Leptomeningeal disease as a presenting feature of gestational trophoblastic neoplasia: A review and recommendations for management.

OBJECTIVES: Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD) related to GTN is not well reported with no consensus in optimal treatment. We offer recommendations for management of these patients. METHODS: We discuss five patients with GTN who presented with features of LMD and were diagnosed with gadolinium-enhanced MRI brain, all of whom received low dose induction etoposide-cisplatin (EP) followed by either EP-etoposide, methotrexate (CNS) and actinomycin-D (EMA) or EMA(CNS)-cyclophosphamide and vincristine (CO). RESULTS: Four out of the five patients additionally received intrathecal methotrexate. Four patients had complete hCG response to first line multi-agent chemotherapy, one patient required second line paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE), where paclitaxel was substituted with nab-paclitaxel due to anaphylaxis, followed by hysterectomy. One of the four initial complete hCG responders relapsed in the lung requiring further systemic treatment with subsequent lobectomy. Patient reported outcomes indicate persistent neurological symptoms are mild and do not affect functionality and quality of life. CONCLUSION: With a follow-up range of 2-6 years, all five patients remain cured demonstrating excellent survival outcomes with the avoidance of whole-brain radiotherapy in all cases.

Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Compliance and patient reported toxicity from oral adjuvant bisphosphonates in patients with early breast cancer. A cross sectional study.

BACKGROUND: Adjuvant bisphosphonates (BPs) are recommended as part of routine early breast cancer treatment for many postmenopausal (PM) women within the past year. There is a paucity of 'real world' data on compliance and patient satisfaction with oral BPs in this population. The aim of our study was to investigate patient reported compliance and toxicity of these drugs in a retrospective cohort study. PATIENTS AND METHODS: 413 patient were identified as receiving adjuvant oral BPs as part of their breast cancer treatment in the past 12 months from five NHS hospitals. The validated Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q) was sent to all suitable patients (n = 389). RESULTS: 295 (76%) of patients responded. Average age was median (range) 67 (35-89). The majority of patients had T1 (52%), N0 (61%) grade 2 (58%) ER positive (87%), HER2 negative (84%) breast cancer and were PM at diagnosis of breast cancer (93%). All patients had been prescribed at least 1 month of oral ibandronate 50 mg daily. Review of items rated on the 7-point scale (1 = very dissatisfied to 7 = very satisfied), the mean item scores ranged from 5.0 (lowest) for time required to take oral BPs, to 6.1 (highest) for how easy it is to remember to take the medication. <10% of patients were extremely bothered by heartburn or stomach upset. 16% of responders stopped oral BPs with 10% of those converting onto IV BPs. CONCLUSIONS: Prevalence of severe side effects in a 'real world' population of PM women receiving adjuvant BPs is low and these drugs are generally well accepted and tolerated by patients.

The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia.

OBJECTIVE: The objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs). METHODS: Databases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS). RESULTS: HDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred. CONCLUSIONS: Despite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy.

Do we need post-pregnancy screening with human chorionic gonadotrophin after previous hydatidiform mole to identify patients with recurrent gestational trophoblastic disease?

OBJECTIVE: To determine whether post-pregnancy human chorionic gonadotrophin screening after previous hydatidiform mole identifies patients with recurrent gestational trophoblastic disease. STUDY DESIGN: A retrospective evaluation of 9315 patients who underwent post-pregnancy screening from 2000 to 2009, as part of the National Gestational Trophoblastic Disease Service in the UK. RESULTS: Patients with previous hydatidiform mole, who had human chorionic gonadotrophin screening after one or more subsequent pregnancies, were identified (n = 9315). Of these, 8630 patients had an initial hydatidiform mole that did not require chemotherapy. In 12,329 subsequent pregnancy events, screening with human chorionic gonadotrophin identified 3 cases of gestational trophoblastic neoplasm. The remaining 685 patients developed gestational trophoblastic neoplasm, following their initial hydatidiform mole and required chemotherapy. In this group there were 1012 further pregnancy events, human chorionic gonadotrophin screening identified 3 patients with gestational trophoblastic neoplasm. The overall recurrence rate was 6 in 13,341 events (risk 1: 2227). The rate was 3 in 12,329 (risk 1:4110) for HM that did not require chemotherapy and 3 in 1012 (1:337) for previously treated gestational trophoblastic neoplasm. All 6 patients with recurrent disease were successfully treated with chemotherapy. CONCLUSION: Routine post-pregnancy human chorionic gonadotrophin screening may be safely discontinued in patients with one previous uncomplicated hydatidiform mole.

Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database.

OBJECTIVE: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT. METHODS: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS). RESULTS: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively). CONCLUSIONS: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN.

Classification systems in Gestational trophoblastic neoplasia - Sentiment or evidenced based?

The classification system for Gestational trophoblastic neoplasia (GTN) has proved a controversial topic for over 100years. Numerous systems simultaneously existed in different countries, with three main rival classifications gaining popularity, namely histological, anatomical and clinical prognostic systems. Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide consensus on the optimal classification system, largely due to a lack of high quality data proving the merit of one system over another. Remarkably, a validated, prospectively tested classification system is yet to be conducted. Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO classification system, and its ability to identify patients most likely to develop primary chemotherapy resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6. This review aims to examine the historical basis of the GTN classification systems and critically appraise the evidence on which they were based. This culminates in a critique of the current FIGO/WHO prognostic system and discussion surrounding clinical preference versus evidence based practice.

Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the outcome of patients treated with second-line chemotherapy for methotrexate-resistant low-risk GTN at the Sheffield Centre, UK between 2001 and 2015, including the novel use of single-agent carboplatin as a strategy to reduce exposure to combination chemotherapy. METHODS: 392 low-risk GTN patients were treated with first-line methotrexate. The selection of chemotherapy regimen following methotrexate-resistance depended on the volume of residual disease as indicated by the serum hCG value at the time, with patients switching to either single-agent dactinomycin at an hCG level<150IU/L from 2001-2010 and <300IU/L since 2010, or to combination treatment with etoposide/dactinomycin (EA) above these thresholds. In order to reduce exposure to more toxic combination chemotherapy regimens, our treatment policy was revised in 2011, with the recommendation of single-agent carboplatin as an alternative to EA at hCG levels >300IU/L. RESULTS: 136 (35%) of 392 received second-line chemotherapy following methotrexate-resistance. 59 patients received single-agent dactinomycin with 53 (90%) patients achieving complete hCG response, 3 patients requiring combination chemotherapy or surgery, and 3 patients subsequently spontaneously resolving. 56 patients received EA chemotherapy with hCG complete response in 50 (89%) patients, and the remaining 6 patients were cured with further multi-agent chemotherapy or surgery. With carboplatin, 17/21 (81%) achieved an overall complete hCG response rate, with 4 patients requiring third-line EA. Carboplatin was well tolerated with no significant alopecia; myelosuppression was the most significant toxicity. Overall survival for all patients was 100%. CONCLUSION: These data show the continued excellent outcomes for methotrexate-resistant low-risk patients treated with single-agent dactinomycin or EA. Our experience with carboplatin is promising and provides an alternative regimen for methotrexate-resistant low-risk disease that avoids alopecia and in-patient treatment.

Late spontaneous resolution of persistent molar pregnancy.

OBJECTIVE: To determine the outcome of women with persistently raised but falling human chorionic gonadotrophin (hCG) levels 6 months after surgical evacuation of a molar pregnancy. DESIGN: An 11-year retrospective review. SETTING: The United Kingdom supra-regional trophoblastic disease treatment centres at Weston Park Hospital (Sheffield) and Charing Cross Hospital (London). POPULATION: Women with raised but falling serum human chorionic gonadotrophin (hCG) levels 6 months after evacuation of a molar pregnancy. METHODS: Retrospective case note review of eligible women identified by the electronic databases held at each supra-regional centre. MAIN OUTCOME MEASURES: The proportion of women that attain normal hCG levels spontaneously without chemotherapy. In addition, rates of gestational trophoblastic neoplasia (GTN), drug resistance, disease relapse and overall survival are reported. RESULTS: Thirty-five women with molar pregnancy and raised but falling serum hCG levels continued surveillance 6 months after evacuation. Levels of hCG in 30 of the patients (86%) fell to normal levels spontaneously. One woman defaulted follow up prior to hCG normalisation (3%) and the remaining four women (11%) were treated with chemotherapy due to a plateau or rise in serum hCG levels indicating GTN. All treated women were successfully salvaged by either first (n = 1) or second line (n = 2) chemotherapy or found to have persistently raised low level hCG of uncertain clinical relevance (n = 1). No women developed relapsed disease and overall survival was 100%. CONCLUSIONS: Women with a molar pregnancy and a raised but falling hCG level beyond 6 months from uterine evacuation can be safely observed with regular hCG monitoring and can usually avoid potentially toxic chemotherapy. TWEETABLE ABSTRACT: Women with treated molar pregnancy may avoid chemotherapy if 6-month hCG levels are raised but falling.

Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials.

PURPOSE: The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. METHODS: Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. RESULTS: pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. CONCLUSION: This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC.

A retrospective study to evaluate single agent methotrexate treatment in low risk gestational choriocarcinoma in the United Kingdom.

OBJECTIVE: To determine whether single agent chemotherapy with intramuscular methotrexate 50mg administered on days 1, 3, 5, and 7 and oral folinic acid 15mg administered on days 2, 4, 6, and 8 in 2 weekly cycles (IM MTX/FA) is an effective treatment regimen for patients with low risk gestational choriocarcinoma. METHOD: Electronic databases were searched to identify patients with gestational choriocarcinoma at the Sheffield and Charing Cross supra-regional trophoblastic disease centres from January 2000 to December 2011. Clinical notes of low risk patients with FIGO score 0-6 were retrospectively reviewed to assess treatment outcomes and subsequent relapse. RESULTS: 65 patients were identified with low risk choriocarcinoma. Serum hCG levels normalised in 24 patients without the requirement of chemotherapy (19 with histological confirmation, 4 highly suspicious histology and 1 clinical diagnosis). Of 23 patients with histologically confirmed choriocarcinoma, 8 (35%) had a sustained complete response to IM MTX/FA and did not relapse. Both patients with FIGO score 6, and 1 patient with FIGO stage III metastatic disease developed resistance to IM MTX/FA and required further treatment. Despite the development of drug resistance or relapse all patients were successfully salvaged by subsequent treatments. CONCLUSIONS: Not all patients with low risk choriocarcinoma that have had primary intervention prior to staging, such as surgical resection or uterine evacuation will require chemotherapy, providing hCG levels continue to decline to normal. Low risk (FIGO 0-5) patients should initially receive IM MTX/FA due to its low toxicity, outpatient administration and reasonable efficacy. Patients with FIGO score 6 or FIGO stage III disease should make an informed choice between IM MTX/FA and combination chemotherapy.

[Importance of nuclear medicine diagnostics in CUP syndrome]. / Stellenwert der nuklearmedizinischen Diagnostik bei CUP-Syndrom.

CLINICAL/METHODICAL ISSUE: The diagnostic work-up in patients with carcinoma of unknown primary (CUP) syndrome is extensive, highly time-consuming and cost-intensive and ultimately often fails to detect a primary site. STANDARD RADIOLOGICAL METHODS: In this context chest X-ray and computed tomography (CT) have been used as standard imaging modalities in CUP syndrome. METHODOLOGICAL INNOVATIONS: Since the introduction of positron emission tomography (PET) evaluation of tumor vitality has become possible. Furthermore, PET-CT hybrid scanners allow the combination of functional and morphological imaging. PERFORMANCE: Several meta-analyses have reported an additional overall detection rate between 24.5 % and 44 % by either PET or PET-CT. Metastatic localization (cervical versus extracervical) did not influence the performance. The sensitivity was usually high (> 80 %) but specificity was moderate ranging from 68 % to 88 % at best. If mentioned, the results obtained by fluorodeoxyglucose (FDG)-PET significantly changed the clinical management in approximately one third of the patients studied. In a direct comparison with PET alone, PET-CT did not depict significantly more primary tumors but was able to reduce false positive findings. ACHIEVEMENTS: To determine the real additional value of PET-CT in the diagnosis of CUP syndrome large prospective studies with more uniform inclusion criteria are needed. Despite the capabilities of FDG-PET-CT there is as yet no evidence that a potentially improved diagnostic algorithm is translated into a better patient outcome. PRACTICAL RECOMMENDATIONS: Nevertheless, FDG-PET-CT should be performed in all CUP patients where conventional imaging failed to detect a primary site or the results are equivocal. In CUP patients with cervical lymph node metastases PET-CT should be carried out prior to panendoscopy to reduce the number of false negative biopsies.

