by p53. The interaction of these regulatory proteins may alter multiple features of their biological activity especially with regard to the specificity of transcriptional control.

Bcl-2 rearrangement in Hodgkin's disease and reactive lymph nodes.

The chromosomal translocation t(14;18)(q32;q21), which involves the bcl-2 oncogene, occurs in most follicular lymphomas. Recent evidence suggests that this translocation occurs in Hodgkin's disease, linking its cellular origin and oncogenesis to follicular non-Hodgkin's lymphomas. Using polymerase chain reaction, the authors examined both Hodgkin's disease (n = 60) and reactive lymph nodes (n = 34) for the presence of bcl-2/JH breakpoint fragments, which are indicative of the t(14;18) chromosomal translocation in the major breakpoint region of the bcl-2 gene. The translocation was detected in approximately 10% of both Hodgkin's disease and nonmalignant reactive lymph node cases. These results suggest the possibility that the translocation may occur in the reactive component of Hodgkin's disease and not in the putative malignant cells, the Reed-Sternberg cells. Furthermore, the detection of the translocation in reactive lymph nodes suggests that it may not be the primary factor in the oncogenesis of follicular lymphoma.

Recent advances in the biology of colorectal cancer.

The identification of the precise molecular defects responsible for the common forms of inherited colorectal cancer has significantly advanced our understanding of both inherited and sporadic disease. These advances coupled with a rapid accumulation of information on the molecular genotype and biological phenotype of colorectal cancer have identified potential markers that may prove to be not only of prognostic value but also important as screening tools and therapeutic targets. These molecular and biological features include replication errors, mutations of oncogenes and tumor suppressor genes and expression of tumor specific antigens and cytokeratins. This review highlights important recent advances that further our understanding of the biology and genetics of colorectal cancer.

Resection of an intracardiac metastasis from malignant teratoma of the testis.

Nonseminomatous germ cell testicular neoplasm is a disease cured primarily by platinum-based combination chemotherapy. Operation is reserved for those patients who continue to harbor residual masses after chemotherapy. Locoregional lymph nodes and lungs are common sites for residual deposits. Intracardiac metastases are very rare. We report a case of successful resection of bilateral lung and single intracardiac secondary deposits from a malignant teratoma, treated by orchidectomy 6 years previously.