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1.  Ectopic intracranial retinoblastoma in childhood. 
Twelve out of a series of 630 children with retinoblastoma, treated in the ocular oncology units at St Bartholomew's and Moorfields Eye Hospitals during the past 30 years, have developed ectopic intracranial retinoblastoma. The ectopic tumour occurred in the pineal region in eight children and in the suprasellar region in four. Ten patients had bilateral retinoblastoma, one unilateral disease, and one child presented with an isolated suprasellar tumour but no evidence of retinal disease. The interval from the initial diagnosis of retinoblastoma to the development of ectopic intracranial disease ranged from 4 to 70 months, median 34 months. Methods of treatment for the ectopic tumour varied, but all 12 children died with a median survival of only 8 months following the diagnosis of ectopic retinoblastoma. Subsequent spread of tumour to other sites within the central nervous system proved to be the most frequent cause of death. Ectopic intracranial retinoblastoma is a potentially curable neoplasm, but it requires adequate therapy to the whole neuraxis as well as high dose equivalent radiotherapy to the primary tumour.
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PMCID: PMC1040731  PMID: 4052359
2.  'JEB'--a carboplatin based regimen for malignant germ cell tumours in children. 
British Journal of Cancer  1990;62(2):257-262.
Between February 1986 and July 1988 a total of 21 children aged 1 to 16 years with malignant germ cell tumours (MGCT), 18 with either metastatic disease or unresectable primary tumour, received the JEB regimen - carboplatin dosage calculated from the EDTA glomerular filtration rate (approximately 600 mg m-2), etoposide 120 mg m-2 daily x 3, and bleomycin 15 mg m-2 weekly. Primary sites were: testis (6), ovary (8), sacrococcyx (4), pineal gland (2) and vagina (1). AFP levels were elevated in 19, beta-HCG in 8. Complete marker response was achieved in 19 out of 19 evaluable patients and complete remission of measurable tumour in 16 out of 19, 12 with chemotherapy alone and 4 with the addition of surgery. A reduction in glomerular filtration rate greater than 10% occurred in 3 of 12 evaluable patients; in none greater than 20%. Sequential audiography was normal in 11 out of 12 evaluated. The regimen was myelosuppressive with WHO grade III or IV myelosuppression occurring in 12 patients. Three patients have relapsed; one with a pineal germinoma who relapsed in the abdomen six months after diagnosis, and two with sacrococcygeal teratomas and lung metastases. Two of these remain in second complete remission after further treatment. There was one death from probable bleomycin pulmonary toxicity. We conclude that this regimen is simple to administer and, apart from myelosuppression, it is well tolerated. It appears to have comparable efficacy to cisplatin-based regimens but with much less nephrotoxicity and ototoxicity and avoids the use of alkylating agents and anthracyclines.
PMCID: PMC1971831  PMID: 1696831
3.  Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours 
British Journal of Cancer  1999;80(9):1392-1399.
The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. ‘Progressive disease’ included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of ‘conventional’ platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0–99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23–38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a ‘small’ centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l−1 or hCG >100 IU l−1) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37–56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60–88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated ‘conventional’ platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l−1 and AFP < 100 kU l−1). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690534
PMCID: PMC2363071  PMID: 10424741
germ cell malignancy; relapse; cisplatin-based chemotherapy; survival
4.  Advanced seminoma: treatment with cis-platinum-based combination chemotherapy or carboplatin (JM8). 
British Journal of Cancer  1985;52(1):7-13.
