• LncRNAs in non-small-cell lung cancer

      Ginn, Lucy; Shi, Lei; La Montagna, Manuela; Garofalo, Michela; Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester (2020)
      Lung cancer is associated with a high mortality, with around 1.8 million deaths worldwide in 2018. Non-small-cell lung cancer (NSCLC) accounts for around 85% of cases and, despite improvement in the management of NSCLC, most patients are diagnosed at advanced stage and the five-year survival remains around 15%. This highlights a need to identify novel ways to treat the disease to reduce the burden of NSCLC. Long non-coding RNAs (lncRNAs) are non-coding RNA molecules longer than 200 nucleotides in length which play important roles in gene expression and signaling pathways. Recently, lncRNAs were implicated in cancer, where their expression is dysregulated resulting in aberrant functions. LncRNAs were shown to function as both tumor suppressors and oncogenes in a variety of cancer types. Although there are a few well characterized lncRNAs in NSCLC, many lncRNAs remain un-characterized and their mechanisms of action largely unknown. LncRNAs have success as therapies in neurodegenerative diseases, and having a detailed understanding of their function in NSCLC may guide novel therapeutic approaches and strategies. This review discusses the role of lncRNAs in NSCLC tumorigenesis, highlighting their mechanisms of action and their clinical potential. Keywords: long non-coding RNAs; non-small-cell lung cancer.
    • Local control in tumor-targeted dose escalation for localized prostate cancer

      Padayachee, J.; Sanmamed, N.; Lee, J.; Liu, Z.; Berlin, A.; Craig, T.; Lao, B.; Rink, A.; Bayley, A.; Catton, C. N.; et al. (2021)
      Purpose/Objective(s) Tumor-targeted dose escalation may improve biochemical disease-free survival in patients with localized prostate cancer. We report outcomes of dose escalation using a strategy of simultaneous integrated boost or HDR brachytherapy boost. Materials/Methods Eighty patients with localized prostate cancer with gross tumor volume (GTV) identified on multiparametric magnetic resonance imaging (mpMRI) were enrolled in this phase 2 non-randomized trial (2012-2016). Patients with GTV > 5mm and less than 33% of total prostate volume were eligible. All patients received whole gland prostate volumetric arc therapy (VMAT), 76 Gy in 38 fractions. GTV dose escalation was delivered by integrated boost VMAT (IB-VMAT) of 95 Gy in 38 fractions (n = 40); or MR-guided HDR boost of 10 Gy in 1 fraction (n = 40). Choice of dose escalation strategy was by physician and/or patient choice. The primary end-point was 3-year local control rates determined by MR-guided biopsy and/or MRI alone. Toxicity data was collected using CTCAE v.4.0. Risk group categorization was similar between the arms; 5% low-, 75% intermediate-, and 20% high-risk. Three patients received 6-months ADT. Results Median (IQR) follow-up was 55.2 months (48.1-71.4). The overall 5-year biochemical failure-free survival was 92% (95% CI, 85-99), with 5 patients developing biochemical relapse (BCR); 1 IB-VMAT, 4 HDR boost. Local control data was available for 66 patients who agreed to the 3-year post-treatment biopsy (20) or MRI alone (46); 32 in IB-VMAT and 34 in HDR boost. Local control in the boost volume was achieved in 61 patients. One patient in the IB-VMAT arm had persistent disease on biopsy, and subsequently developed late BCR. Intraprostatic relapse outside the GTV was seen in 4 patients at last follow-up; 1 treated with IB-VMAT and 3 with HDR boost. All 4 patients developed BCR. Late G2 genitourinary (GU) toxicity was 22.5% and 27.5% in IB-VMAT and HDR boost, respectively. Late G2 gastrointestinal (GI) toxicity was 5% in each arm. Two G3 (1 GI, 1 GU) toxicities were seen in IB-VMAT. Conclusion Dose escalation to mpMRI-defined GTV provided high rates of local and biochemical control with limited severe late toxicity. Intraprostatic failures outside the boost volume appeared to correlate with BCR, which suggests that dose escalation to other subclinical intraprostatic regions may be required. Further characterization using molecular classification, beyond usual clinical parameters, may be warranted in order to improve local control.
    • Local control of carcinoma of the tonsil by radiation therapy: an analysis of patterns of fractionation in nine institutions.

