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Purpose: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. Patients and Methods: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. Results: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. Conclusions: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

BRCA2 reversion mutation detected in cell-free circulating DNA from patient 16.

Purpose:A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown.Patients and Methods:Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies.Results:Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy.Conclusions:A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious.

Supplementary Methodology.

Liquid biopsy time points.

Purpose: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification. Methods and Materials: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/β ratio of 10 Gy for acute reacting tissues). Results: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1). Conclusions: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification.

Background: Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function. Methods: PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness. Results: Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited. Conclusion: PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis.

PURPOSE Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM. METHODS After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy. RESULTS Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0). CONCLUSION There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.

12003 Background: CIPN is a dose limiting toxicity, and a major clinical challenge. This study aims to explore the use of acupuncture with standard care (Acu +SC) against SC alone, to reduce symptoms of CIPN. Methods: A phase II, randomised, parallel group design was used to investigate the effectiveness of a 10 week course of acupuncture to manage CIPN. Patients experiencing CIPN ≥ Grade II (CTCAE v4.03), recording a ‘Most Troublesome’ CIPN symptom score of ≥ 3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised (1:1) to either Acu+SC or SC alone. The primary end-point was a ≥ 2 point improvement in MYMOP2 score at week 10 (logistic regression adjusted for stratification factors and baseline MYMOP2 score). The necessary sample size was 100 patients;120 were randomised to allow for attrition (90% power; 10% one-sided alpha), for a hypothesised improvement in success proportions from 30% to 55%. Results: 120 patients were randomised to ACUFOCIN; diagnosis: breast 61 (51%), multiple myeloma 9 (8%), GI 48 (40%), gynaecological 2 (2%). MYMOP2 score for most troubling CIPN symptom at baseline: 3-4 33 (28%), 5-6 87 (73%). CTCAE CIPN at baseline; grade II 103 (86%), grade III 17 (14%). Baseline characteristics were balanced between arms. Primary outcome data were available for 108 participants with 36/54 (67%) successes in the Acu+SC arm compared to 18/55 (33%) in the SC arm. Adjusted success odds ratio was 4.3 (95% CI 1.9-9.6; p < 0.001; Acu+SC vs SC). Additionally, 27/53 (51%) participants achieved a CIPN success (grade ≤ I) in the Acu+SC arm compared to 4/56 (7%) in the SC arm with adjusted odds ratio 13.1 (95% CI 4.1-41.7; p < 0.001; Acu+SC vs SC). Significant reduction in week 10 pain score; mean difference (SC+Acu – SC alone) -1.45 with 95% CI (-2.25, -0.65) after adjustment for week 1 pain, breast cancer diagnosis and treatment complete status. (note pain on a 0-10 scale). Significant increase in the EORTC QLQ-C30 summary score; mean difference (SC+Acu – SC alone) 9.51 with 95% CI (5.01, 14.02) after adjustment for the baseline score, breast cancer diagnosis and treatment complete status. (note summary score on a 0-100 scale). Significant effects seen at week 10 are also present at week 6. The week 6 effect estimates are consistently less than the week 10 effects (but not usually statistically significantly so). Conclusions: In this patient cohort, a 10 week course of acupuncture significantly improved symptoms of CIPN. These results support further investigation within a phase III trial. Clinical trial information: NCT02275403 .

Aims: This feasibility study aimed to identify relationships between radiation doses to the masticatory apparatus as a combined block or as individual subunits with changes in trismus following radiotherapy. Material and methods: Twenty patients from a single center were recruited prospectively as part of a randomized trial comparing proactive exercises in the management of trismus. Patients with stage III/IV oral cavity or oropharyngeal squamous cell cancers received intensity-modulated radiotherapy with concurrent systemic therapy. All patients had trismus prior to radiotherapy. Maximal inter-incisor distance (MID) was measured pre- and 6 months from the start of radiotherapy. Bilateral muscles of mastication: medial and lateral pterygoids (MP and LP), masseters (M), temporalis (T), temporomandibular joint (TMJ) were contoured on CT images. The block comprised all muscles excluding the TMJ below the orbital floor. Mean dose, equivalent uniform dose (EUD) and V35–V60 Gy were compared with change in MID. Results: In six patients, the MID deteriorated at 6 months from the start of radiotherapy compared with 14 whose MID improved. No significant association was observed between age, gender, smoking, alcohol status, exercise compliance, cisplatin, tumor site, stage, V35–V60 Gy or EUD with change in MID. A clinical outlier was excluded. Without the outlier (n = 19), a significant association was seen between mean dose and change in MID at 6 months for the ipsilateral block (p = .01), LP (p = .04) and M (p 40 Gy to the block. Conclusion: Higher mean radiation doses to the ipsilateral block, LP and M were significantly associated with deterioration in trismus. Limiting dose to these structures to ≤40 Gy for tumors not invading the masticatory muscles may improve treatment-related sequelae. The ipsilateral block, LP and M should be studied further as possible alternative avoidance structures in radiotherapy treatment planning.