Between 1978 and 1983, 44 patients with advanced seminoma were treated with cis-platinum-based combination chemotherapy (39 patients) or with carboplatin (JM8), as a single agent (5 patients). Of the total group, 40 (90%) are alive and disease free. Two of the 4 patients who died relapsed as non-seminomatous germ-cell tumours. Results in previously untreated patients indicate that tumour volume is less important as a prognostic factor than in non-seminomas. Residual masses were present in almost 80% of patients 1 month after chemotherapy; such masses regress slowly and surgery is not indicated. Elective radiotherapy after chemotherapy appears to be inessential since relapse rates are comparable in irradiated (1/15) and unirradiated patients (1/16). Pretreatment serum HCG concentrations did not influence the outcome of chemotherapy. Preliminary results with JM8 suggest that it is an active single agent in the treatment of seminoma.
PMCID: PMC1977156  PMID: 3893507
5.  Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery. 
British Journal of Cancer  1993;67(5):1098-1101.
A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.
PMCID: PMC1968447  PMID: 8494705
6.  A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas 
Journal of Medical Genetics  2005;42(1):31-37.
Background: Platelet derived growth factor receptor α (PDGFRα) expression is typical for a variety of brain tumours, while in normal adult brain PDGFRα expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFRα expression in tumours are not known, but in the absence of amplification, changes in transcriptional regulation might be an important factor in this process.
Methods and results: We have investigated the link between single nucleotide polymorphisms (SNPs) within the PDGFRα gene promoter and the occurrence of brain tumours (medulloblastomas, supratentorial primitive neuroectodermal tumours (PNETs), ependymal tumours, astrocytomas, oligodendrogliomas, and mixed gliomas). These SNPs give rise to five different promoter haplotypes named H1 and H2α–δ. It is apparent from the haplotype frequency distribution that both PNET (10-fold) and ependymoma (6.5-fold) patient groups display a significant over-representation of the H2δ haplotype. The precise functional role in PDGFRα gene transcription for the H2δ haplotype is not known yet, but we can show that the H2δ haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes.
Conclusions: The specific over-representation of the H2δ haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFRα pathway in the pathogenesis of these tumours.
doi:10.1136/jmg.2004.024034
PMCID: PMC1735903  PMID: 15635072
7.  A Case Series of Transformation of Teratoma to Primitive Neuroectodermal Tumor: Evolving Management of a Rare Malignancy 
Rare Tumors  2014;6(1):5268.
Primitive neuroectodermal tumor (PNET) is a pathologic diagnosis that encompasses several different tumor types, including central nervous system tumors and Ewing’s sarcomas. Teratoma, a common element of germ cell tumor (GCT), has the ability to transform to malignant PNET in a small number of patients. Making a definitive diagnosis of PNET is difficult given its deviation from elements of GCT and its non-specific pathologic findings. Establishing the diagnosis is crucial as PNETs respond poorly to standard platinum-based chemotherapy used for treatment of GCT. Primary treatment for PNET is surgical, though this is often not feasible in many patients due to extensive disease at diagnosis. As an alternative, chemotherapy regimens traditionally used for Ewing’s sarcoma, such as vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide, have shown limited efficacy in the neoadjuvant, adjuvant, and palliative settings. Future research should delineate the genetic underpinnings of PNET and develop therapeutic options accordingly.
doi:10.4081/rt.2014.5268
PMCID: PMC3977172
primitive neuroectodermal tumor; PNET; teratoma; chemotherapy
8.  Pineal yolk sac tumour with a solid pattern: a case report in a Chinese adult man with Down’s syndrome 
Journal of Clinical Pathology  2004;57(8):882-884.
Intracranial germ cell tumours are rare. The incidence of primary intracranial yolk sac tumour is even more uncommon, with only two reported cases being associated with Down’s syndrome in the English literature. This report details the findings of yolk sac tumour in the pineal region affecting a 22 year old Chinese man with Down’s syndrome. Histology revealed yolk sac tumour with only a solid pattern, potentially mimicking the more common germinoma in the pineal region. No other germ cell components were identified. This is the third report of intracranial yolk sac tumour manifesting in a patient with trisomy 21. The pathology of this tumour and its differential diagnoses are discussed.