The outcome of patients with low risk gestational trophoblastic neoplasia treated with single agent intramuscular methotrexate and oral folinic acid.

BACKGROUND: Gestational trophoblastic neoplasia (GTN) persisting despite local treatment requires chemotherapy. In 2000, the revised International Federation of Gynaecology and Obstetrics (FIGO)/World Health Organisation (WHO) staging system was introduced, classifying patients as at 'low' or 'high' risk for resistance to single agent treatment. PATIENTS AND METHODS: We have evaluated the complete response rates of patients with low risk GTN treated with 2 weekly intramuscular (IM) methotrexate 50mg four doses days 1, 3, 5, 7 and oral folinic acid 15 mg days 2, 4, 6, 8 (MTX/FA). Patient data between January 2000 and December 2011 were collated and the relationships between FIGO/WHO risk score and outcomes evaluated. RESULTS: Two hundred and eighty nine patients were treated with single agent IM MTX/FA and assessed for treatment response. 29/36 (81%) patients with a FIGO/WHO total score of 6 developed resistance to MTX/FA compared with 87/253 (34%) patients with a score of 0-5 (p ≤ 0.0001). Significantly higher rates of resistance were found for patients with an hCG level of >100,000 iu/l compared to an hCG level of <100,000 iu/l (84% versus 34% p ≤ 0.0001). All patients were eventually cured with chemotherapy or surgical salvage. CONCLUSIONS: Patients with low risk GTN that have a FIGO/WHO score of 6 or hCG level of >100,000 iu/l have high rates of resistance to MTX/FA and require further treatment. Revision of the FIGO/WHO scoring system may be appropriate to enable selection of more effective first line chemotherapy.

Bisphosphonates in the adjuvant treatment of breast cancer.

Bisphosphonates, as potent inhibitors of osteoclast-mediated bone resorption, significantly reduce the risk of skeletal complications in metastatic bone disease and also prevent cancer treatment-induced bone loss (CTIBL). However, more recently, there has been increasing data indicating that bisphosphonates exhibit anti-tumour activity, possibly via both indirect and direct effects, and can potentially modify the metastatic disease process providing more than just supportive care. The evidence from previous studies of an anti-tumour effect of bisphosphonates was inconclusive, with conflicting evidence from adjuvant oral clodronate trials. However, more recent trials using zoledronic acid have shown benefits in terms of disease-free and overall survival outcomes in certain subgroups, most evidently in older premenopausal women with hormone-sensitive disease treated with ovarian suppression, and in women in established menopause at trial entry. In the adjuvant setting, the use of bisphosphonates has also been focused on the prevention and treatment of CTIBL and recent guidelines have defined treatment strategies for CTIBL. The role of bisphosphonates in CTIBL in early breast cancer is well defined. There have been mixed results from large adjuvant metastasis-prevention studies of bisphosphonates, but there are strong signals from large subgroups analyses of randomised phase III trials suggesting significant anti-tumour beneficial effects in specific patient populations.

Current opinion of aromatase inhibitor-induced arthralgia in breast cancer in the UK.

AIMS: Aromatase inhibitors are now a standard of care in the management of hormone-responsive early breast cancer in postmenopausal women. The troublesome side-effect of arthralgia remains a distinct clinical problem, with limited data on its aetiology and management. The aim of this questionnaire study was to evaluate the opinion of UK breast cancer clinicians on the importance of this treatment side effect. MATERIALS AND METHODS: In 2009, a questionnaire was sent to 772 breast surgeons and oncologists who manage breast cancer within the UK. The questionnaire evaluated the importance, investigation, management and the need for guidelines for aromatase inhibitor-induced arthralgia (AIA). RESULTS: Four hundred and sixteen (54%) returned questionnaires were suitable for analysis. By specialty, 234 (56%) were completed by breast surgeons, 134 (32%) by clinical oncologists, 45 (11%) by medical oncologists and one by a general surgeon. Three hundred and eighty-three (92%) specialists graded the importance of AIA as either very important or important; 211 (51%) did not know the aetiology of AIA; 280 (68%) did not perform bloods; 254 (61%) did not request radiology and 251 (60%) felt management was the responsibility of the oncologists. Three hundred and forty-nine (84%) considered that their practice would benefit from national guidelines. CONCLUSION: This questionnaire has highlighted that AIA is a major patient concern. Further research, educational initiatives and guidance are needed to improve the management of this treatment complication.