Background: Endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumour growth in vitro. Pre-surgical window studies allow rapid in vivo assessment of anti-tumour activity. Previous window studies found short-term metformin treatment reduced endometrial cancer proliferation but these lacked methodological rigor, particularly control arms for comparison. PREMIUM was designed to definitively determine the anti-proliferative effect of metformin in vivo using a robust window study design. Methods: A randomised, double-blind, placebo-controlled phase 3 trial was conducted in five hospitals in England. Eligible women had biopsy-proven atypical endometrial hyperplasia or endometrioid endometrial cancer and were not receiving anti-diabetic medication. Women were computer-randomised (1:1) using the permuted block method (block size 30) to metformin (850mg daily for three days, increased to twice daily thereafter) or placebo for 1-5 weeks, until the evening before surgery. Participants and researchers were blinded to treatment group allocation. The primary outcome was post-treatment immunohistochemical expression of Ki-67 in the hysterectomy specimen; a modified intention-to-treat analysis included all women taking at least one dose of study drug and undergoing tumour biopsy within 72 hours of treatment discontinuation. Safety analysis included all women receiving at least one dose of drug. Findings: Between February 2015-2017, 93 women were randomised to metformin (n=47) or placebo (n=46), with five withdrawals (four without taking any drug and one because of no post-treatment biopsy). Eighty-eight women were included in the final analysis (metformin n=45, placebo n=43). There was no overall difference in post-treatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0·57%, 95% CI -7·57% to 6·42%, p=0·87). Women receiving metformin reported significantly more adverse events than those receiving placebo (37 [82·2%] vs. 25 [58·1%], p=0·001), especially nausea and vomiting (17 [37·8%] vs. 6 [13·6%], p=0·015), diarrhoea (23 [51·1%] vs. 6 [13·6%], p=0·0003) and anorexia (9 [20·0%] vs. 0 [0·0%], p=0·003), but did not discontinue treatment.. Interpretation: Short term treatment with standard diabetic doses of metformin does not reduce tumour proliferation in women with endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings. Future studies should focus on primary and secondary prevention of endometrial cancer and pursue longer treatment windows. Clinical Trial Number: The study was registered on UK and European clinical trials databases (ISRCTN 88589234, EudraCT number 2014-000991-25) and is closed to recruitment. Funding Statement: National Institute for Health Research Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written, informed consent. The trial was approved by the North West Research Ethics Committee (14/NW/1236), Medicine and Healthcare Products Regulatory Authority (MHRA, reference 21387/0232/001-0001) and local Research and Development departments.

The randomized NCRN phase III ABC-02 trial provided level-A evidence for first-line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo-responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting.

Recent clinical series suggest that treating patients with isotoxic twice-daily radiotherapy may be beneficial. This dosimetric planning study compared the use of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DRT) to deliver isotoxic treatment for non-small cell lung cancer (NSCLC) patients.Twenty patients with stage II/III NSCLC were selected. A dose-escalated plan was produced retrospectively for each using three different methods: (i) three to five beams 3DRT; (ii) seven beams inverse-planned conformal radiotherapy; (iii) seven beams IMRT. The starting point for dose escalation was 55.8 Gy in 1.8 Gy per fraction twice-daily. The number of fractions was then increased until one or more organ at risk tolerance dose was exceeded or a maximum dose of 79.2 Gy was reached.The median escalated doses were 70.2, 66.6 and 64.8 Gy for IMRT, 3DRT and inverse-planned conformal radiotherapy, respectively. IMRT allowed a significant dose increase in comparison with the other two methods (P0.05), whereas no significant difference was found between 3DRT and inverse-planned conformal radiotherapy. IMRT was more successful at escalating dose in patients where the brachial plexus and spinal canal were close to the planning target volume. IMRT did not allow the escalation of dose beyond 70.2 Gy (82.8 Gy BED10, 69 Gy EQD2) due to the proximity of disease to the great vessels and the proximal bronchial tree.IMRT allows increased dose escalation compared with conformal radiotherapy. However, there is limited opportunity to escalate the prescription dose beyond 70.2 Gy twice-daily in disease close to the central mediastinal structures.

