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A prospective study of duplex Doppler ultrasound in 29 renal transplants was undertaken to determine how to interpret Doppler findings in the immediate postoperative period. The study included intraoperative pulsed Doppler recordings from grafts immediately following release of vessel clamps. Subsequent follow-up studies were performed in the immediate postoperative period. Intraoperative Doppler appearances in the group as a whole were normal; there was a significant deterioration in Doppler appearances in the first 24–48 h of the postoperative period. In the absence of rejection subsequent Doppler appearances returned to normal. An abnormal Doppler appearance immediately following transplantation should be an expected result. If the Doppler fails to improve, or deteriorates having started to improve, rejection should be strongly suspected. [ABSTRACT FROM PUBLISHER]

Background: Immunotherapy directed at 5T4 tumor antigen may delay the need for further chemotherapy. An attenuated modified vaccinia Ankara virus containing the gene encoding for 5T4 (MVA-5T4) was studied in asymptomatic relapsed ovarian cancer., Objective: To assess the effectiveness and safety of MVA-5T4 as treatment for asymptomatic relapsed ovarian cancer., Methods: TRIOC was a phase II randomized (1:1), placebo-controlled, double-blind multicenter study. The primary aim was to assess the effectiveness and safety of MVA-5T4 as a treatment for asymptomatic patients with relapsed ovarian cancer. Eligible patients had International Federation of Gynecology and Obstetrics (FIGO) stage IC1-III or IVA epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, Eastern Cooperative Oncology Group (ECOG) 0-1, with relapse defined by a rise in CA-125 to twice the upper limit of normal or low-volume disease on CT scan. The primary endpoint was disease progression (including deaths from ovarian cancer) at 25 weeks. Following a brief suspension, the trial restarted as a single-arm study. The revised single-arm design required 45 evaluable patients treated with MVA-5T4 to detect a 25-week progression rate of 50%, assuming an expected 70% rate without MVA-5T4; 85% power with one-sided 5% significance., Results: A total of 94 eligible patients were recruited, median age was 65 years (range 42-82), median follow-up 34 months (range 2-46). Overall, 59 patients received MVA-5T4 and 35 patients received placebo. The median number of MVA-5T4 injections received was 7 (range 0-9), compared with a median of 6 (range 1-12) for patients receiving placebo. Median progression-free survival was the same in both arms (3.0 months). The 25-week progression rate was similar in both arms: 80.0% for patients treated with MVA-5T4 and 85.7% for those receiving placebo (risk difference -5.7%, 95% CI -21.4% to 10.0%). Median time to clinical intervention was improved with MVA-5T4: 7.6 months (range 6.7-9.5) vs 5.6 (range 4.9-7.6), CONCLUSION: MVA-5T4 vaccination in patients with asymptomatic relapse was well-tolerated but did not improve the progression rate at 25 weeks. The majority of patients who received MVA-5T4 had clinical intervention later than those assigned to placebo., Trial Registration Number: NCT01556841., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Gender based violence (GBV) is disproportionately higher in women who use substances. This vulnerable population are also at a disadvantage when it comes to accessing harm reduction services. Between May and October 2021 there were 77 cases discussed at Multi-Agency Risk Assessment Conferences (MARAC) in Dundee. The majority of these cases (62) had substance misuse as a risk factor. It is at these meetings that the vulnerability of women comes to the fore and issues of violence are highlighted. During this time period, 44 cases involved the victim being strangled/choked or suffocated and 43 cases had weapons as a risk factor. 56 of the cases included children. The issue of GBV or Intimate Partner Violence (IPV) is often hidden, especially in and by those affected by substance use. Women experiencing GBV require specialist support, often across different services to address different needs. How well violence against women is understood in relationships that are affected by drugs is difficult to determine. In many instances it isn't until a MARAC meeting, or similar crisis point is met, that the extent of the abuse is highlighted. What services can provide singularly is limited in many of these cases but joint-working and innovative practices, such as the Hub model and the Gendered Services Project in Dundee, strive to change the landscape of service delivery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moir, Gwyther, Wilkins and Boland.)

Purpose: The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA., Methods: We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease., Results: Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs., Conclusion: This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication., (Copyright © 2016. Published by Elsevier Ltd.)

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation., (Copyright © 2016. Published by Elsevier Ltd.)

Background: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan., Methods: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation., Results: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference., Interpretation: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC., Funding: The trial was funded by Cancer Research UK and supported by Amgen Pharma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer., Methods: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876., Results: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group., Interpretation: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents., Funding: Cancer Research UK, Amgen Inc., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC ran a phase II study to assess the therapeutic activity of high-dose ifosfamide in patients with advanced soft tissue sarcomas by means of response rate (RR). Investigators claiming a response submitted the relevant chest radiographs (CXR) or scans to two other members of the STBSG for peer review. The reviewers completed a questionnaire indicating overall response or reasons for rejecting the claimed responses. An independent radiologist also reviewed the cases and he was blinded to the results of the peer review until the study was concluded. Twenty-two patients were reviewed by the radiologist and peer review, and the completed questionnaires were retrospectively reviewed. Two differences were noted, one partial responder (PR) was regarded as stable disease by the radiologist and one PR by peer review was determined a complete response by the radiologist. The radiologist found subsequent evidence of progressive disease in three patients who initially showed a PR, whilst the review group noted only one. This study suggests peer review in this tumor type is a satisfactory method of achieving an accurate, objective RR.