doi:10.1136/jcp.2004.016659
PMCID: PMC1770394  PMID: 15280413
yolk sac tumour; pineal; diagnosis; Down’s syndrome
9.  Rapid palliation of symptoms with platinum-based chemotherapy plus cetuximab in recurrent oral cancer: a case report 
Background
Symptom control is an important consideration in the choice of treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients who demonstrate objective tumour responses to platinum-based chemotherapy are more likely to have symptom relief than those who do not have such responses. A phase III trial (EXTREME) showed that adding the epidermal growth factor receptor (EGFR)-targeting IgG1 monoclonal antibody cetuximab to first-line platinum-based chemotherapy significantly prolongs progression-free and overall survival and increases response rate compared with platinum-based chemotherapy alone. We report here the case of a 60-year old female with recurrent squamous cell carcinoma of the gum who had rapid palliation of symptoms and reduction of facial disease mass following treatment with a combination of carboplatin/5-fluorouracil (5-FU) and cetuximab.
Case presentation
The patient was diagnosed with T4N0 M0 disease of the oral cavity in November 2006 and underwent surgery, with R0 resection, followed by adjuvant radiotherapy and concomitant cisplatin chemotherapy. Around 3 months later, the disease recurred and the patient had severe pain (9/10 on a visual pain scale), marked facial oedema and a palpable facial mass of 89 mm. The patient received 4 21-day cycles of carboplatin (AUC 5), 5-FU (1,000 mg/m2/day for 4 days) and cetuximab (400 mg/m2 initial dose followed by subsequently weekly doses of 250 mg/m2), with continuation of cetuximab monotherapy at the end of this time, and pain relief with topical fentanyl and oral morphine. After 7 days of treatment, pain had reduced to 2/10, with discontinuation of morphine after 4 days, and the facial mass had reduced to 70 mm. After 2 cycles of treatment, the facial mass had decreased to 40 mm. After 3 cycles of treatment, pain and facial oedema had resolved completely and a cervical computed tomography scan showed a marked reduction in tumour mass. Cetuximab monotherapy was continued uninterrupted for 7 months.
Conclusion
This case illustrates the rapid reduction of tumour mass and disease-associated pain and oedema that can be achieved with a combination of platinum-based chemotherapy and cetuximab in recurrent and/or metastatic SCCHN.
doi:10.1186/1758-3284-2-3
PMCID: PMC2832769  PMID: 20181021
10.  Optimal chemotherapy treatment for women with recurrent ovarian cancer 
Current Oncology  2007;14(5):195-208.
Question
What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy?
Perspectives
Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy.
Outcomes
Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada.
Results
Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer.
In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials.
In eight of the thirteen trials in which 35%–100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038; hazard ratio: 1.23; 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001).
Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.
Practice Guideline
Target Population
This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy. As a general categorization within what is actually a continuum, “platinum sensitivity” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy, and “platinum resistance” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped. “Platinum-refractory disease” refers to a lack of response or to progression while on platinum-based chemotherapy.
Recommendations
Although the body of evidence that informs the clinical recommendations is based on randomized trial data, those data are incomplete. Based on the available data and expert consensus opinion, the Gynecology Cancer dsg makes these recommendations:
Systemic therapy for recurrent ovarian cancer is not curative. It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. All suitable patients should be offered the opportunity to participate in randomized trials, if available.
In the absence of contraindications, combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy. As compared with carboplatin alone, the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival.
If combination platinum-based chemotherapy is not indicated, then a single platinum agent should be considered. Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile.
If a single platinum agent is not being considered, then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin are seen as reasonable treatment options.
Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy.
For patients with platinum-refractory or platinum-resistant disease, the goals of treatment should be to improve quality of life by extending the symptom-free interval, by reducing symptom intensity, and by increasing progression-free interval, and, if possible, to prolong life.
With non-platinum agents, monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options.
No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence. Many treatment options have shown modest response rates, but their benefits over best supportive care have not been studied in clinical trials.