Purpose We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated 90Y-ibritumomab tiuxetan (90Y-IT) as initial therapy of follicular lymphoma (FL). Patients and Methods A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of 90Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m2) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). Results Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. Conclusion Fractionated RIT using 90Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

Our aim was to investigate the effect of active manuka honey on radiation-induced mucositis. A total of 131 patients diagnosed with head and neck cancer who were having radiotherapy to the oral cavity or oropharyngeal area were recruited into the study, and were randomly allocated to take either manuka honey or placebo (golden syrup) 20 ml 4 times daily for 6 weeks. Mucositis was assessed according to the Radiation Therapy Oncology Group (RTOG) scale at baseline, weekly during radiotherapy, and twice weekly thereafter until the mucositis resolved. The patient's weight was recorded at the same time as the mucositis was assessed. Throat swabs to identify bacterial or fungal infections were taken at baseline, and during and after radiotherapy. There was no significant difference between honey and golden syrup in their effects on mucositis. Active manuka honey did not improve mucositis, but both the honey and the syrup seemed to be associated with a reduction in bacterial infections. Compliance was a problem after the onset of mucositis, which may have affected the findings.

Background: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study. Patients and methods: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms. Results: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0–240) vs 0 (range 0–144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms. Conclusion: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management.

Objective:Management of patients with head and neck squamous cell carcinoma is often based on clinical parameters, with little appreciation of the underlying tumour biology. Single biological marker studies fail to acknowledge the complexity of these tumours. Our aim was to define a profile of biological markers associated with outcome.Design:This retrospective study involved consecutive patients with oropharyngeal squamous cell carcinoma treated with primary radiotherapy between 1996 and 2001. Pre-treatment biopsies were used to study the immunohistochemical expression of nine biological markers. Markers were chosen to reflect biologically relevant pathways.Results:Following analysis of nine markers, a profile of two markers was derived (carbonic anhydrase 9 and major vault protein), the co-expression of which conferred a significantly poor probability of locoregional control. The prognostic effect of these biomarkers in combination was greater than their effect individually.Conclusion:Biomarker profiles can be established which highlight large differences in locoregional control. Identifying tumours that express both carbonic anhydrase 9 and major vault protein may facilitate patient selection for more aggressive treatment.

TSH secretion in hypopituitary patients may be decreased due to TSH deficiency but it also remains under feedback inhibition by free thyroxine (fT4). We propose a TSH index (TSHI), as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, to provide a true estimate of pituitary thyrotroph function and any pathological pituitary suppression.A total of 9519 thyroid function tests (TFTs) (Bayer Immuno-1) in 4064 patients of our institution were examined, including 444 patients investigated for hypopituitarism. Based on the physiological log-linear relationship between fT4 and TSH, we estimated the amount of feedback-induced change in log TSH per change in fT4, which allowed the extrapolation of log TSH to a fixed fT4 of 0, defining the TSHI. TSHIs were compared with other measures of pituitary function.Feedback inhibition was estimated to cause a 0.1345 decrease in log TSH (mU/l) for 1 pmol/l increase in fT4 concentration, therefore TSHI = log TSH + 0.1345 x fT4. Patients with lower peak-stimulated GH and cortisol concentrations had a significantly lower TSHI (P0.0001). TSHIs measured before pituitary stimulation tests predicted highly significantly the risk of test failure (P = 0.0002). Of all potential fT4-TSH combinations within the current reference ranges, 21.9% were identified as abnormal on the basis of the TSHI.The TSHI provides an accurate estimate of the severity of pituitary dysfunction in hypopituitary patients based on simple TFTs. It predicts the probability of pituitary stimulation test failure and extends the diagnosis of TSH deficiency into areas of the normal TFT reference ranges.

Purpose To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkin's lymphoma (HL). Patients and Methods Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. Results At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). Conclusion There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.