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer.

BACKGROUND: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT+/-ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5-20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Raised serum urea predicts for early death in small cell lung cancer.

AIMS: Previous studies have defined prognostic factors predicting a favourable response to treatment and long-term survival in small cell lung cancer (SCLC) patients. Here we sought specific pre-treatment features predicting early death in SCLC. MATERIALS AND METHODS: An exploratory cohort of 62 patients with poor prognosis SCLC and a separate confirmatory independent cohort of 152 unselected SCLC patients were identified to determine risk factors for early death, defined as within 8 weeks of diagnosis. RESULTS: In an exploratory cohort of patients with poor prognosis SCLC, 46 received chemotherapy and 16 patients received no chemotherapy. Multivariate analysis of chemotherapy patients showed a raised serum urea to be predictive of early death - increasing the risk by 13-fold (odds ratio 13.3, 95% confidence interval=2.8-64). In a separate cohort of 152 unselected SCLC patients, 123 received chemotherapy and 29 did not. Logistic regression analysis of treated patients showed that performance status >2 (P=0.009), urea>upper limit of normal (P=0.01), neutrophil count >10 (P=0.024) and weight loss >10% (P=0.03) significantly contributed to the risk of early death. Of note, raised serum urea increased the risk of early death by 12-fold (odds ratio 11.8, 95% confidence interval=1.8-76.9). CONCLUSION: We have shown that pre-treatment raised serum urea is a significant predictor of early death. This readily available information will be useful for assessing SCLC patients at the bedside and discussing the risks of chemotherapy with them.

Exploring the anti-tumour activity of bisphosphonates in early breast cancer.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are firmly established in the management of breast cancer patients with metastatic skeletal disease. There are extensive data that bisphosphonates, particularly nitrogen-containing bisphosphonates such as zoledronic acid, exhibit anti-tumour activity potentially via both indirect and direct mechanisms in vitro. In vivo studies using animal models of breast cancer induced bone disease have shown that bisphosphonates exert anti-tumour effects via inhibiting osteolysis and reducing skeletal tumour burden. Furthermore, pre-clinical studies have demonstrated synergistic anti-tumour effects between chemotherapy agents commonly used in breast cancer treatment and nitrogen-containing bisphosphonates. This, coupled with emerging evidence from pre-clinical in vivo studies suggesting that bisphosphonates may have additional anti-tumour activity outside of the bone microenvironment, could be of significant importance in the clinical management of breast cancer. The evidence in favour of an anti-tumour effect of bisphosphonates in the clinical setting is inconclusive however, with conflicting evidence from several trials. This review focuses on the anti-tumour activity of bisphosphonates in breast cancer, with particular focus on zoledronic acid. The pre-clinical evidence for anti-tumour activity will be reviewed, followed by the synergistic effects with anti-cancer agents. Finally, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer will be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zoledronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer.

Histamine alters cadherin-mediated sites of endothelial adhesion.

We tested the hypothesis that histamine alters the focal apposition of endothelial cells by acting on sites of cadherin-mediated cell-cell adhesion. Focal apposition was measured as the impedance of a cell-covered electrode, which was partitioned into a cell-matrix resistance, a cell-cell resistance, and membrane capacitance. Histamine causes an immediate, short-lived decrease in the impedance of an electrode covered with human umbilical vein endothelial (HUVE) cells. ECV304 cells are a line of spontaneously transformed HUVE cells that do not express the endothelial cadherin, cadherin-5. Histamine increased ECV304 cell calcium to 600 nM. Histamine did not increase myosin light chain phosphorylation of control or transfected ECV304 cells. ECV304 cells transfected with either E-cadherin or cadherin-5 on a dexamethasone-responsive plasmid (pLKneo) increased their cell-cell resistance when stimulated with dexamethasone, whereas ECV304 cells transfected with pLKneo-lacZ did not. Histamine did not affect the impedance of ECV304 cells transfected with pLKneo-lacZ. In contrast, histamine decreased the cell-cell resistance of ECV304 cells transfected with either pLKneo-E-cadherin or pLKneo-cadherin-5. From these data, we conclude that histamine acts on sites of cadherin-mediated cell-cell apposition.