      Withers, H R; Peters, L J; Taylor, J M; Owen, J B; Morrison, W H; Schultheiss, T E; Keane, T; O'Sullivan, B; Van Dyk, J; Gupta, Nirmal K; et al. (1995-10-15)
      PURPOSE: To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS: A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS: There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per day's extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each day's extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS: Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.
    • Local radiotherapy in the management of squamous carcinoma of the anus.

      James, Roger D; Pointon, R C S; Martin, S; Christie Hospital and Holt Radium Institute, Manchester M20 9BX UK (1985-04)
      This paper describes the results of treating 74 patients with squamous cell carcinoma of the anal canal and perianal skin using interstitial radiotherapy as primary treatment. This technique does not involve irradiation of regional lymph nodes. The local control rate for patients with tumours smaller than 5 cm and with negative inguinal nodes was significantly better than for the remaining patients (64 versus 23 per cent). Only 3 of 41 patients with tumours less than 5 cm diameter had clinically significant nodes at presentation, while in 33 patients with tumours larger than 5 cm there were 6 with involved nodes at presentation. Local treatment using interstitial radiotherapy is suggested as useful primary treatment for small, node-negative carcinomas, with surgery held in reserve for failures.
    • Local recurrence of breast cancer following surgery and radiotherapy: incidence and outcome.

      McBain, Catherine A; Young, E A; Swindell, Ric; Magee, Brian; Stewart, Alan L; Department of Clinical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK. (2003-02)
      Local recurrence of cancer in the treated breast following breast-conserving surgery and radiotherapy occurs in a minority of patients, but can represent a significant clinical problem. The impact of local relapse on the subsequent course of the disease is disputed. The aim of this retrospective review was to identify the rate and prognostic factors for breast recurrence and to determine the subsequent outcome. The case notes of 2159 patients treated between 1989 and 1992 were reviewed. Actuarial local relapse rate was 6.3% at 5 years. Factors predictive for recurrence on multivariate analysis were age (P<0.001), status of excision margins (P=0.019), and pathological UICC stage (P=0.01). One hundred and sixty-one patients developed local recurrence in the treated breast of whom 101 were treated with further surgery. The 5-year cancer-specific survival of this group was comparable with that of the patients who remained free of breast relapse (82 vs. 88%) but subsequently fell to 61 vs. 80% at 8 years (P<0.001). Sixty patients were unable to have salvage surgery; their cancer-specific survival was much worse than that of patients with operable recurrences at 33% at 5 years and 13% at 8 years. Eighty-three patients (4% of the original 2159 patients) had uncontrolled local disease at time of death or last follow-up. The prognosis of patients who developed recurrence within 2 years of their initial treatment was inferior to those who developed recurrences after 4 years (cancer-specific survival 5 years post-recurrence 23 vs. 57% P=0.008). Systemic therapy should be considered for patients with early breast recurrence in view of their inferior survival.
    • Local treatment with electrochemotherapy of superficial angiosarcomas: Efficacy and safety results from a multi-institutional retrospective study.

      Guida, M; Campana, L; Curatolo, P; Strippoli, S; Bonadies, A; Grilz, G; Cabula, C; Rotunno, R; Bucher, S; Solari, N; et al. (2016-05-09)
      Angiosarcoma is an aggressive vascular neoplasm with a high propensity for local recurrence. Electrochemotherapy is an emerging skin-directed therapy, exerting prominent cytotoxic activity, and antivascular effects. Its efficacy in angiosarcoma has not been investigated.
    • Local, regional and pulmonary failures in the randomised PET-boost trial for NSCLC patients