Purpose: Some data have suggested that major surgery is associated with the post-operative growth of residual tumour masses but the mechanism of this is unknown. This study was designed to determine the relationship between intraperitoneal (IP) cytokine levels, and laparotomy in benign and malignant settings. Methods: Intraperitoneal fluid specimens were obtained at the start and at the end of laparotomy in patients with benign conditions (n=10) and in others undergoing resection of hepatic metastases from colorectal cancer (n=10). Using ELISA the concentration of the angiogenic cytokines, HGF, VEGF-A, VEGF-C, VEGF-D and FGF-2 was determined. Results: The data show that in 16 of 20 patients there was a significant increase (P=0.006) in the IP concentration of hepatocyte growth factor (HGF) but not in the other growth factors by the end of the operation. The mean increase in HGF concentration was 821.5 pg/ml (95% CI: 11.0–6,426.0). Neither the groups (malignant and non-malignant) nor the length of operation correlated with greater or lesser increases in HGF. Conclusion: The observation that the increase in HGF occurred in both the cancer and non-cancer groups suggests that it is the surgery rather than the disease that is associated with the increased cytokine concentration. As HGF is a potent endothelial, epithelial and mesenchymal mitogen the data highlight HGF as a potential target for anti-cancer treatments in the peri-operative period. However, investigators should closely monitor wound healing as this may be compromised by this new class of drugs.

Purpose To investigate whether delivering an increased radiation dose to the tumor-bearing region of the bladder alone would improve local disease control without increasing treatment toxicity. Methods and materials A total of 149 patients with unifocal T2-T3N0M0 bladder carcinoma were randomized between whole bladder conformal radiotherapy (WBRT, 52.5 Gy in 20 fractions, n = 60) and partial bladder conformal RT (PBRT) to tumor alone with 1.5-cm margins within either 4 weeks (PBRT4, 57.5 Gy in 20 fractions, n = 44) or 3 weeks (PBRT3, 55 Gy in 16 fractions, n = 45). The response was assessed cystoscopically after 4 months. Results The 5-year overall and CFS rate was 58% and 47%, respectively, for the whole population. The CR rate was 75% for WBRT, 80% for PBRT4, and 71% for PBRT3 ( p = 0.6), with a 5-year local control rate of 58%, 59%, and 34%, respectively ( p = 0.18). Solitary new tumors arose within the bladder, outside the irradiated volume, in 6 (7%) of 89 patients who underwent PBRT. The 5-year overall survival and cystectomy-free survival rate was 61% and 49% for WBRT, 60% and 50% for PBRT4, and 51% and 41% for PBRT3 ( p = 0.81 and p = 0.59). The treatment toxicity was mild and equivalent across the three trial arms. Conclusion The reduction in treatment volume allowed delivery of an increased radiation dose without a reduction in local tumor control or the development of excess toxicity. However, this dose-escalated partial bladder approach did not result in significantly improved overall survival.

CONTEXT: Both positive and negative results have been reported in the literature from the use of acupressure at the P6 point, providing evidence of highly suggestive but not conclusive results.OBJECTIVES: To clarify whether acupressure is effective in the management of chemotherapy-related nausea and vomiting.METHODS: A randomized, three-group, sham-controlled trial was designed. Patients with cancer receiving chemotherapy were randomized to receive standardized antiemetics and acupressure wristbands, sham acupressure wristbands, or antiemetics alone. Primary outcome assessment (nausea) was carried out daily for seven days per chemotherapy cycle over four cycles. Secondary outcomes included vomiting, psychological distress, and quality of life.RESULTS: Five hundred patients were randomized. Primary outcome analysis (nausea in Cycle 1) revealed no statistically significant differences between the three groups, although nausea levels in the proportion of patients using wristbands (both real and sham) were somewhat lower than those in the proportion of patients using antiemetics-only group. Adjusting for gender, age, and emetic risk of chemotherapy, the odds ratio of lower nausea experience was 1.18 and 1.42 for the acupressure and sham acupressure groups, respectively. A gender interaction effect was evident (P = 0.002). No significant differences were detected in relation to vomiting, anxiety, and quality-of-life measures.CONCLUSION: No clear recommendations can be made about the use of acupressure wristbands in the management of chemotherapy-related nausea and vomiting as results did not reach statistical significance. However, the study provided evidence of encouraging signals in relation to improved nausea experience and warrants further consideration in both practice and further clinical trials.TRIAL REGISTRATION: This trial is registered with the ISRCT register, number ISRCTN87604299.

OBJECTIVE: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possible determinants. PATIENTS: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r). RESULTS: For acromegalic patients, GH was significantly correlated with IGF-I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) microg/l and 305 (200, 410) microg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF-II and IGFBP-2. The (IGF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not correlate with IGF-II, but molar concentration significantly correlated with the IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). CONCLUSIONS: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF-II values, which, in turn, expressed as a ratio of IGFBP-3, is related to IGFBP-2. These observations offer new insights into the regulation of these peptides.