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

Response rates reported in early phase II clinical trials are often not reproduced in subsequent larger or phase III studies. Independent review of claimed partial or complete responders to gemcitabine was undertaken in four pivotal, open-label phase II studies of advanced, non-small cell lung cancer (NSCLC) to provide accurate, consistent, reproducible response rates. Patients were chemonaive and had stage III or IV NSCLC. In three trials, gemcitabine (800 and 1250 mg/m2) was administered once-weekly for 3 weeks followed by a rest week. In the fourth, gemcitabine (90 mg/m2) was given twice-weekly for 3 weeks in every 4 weeks. The primary endpoint was response rate. Of the 374 evaluable patients, 114 (30%) were claimed as responders. Independent review reduced this to 79 (21%). The response range was reduced from 25-35 to 20-23% after validation; 95% confidence intervals did not overlap. Consistent application of response criteria by an independent panel significantly reduced response rates but produced greater consistency and reproducibility. These results confirm that gemcitabine is active against NSCLC. Subsequent larger-scale studies have produced comparable response rates, vindicating the use of independent review. Independent review is recommended for all trials using response rate as a primary endpoint.

Background: The results of phase II clinical trials are usually based on response of tumours to new oncolytic agents as evidenced by radiological imaging techniques. In this trial, all claimed responders were reviewed at a specially convened meeting by the peer group of study investigators and a radiologist, independent of the study institutions., Patients and Methods: One hundred eleven patients with advanced epithelial ovarian cancer who had previously been treated with a platinum based regimen and had subsequently relapsed and who had measurable disease were treated with topotecan at a dose of 1.5 mg/m2/day i.v. on five consecutive days repeated every 21 days to assess efficacy and tolerability. Ninety-three were considered eligible for the study per protocol and lesions were assessed by either computerised tomography (CT) or ultrasound (US). At the meeting, scans from all 24 (25.8%) claimed responders were reviewed, lesions remeasured by the radiologist and a group discussion led to a final response classification., Results: Ninety-two patients were found to be eligible for the study and 14 (15.2%) were confirmed as responders. Ten were rejected as responders, mainly because the lesion did not decrease in size by < or = 50%, but one patient failed to meet the entry criteria. Remeasurement of CT scans was more objective than US scans. Difficulties were encountered during review of some CT scan sequences because of non-uniform imaging parameters., Conclusions: Independent radiological review in conjunction with the peer review group in this trial enabled rigorous and consistent application of response criteria. This decreased the response rate from 25.8% to 15.2%, but this represents a more objective assessment. CT scanning is an objective technique for assessing response rates in phase II studies whereas US is subjective and dose not necessarily allow accurate lesion assessment on subsequent examinations, nor allows independent review at a later date. For these reasons it should not be used in such studies for accurate lesion assessment. Cross-sectional imaging techniques such as CT and magnetic resonance imaging (MRI) do allow accurate lesion assessment and independent review at a later date, but standard protocols need to be instituted, to allow consistency and a comparison to be made with subsequent studies using the same agent and a broad comparison to be made with other agents.

Background: Radiological imaging has existed for about 100 years and there have been significant advances in computer technology during the last 25 years. The ideal investigation should be non-invasive, repeatable, and have a sensitivity (detection of the lesion) and specificity (ability to predict the absence of disease) of 100%., Techniques: Recent advances in ultrasonography, computed tomography (CT) scanning and magnetic resonance imaging (MRI) have enabled a more accurate demonstration of anatomical structures and better spatial resolution. This has led to the detection of smaller lesions and faster scan times, and thus new or recurrent disease is demonstrated at an earlier stage and motion artefacts are reduced. Advances in imaging techniques have also enabled percutaneous manoeuvres, ranging from diagnostic biopsy of suspicious lesions to therapeutic stenting of malignant strictures, to be performed. Magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) represent a different concept. They assess in vivo tissue metabolism and provide a physiological approach which allows comparison of normal and abnormal tissue, such as tumour. The measurement of certain metabolites or isotope tracers correlates with tumour metabolism, and the response to treatment can be predicted by quantitative changes. Thus, PET scanning and MRS will probably be valuable in assessing new chemotherapeutic agents in animals and patients in vivo. Patients likely to respond to a certain drug can be selected and further studies may help determine ideal dosing regimens. Lack of fine anatomical detail on PET images can be overcome by 'fusing' the 'slice' with the corresponding CT or MRI slice, allowing accurate anatomical and physiological information to be displayed., Conclusion: As more specific indicators of disease and the response to therapy become available, the combination of anatomical and functional imaging modalities will enable treatment to be undertaken at an earlier stage with the potential for increased survival.

A rare cause of pulmonary embolism and pulmonary artery hypertension in young women is choriocarcinoma growing in the pulmonary artery. This growth is reversible, and the disorder can be cured. We describe three patients with this feature who have been treated with appropriate high-risk chemotherapy and who are now in remission. Contrast-enhanced computed tomography can be used to identify major emboli, and progress of the disease can be monitored by serial ventilation/perfusion scans and measurement of serum human chorionic gonadotropin. Recognition of this rare syndrome is important because of the generally excellent outlook with appropriate treatment.

Duplex doppler examination of blood flow in renal interlobar arteries was analysed in twelve critically ill patients before and during low-dose dopamine infusion (2 micrograms/kg/min). Renal vasodilatation and increased blood flow were observed with dopamine, confirming results with indirect or invasive techniques. The doppler ultrasound technique is entirely non-invasive, is simple and quick to carry out, provides instant results, and will allow tailoring of inotropic support in critically ill patients to provide optimum renal blood flow.