      Cooke, S.; De Ruysscher, D; Reymen, B.; Lambrecht, M.; Persson, G. F.; Faivre-Finn, Corinne; Dieleman, E.; Van Diessen, J.; Sikorska, K.; Lalezari, F.; et al. (2021)
      Introduction: In the phase II PET-Boost trial (NCT01024829), patients with stage II-III non-small cell lung cancer (NSCLC) were treated with hypofractionated dose escalation to either the primary tumour (PT) as a whole (armA) or the high FDG-uptake region inside the PT (>50%SUVmax) (armB). Results on Freedom From Local Failure at 1-year (primary endpoint), and overall survival (a secondary endpoint) were reported previously (Cooke et al,ESTRO,2020). Here we report on local and regional failure. Methods: Patients with stage II-III NSCLC were randomised to armA or armB, after a treatment plan was made for both arms that were normalized to the mean lung dose. Concurrent/ sequential/no chemotherapy was allowed. Followup chest CT-scans - scheduled at 3/6/12/18 months - were centrally reviewed by a thoracic radiologist. Definitions: local failure (LF): 20% growth of PT. Regional failure (RF): lymph node (LN) failure either in-field (IF) or out-of-field (OF) on CT-scan. Kaplan Meier analysis was performed to assess LF and RF rates at 2 years. Analysis of distant metastases is on-going. Results: Between April 2010 and Sep 2017, 107 patients were randomised. 82% had stage III disease and 80% had N 1 disease. Most patients received concurrent-chemoradiotherapy (72%). In arms A and B, median GTV-PT was 100 and 115cm3, median GTV-LN was 18 and 20cm3, median fraction dose was 3.25Gy to PTVwhole PT and 3.50Gy to PTV50%SUVmax, resulting in total planned physical dose 78.0 and 84.0 Gy, in 24 fractions (median OTT 34 days in both arms). Median follow-up for CT-scans in central review was 12.6months. In armsA and B respectively, loco-regional failure occurred in 12 and 15 patients, of which 2 and 4 had LF-without-RF, while 9 and 10 had RF-without- LF. One patient in armA had LF with synchronous RF, while in armB one patient had non-synchronous LF and RF. Analysis of all RF’s (10 and 11 total) showed 3 and 4 IF, 3 and 5 OF, 3 and 0 IF as well as OF (missing n¼3). In arms A and B respectively, the 2-year cumulative incidence of LF was 11% and 18%, and for RF 28% and 25% Conclusion: In this randomised, phase II trial dose escalation to the whole PT or 50%SUVmax in NSCLC patients led to excellent local control rates in both treatment arms. The 2-year local failure rate was below 20% and regional failures rate about 27%. In future trials, dose escalation on the PT, sparing central structures as much as possible, may be considered.
    • Localisation and cellular origin of hyaluronectin.

      Ponting, Julie M; Kumar, Shant; Department of Clinical Research, Christie Hospital, Manchester, UK. (1995-10)
      Hyaluronectin is an extracellular matrix glycoprotein which specifically binds to hyaluronan. Isoforms of hyaluronectin are present in nervous and mesenchymal tissues but, while the nervous tissue isoform has been characterised in some detail, less is known about the mesenchymal isoform. Although its tissue localisation suggests a role in tumour development, neither its cellular origin nor its exact function are known. In this study we demonstrate hyaluronectin synthesis in fibroblasts and smooth muscle cells in vitro. The pattern of immunolocalisation of hyaluronectin in fibroblasts depended on the cell type, length of time spent by the cells in culture and cell density. Immunoreactivity in sparsely plated migratory cells was seen mainly in a patchy distribution at the attached cell surface and in the migration tracks left by the cells on the subtratum. In stationary cells a more uniform distribution associated with the attached cell surface was observed, while in confluent cultures hyaluronectin immunoreactivity was mainly seen as a network of fibrillar material above the cell. The pattern of staining was distinct from that of other hyaluronan-binding proteins. Immunoprecipitation, using antihyaluronectin antibodies, of the substratum-attached material deposited by human fetal fibroblasts revealed a family of proteins ranging from 22 to 90 kDa, the major protein being of approximately 60 kDa. These results lead us to propose that hyaluronectin plays an important role in cell migration, probably by regulation of hyaluronan distribution and binding.
    • Localised activation of the EMT switch by peri-neural invading epithelial cells in prostate cancer