We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated (90)Y-ibritumomab tiuxetan ((90)Y-IT) as initial therapy of follicular lymphoma (FL).A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of (90)Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m(2)) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS).Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity.Fractionated RIT using (90)Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

Background. Carcinomatous meningitis is a rare and often devastating complication in patients with breast cancer, and the treatment is controversial. Methods. A retrospective analysis of 35 patients with carcinomatous meningitis from breast cancer was performed to define the biology of the disease and to guide treatment. Results. An aggressive variant of breast cancer was revealed meningeal metastasis complicates less than 3.5% of cases of metastatic breast carcinoma. Sixty-seven percent of these patients had tumors that were lobular or combined lobular/ductal histology; the median intervals from primary treatment to disease recurrence and from recurrence to death were 10.9 and 15 months, respectively. The median survival after diagnosis of carcinomatous meningitis was 77 days. The most significant prognostic factor was the Karnofsky performance status (KP) at presentation of meningeal disease. Patients with a KP greater or equal to 70 survived a median of 313 days, whereas those with a KP of 60 or less survived for a median of 36 days (P = 0.0002). In addition, there was a trend suggesting that the response 2 weeks after treatment was initiated, correlated with survival. Conclusions. Carcinomatous meningitis from breast carcinoma is an aggressive metastatic complication with a poor prognosis. The authors suggest that patients with a poor KP (< 70) should be treated symptomatically and those with a good KP (2 70) should receive more aggressive treatment. The patients' survival in this study compared well with other reports, and yet, only one patient was treated with intraventricular chemotherapy. Therefore, these data question the superiority of intraventricular treatment versus other modalities.

Purpose Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor–1α (HIF-1α) expression in a homogeneous series of patients who underwent radiotherapy. Methods and Materials An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1α expression was examined in 79 patients. Results Features associated with poor locoregional control were low Hb level ( p = 0.05) and advancing T ( p = 0.008), N ( p = 0.03), and disease ( p = 0.008) stage. HIF-1α expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04–176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14–7.19) group ( p = 0.03, test for interaction). High tumor HIF-1α expression was associated with low blood Hb levels ( p = 0.03). In a multivariate analysis HIF-1α expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07−16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90−21.6). Conclusions There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area.

Purpose: Vaults are multi-subunit structures that may be involved in nucleo-cytoplasmic transport, with the major vault protein (MVP or lung resistance-related protein [LRP]) being the main component. The MVP gene is located on chromosome 16 close to the multidrug resistance-associated protein and protein kinase c- genes. The role of MVP in cancer drug resistance has been demonstrated in various cell lines as well as in ovarian carcinomas and acute myeloid leukemia, but nothing is known about its possible role in radiation resistance. Our aim was to examine this in head-and-neck squamous cell carcinoma (HNSCC). Methods and Materials: Archived biopsy material was obtained for 78 patients with squamous cell carcinoma of the oropharynx who received primary radiotherapy with curative intent. Immunohistochemistry was used to detect MVP expression. Locoregional failure and cancer-specific survival were estimated using cumulative incidence and Cox multivariate analyses. Results: In a univariate and multivariate analysis, MVP expression was strongly associated with both locoregional failure and cancer-specific survival. After adjustment for disease site, stage, grade, anemia, smoking, alcohol, gender, and age, the estimated hazard ratio for high MVP (2/3) compared with low (0/1) was 4.98 (95% confidence interval, 2.17‐11.42; p 0.0002) for locoregional failure and 4.28 (95% confidence interval, 1.85‐9.95; p 0.001) for cancer-specific mortality. Conclusion: These data are the first to show that MVP may be a useful prognostic marker associated with radiotherapy resistance in a subgroup of patients with HNSCC. © 2007 Elsevier Inc.

Intensive chemotherapy is the treatment of choice for selected elderly patients with acute myeloid leukaemia (AML). We recently developed a model to predict survival, thereby providing objective information upon which to select appropriate therapy for such patients. Such models, however, must be validated on a cohort of patients not used during the development of the model. We have tested the model using a series of 61 elderly patients consecutively treated with intensive chemotherapy. Using several statistical techniques, we have shown that the model is of value in predicting prognosis, though two patients did markedly better than the model prediction. This model may be useful for predicting survival in elderly patients with AML and warrants more extensive validation.

It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPBI type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86–2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27–0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02–5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10–0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32–104.36), and resistance with *1101 (RR = 0.08; CI 0.01–0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17–326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84–99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04–25.77), Alanine-55 (RR = 15.17; CI 2.00–115.20) and Valine-84 (RR = 15.94; CI 3.55–71.49). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03–0.60). Certain DPB1 alleles and individual DPβ1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent. © 1999 Cancer Research Campaign