PMCID: PMC2002482  PMID: 17938703
Chemotherapy; drug therapy; ovarian cancer; ovarian neoplasms; practice guideline; systematic review
11.  Phase 2 Trial of Pemetrexed in Children and Adolescents with Refractory Solid Tumors: a Children’s Oncology Group Study 
Pediatric blood & cancer  2012;60(2):237-241.
Background
Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile.
Procedure
Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma.
Results
Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in 5 patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n=1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%).
Conclusions
Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.
doi:10.1002/pbc.24244
PMCID: PMC3463652  PMID: 22745043
pemetrexed; phase 2; antifolate
12.  Magnetic resonance imaging of pineal region tumours 
Insights into Imaging  2013;4(3):369-382.
Objectives
Pineal lesions can present as a heterogeneous collection of benign and malignant disease conditions. Pineal lesions include germ cell tumours, neoplasms arising from the pineal parenchyma, as well as other pineal region masses.
Methods
A variety of cases of pineal lesions are presented. The important clinical features and typical imaging findings of each pineal lesion are described with emphasis on their morphological appearance and signal intensity characteristics on magnetic resonance imaging (MRI).
Conclusion
Knowledge of the imaging characteristics and clinical features of varying pineal lesions can assist in narrowing the differential diagnosis for more accurate and rational therapeutic planning.
Teaching Points
• Pineal parenchymal tumours show an “explosion” of normal pineal calcifications towards the periphery.
• Pineoblastomas often have restricted diffusion, with apparent diffusion coefficient (ADC) values lower than germinomas.
• Pineal teratomas and pineal lipomas display fat signal characteristics and fat saturation on MRI.
• Pineal lesions in patients with known malignancy should raise suspicion of metastatic involvement.
• Pineal cysts and arachnoid cysts show MRI signal characteristics similar to cerebrospinal fluid (CSF).
doi:10.1007/s13244-013-0248-6
PMCID: PMC3675249  PMID: 23640020
Pineal gland; Pineal tumors; Pineal neoplasm; Pineal parenchyma tumors; MRI
13.  Long-term follow-up of residual masses after chemotherapy in patients with non-seminomatous germ cell tumours 
British Journal of Cancer  2000;83(10):1274-1280.
This retrospective study was undertaken to determine the outcome of patients with non-seminomatous germ cell tumour who achieved a serological complete response but who had residual radiologic abnormalities upon completion of primary platinum-based chemotherapy. This was an analysis of 76 consecutive patients treated at Mount Vernon Hospital between 1983 and 1997. The patients were placed into two groups based upon whether they had surgical resection (surgery group, 48 patients) or observation (observation group, 28 patients) of residual radiologic masses on completion of initial chemotherapy (to enter the surgery group, complete surgical resection must have been achieved). The primary end-points were progression-free and overall survival. The percentage of patients alive with median follow-up 66 months was 90% for the surgery group and 80% for the observation group (P= 0.53, not significant). The percentage of patients continuously disease-free was 70% in the surgery group and 80% in the observation group (P= 0.31, not significant). In the small sub-group of patients with differentiated teratoma (TD) in the primary lesion who were observed, there was no excess risk of relapse or death. Patients who achieve a serological complete response after primary chemotherapy, but are left with ≤ 2 cm radiological masses that are not cystic and have responded, can be safely observed with diligent follow-up. © 2000 Cancer ResearchCampaign
doi:10.1054/bjoc.2000.1416
PMCID: PMC2408794  PMID: 11044349
testicular neoplasms; surgery; retroperitoneal lymph node dissection
14.  Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer 
BMC Cancer  2013;13:549.
Background
Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer.
Methods
The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with standard platinum-based chemotherapy. Twelve patient tumours demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumours from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using an Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumours from the resistant group and the sensitive group.
Results
Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NF κB/ERK gene signalling networks.
Conclusions
This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. In addition, our results provide a pathway context for further experimental validations, and the findings are a significant step towards future therapeutic interventions.
doi:10.1186/1471-2407-13-549
PMCID: PMC3840597  PMID: 24237932
Ovarian cancer; Chemotherapy resistance; Biomarkers; Gene expression; Microarray
15.  Salvage treatment in male patients with germ cell tumours. 
British Journal of Cancer  1993;67(3):568-572.
The outcome of salvage treatment was reviewed in 55 patients relapsing during or after their primary chemotherapy for advanced malignant germ cell tumours. Fifty-two patients had been given cisplatin-based chemotherapy as their primary treatment, whereas three patients had received carboplatin-based chemotherapy. The median time to relapse was 2 months (range: 0-96 months) from discontinuation of the primary treatment. Two patients underwent radical surgery only, and one patient had radiotherapy to a brain metastasis as his only curatively intended salvage treatment. Six patients did not receive any treatment for their recurrent malignancy (refusal, terminal condition) except for purely palliative measures. The disease-free survival for the total group was 27% at 5 years. Complete response to primary treatment lasting for > or = 6 months was the only parameter which significantly predicted a favourable outcome (45% 5 year disease-free survival in 12 eligible patients).
PMCID: PMC1968255  PMID: 8382512
16.  Platinum drugs in the treatment of non-small-cell lung cancer 
British Journal of Cancer  2002;87(8):825-833.
The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours.
British Journal of Cancer (2002) 87, 825–833. doi:10.1038/sj.bjc.6600540 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600540
PMCID: PMC2376170  PMID: 12373594
cisplatin; carboplatin; ZD0473; BBR3464; oxaliplatin; non-small-cell lung cancer
17.  Malignant transformation of an intracranial germinoma into a choriocarcinoma 
BMJ Case Reports  2009;2009:bcr12.2008.1351.
The recurrence or metastasis of intracranial pure germinomas as germ cell tumours of different histological types has rarely been reported. The present report concerns the first case in the literature of intracranial recurrence of a germinoma transformed into a choriocarcinoma. A 17-year-old man presented with a 1 month history of headache. MRI revealed a homogeneously enhanced mass within the pineal and suprasellar regions. The tumour was resected, and histological examination identified it as a pure germinoma. After resection, the patient underwent chemotherapy and radiotherapy and the mass disappeared. At 5 years and 5 months later, the patient presented with nausea and headache, and recurrence of the tumour was revealed in the left lateral ventricle. The tumour was resected and histological diagnosis identified it as a choriocarcinoma. The patient was treated with chemotherapy and radiotherapy, but died due to dissemination 1 month later. An autopsy was not performed.
doi:10.1136/bcr.12.2008.1351
PMCID: PMC3027365  PMID: 21686358
18.  The RB1 gene mutation in a child with ectopic intracranial retinoblastoma. 
British Journal of Cancer  1997;76(11):1405-1409.
The RB1 gene mutation was investigated in a child with ectopic intracranial retinoblastoma using DNA obtained from both the pineal and retinal tumours of the patient. A nonsense mutation in exon 17 (codon 556) of the RB1 gene was found to be present homozygously in both the retinal and the pineal tumours. The same mutation was present heterozygously in the DNA from the constitutional cells of the patient, proving it to be of germline origin. The initial mutation was shown to have occurred in the paternally derived RB1 allele. The mutation is in an area of the gene that encodes the protein-binding region known as the 'pocket' region and has been detected in other cases of retinoblastoma.
Images
PMCID: PMC2228178  PMID: 9400934
19.  Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours 
Introduction:
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
Methods:
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
Results:
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
Conclusions:
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
doi:10.5489/cuaj.11233
PMCID: PMC3328550  PMID: 22511417
20.  Human germ cell tumours: expression of γ-glutamyl transpeptidase and sensitivity to cisplatin 
British Journal of Cancer  1999;81(1):75-79.
Previous studies have shown that the enzyme γ-glutamyl transpeptidase (GGT) is essential for the nephrotoxicity of cisplatin. This study was designed to determine whether GGT activity is necessary for the therapeutic effect of the drug. The relationship between GGT expression and clinical response to platinum-based chemotherapy was examined in 41 human germ cell tumours. Sections of formalin-fixed, paraffin-embedded tumours were immunohistochemically stained with an antibody directed against human GGT. There was no expression of GGT in any of the 17 seminomas or four dysgerminomas; whereas, 12/12 ovarian yolk sac tumours and 4/4 embryonal carcinomas of the testis were GGT-positive. In stage I tumours fewer tumour cells expressed GGT than in later stage tumours. In four germ cell tumours of mixed histology, the seminomatous and dysgerminoma areas were GGT-negative while the areas of the tumour with yolk sac or embryonal histology contained GGT-positive tumour cells. The patients with seminomas or dysgerminomas who were treated with cisplatin-based chemotherapy, all had a complete response despite the absence of GGT expression in these tumours. Fifteen of the 16 patients with yolk sac or embryonal carcinomas received cisplatin-based chemotherapy following surgery. Twelve had a complete response, while three failed to respond to platinum-based therapy. There was no correlation between the level of GGT-expression and response to therapy in this group. Three of the four patients with tumours of mixed histology were treated with cisplatin-based therapy, and had a complete response. Therefore, expression of GGT is not necessary for the therapeutic effect of cisplatin in germ cell tumours. The results from this study suggest that systemic inhibition of GGT would inhibit the nephrotoxic side-effect of cisplatin without interfering with its activity towards germ cell tumours. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690653
PMCID: PMC2374348  PMID: 10487615
glutathione; human tumours; platinum-based therapy; chemotherapy
21.  A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer 
British Journal of Cancer  2002;86(9):1379-1384.
Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m−2; doxil 20, 30, 40 and 50 mg m−2. Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m−2 and doxil 30 mg m−2 q 21. Reducing the paclitaxel dose to 135 mg m−2 did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m−2 also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m−2, doxil 30 mg m−2 q 28 or carboplatin AUC 5, paclitaxel 175 mg m−2, doxil 20 mg m−2 q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.
British Journal of Cancer (2002) 86, 1379–1384. DOI: 10.1038/sj/bjc/6600250 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600250
PMCID: PMC2375380  PMID: 11986767
ovarian cancer; liposomal doxorubicin; carboplatin; paclitaxel
22.  Ploidy as a prognostic indicator in end stage squamous cell carcinoma of the head and neck region treated with cisplatinum. 
British Journal of Cancer  1990;61(5):759-762.
We measured tumour cellular DNA in 102 patients entered into two phase III trials of chemotherapy for end stage squamous carcinoma of the head and neck. The median survival of untreated patients with aneuploid tumours was 55 days compared with 224 days for patients treated with cisplatinum. This difference was highly significant. In contrast the median survival of untreated patients with diploid tumours was 74 days compared with 118 days for treated patients. Although this difference is statistically significant, the increased survival of 6 weeks is of no clinical benefit compared with the prolongation of survival of 6 months in patients with aneuploid tumours. Multivariate analysis showed that the significant predictors of survival were Karnofsky status, response to chemotherapy and ploidy.
PMCID: PMC1971589  PMID: 2337512
23.  Late deaths after treatment for childhood cancer. 
Archives of Disease in Childhood  1990;65(12):1356-1363.
An investigation of 749 deaths occurring among 4082 patients surviving at least five years after the diagnosis of childhood cancer in Britain before 1971 has been undertaken. Of the 738 with sufficient information the numbers of deaths attributable to the following causes were: recurrent tumour, 550 (74%), a second primary tumour, 61 (8%), a medical condition related to treatment of the tumour, 49 (7%), an traumatic death unrelated to the tumour or its treatment, 34 (5%), finally, any other cause unrelated to the tumour or its treatment, 44 (6%). Less than 10% of five year survivors of non-Hodgkin lymphomas, neuroblastoma, retinoblastoma, Wilms' tumour, or a soft tissue sarcoma died of recurrent tumour during the next 15 years, while more than 25% of five year survivors of Hodgkin's disease, ependymoma, medulloblastoma, and Ewing's tumour died of recurrent tumour during the corresponding period. Almost 50% of five year survivors of acute lymphoblastic leukaemia died of recurrent disease during the corresponding 15 years, a large proportion of deaths being due to central nervous system relapse in an era before central nervous system prophylaxis was routinely given. Comparison of the mortality observed with that expected from mortality rates in the general population indicated three times the expected number of deaths from non-neoplastic causes. Five times the expected number of deaths from cardiovascular causes were observed, these were predominantly myocardial infarction and cerebrovascular accidents. There was no evidence of an excess in the number of suicides observed, but there were three times the expected number of deaths from accidents observed after central nervous system tumours. Two groups of patients were identified whose deaths were potentially avoidable. Seven patients with craniopharyngioma and panhypopituitarism presented with addisonian crises during periods of stress not adequately covered by exogenous corticosteroids. In the other group were children who received radiotherapy and later developed problems related to radiation fibrosis. We emphasize that our investigation relates to patients diagnosed with childhood cancer before 1971. The pattern of mortality that will emerge after recent treatment regimens, in which chemotherapy is being used more extensively, is likely to be different from that observed in our study.
PMCID: PMC1793098  PMID: 2270944
24.  Mitomycin C and Vinorelbine for second-line chemotherapy in NSCLC – a phase II trial 
British Journal of Cancer  2007;96(7):1052-1056.
Single-agent therapy with Docetaxel or Pemetrexed is the current therapy of choice for second-line treatment in advanced non-small-cell lung cancer (NSCLC). The role of older agents was underattended over the last years. This study presents the combination of Mitomycin C and Vinorelbine in pretreated patients. Forty-two patients (stage IIIB and IV, pretreated with platinum-based chemotherapy) received 8 mg m−2 Mitomycin C on day 1 and 25 mg m−2 Vinorelbine on days 1 and 8 of a 28-day cycle. End points were objective tumour response, survival, and toxicity. Additionally, quality of life (QoL) was assessed. Five patients (11.9 %) achieved partial responses and 13 patients (31.9%) stable disease. Progression-free survival was 16 weeks. The median overall survival was 8.5 month. Eleven patients (26.2 %) suffered from grade 3 or 4 neutropenia and four patients (9.52%) from grade 3 or 4 anaemia. Evaluation of QoL showed that some items ameliorated during therapy. The therapeutic concept including Mitomycin C and Vinorelbine offers an efficacious and well-tolerated regimen, with relatively low toxicity. Objective response and survival data correlate with other second-line studies using different medication. As costs of Mitomycin C and Vinorelbine are lower compared with current drugs of choice, this regimen is likely to be cost-saving.
doi:10.1038/sj.bjc.6603683
PMCID: PMC2360135  PMID: 17353918
lung cancer; NSCLC; chemotherapy; second-line therapy; mitomycin; Vinorelbine
25.  p18Ink4cand p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor 
Cancer research  2009;69(2):440-448.
The RB tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10-15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with Cyclin-dependent kinases (Cdk) 4 and 6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where Cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to ~ 4 months. Interestingly, the Cdk-inhibitor p18Ink4c was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, though at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable retinoblastoma often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4-inhibitor p18Ink4c is a tumor suppressor in Cyclin D1-driven PNET suggests that pharmacological interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary Rb pathway disruption.
doi:10.1158/0008-5472.CAN-08-1892
PMCID: PMC2629408  PMID: 19147556
Cyclin D1; p53; Ink4c; PNET; brain

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