      Brown, M.; Hart, C.; Sachdeva, A.; Oliveira, Pedro; Fankhauser, Christian D; Wedge, D; Clarke, Noel W; University of Manchester, Dept. of Genito Urinary Cancer Research, Manchester (2021)
      Introduction & Objectives: Invasion of the peri-neural space by malignant epithelial cell, known as Peri-neural Invasion (PNI), is an acknowledged prostate cancer (PCa) pathological feature associated with recurrence, increased risk of bone metastasis and poor survival. However the molecular mechanism underlying this pathology is relatively unknown. Here we assess the presentation of a metastatic phenotype by the peri-neural invading prostate epithelial cells, their spatial relationship to the tumour lesion and clinical outcome. Materials & Methods: FFPE blocks from an archival cohort (n=54) of radical prostatectomy patients, with associated full clinical history was retrieved under research ethics REC07/H1003/161+5 10_NOCL_02. Serial 4µm sections were stained using an automated multiplex TSA protocol on a Ventana Discovery platform for a panel of metastatic biomarkers (EphA2, pEphA2s897 , pMLC2, E-Cadherin, Vimentin, TOMM20, MTC01, NDUFB8, PTEN) along with the housekeeping landmark markers S100 (neural), pan-cytokeratin and DAPI. Slides were scanned on a Versa 3 platform with Halo image analysis. Prostate spatial zones were defined at 500µm intervals either side of the prostate capsule and pathological features were characterised. Univariate and multivariate (hierarchical clustering, UMap clustering) expression analysis and correlation with clinicopathological features was conducted within GraphPad Prism and R. Results: Marker expression analysis of the pooled (patient independent) PNI showed that all markers have significantly different expression levels dependent on their spatial location in relation to the prostate organ and tumour lesion (Kruskal Wallis p-value <2.2x10-16 except MCT01 (p=5.3x10-10)). Marker expression of amoeboid signalling (EphA2, pEphA2s897 , pMLC2) and mitochondrial defects (loss of Complex I/IV and gain of mitochondrial mass (TOMM20)), associated with a migrational switch to an activated metastatic phenotype in peri-neural invading epithelial cells in PNI close to the prostate edge but outside the tumour lesion correlates with a reduction in overall survival of 28 months (119 months 95%CI 0.3572-1.835 vs 147 months 95% CI 0.5451-2.8; p=0.0249). Conclusions: Peri-neural invading epithelial cells close to the edge of the prostate have features consistent with a switch metastatic behaviour in contrast to the tumour embedded peri-neural invading epithelial cells. This switch was associated with a significant reduction in overall survival.
    • Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique.

      Menasce, Lia P; White, Gavin R M; Harrison, Christine J; Boyle, John M; Cancer Research Campaign Department of Cancer Genetics, Christie CRC Research Centre, Manchester, United Kingdom. (1993-07)
    • Localized activation of the metastatic phenotype within the perineural region in prostate cancer

      Brown, Michael D; Hart, Claire A; Sachdeva, A.; Faulkner, C.; Wedge, David C; Clarke, Noel W; GUCR Group, University of Manchester, Manchester, (2021)
      Background: Perineural Invasion (PNI) is defined as malignant epithelial cell invasion of the perineural space and nerves. Despite widespread acknowledgement of the clinical significance of PNI as a PCa pathological finding associated with recurrence, increased risk of bone metastasis and poor survival, the molecular mechanism underlying this pathology is relatively unknown. The malignant epithelial cells within the PNI potentially provides a spatially defined “snapshot” of disease progression, as the cells switch to a more migrational phenotype associated with metastatic progression. Here we present the initial spatial PNI phenotypic characterisation in PCa. Methods: Archival FFPE blocks, with associated full clinical history, from patients who underwent a radical prostatectomy for prostate cancer were retrieved under research ethics REC#07/H1003/161+5 10_NOCL_02. Biomarkers EphA2, pEphA2s897, pMLC2, E-Cadherin, Vimentin, TOMM20, MTC01, NDUFB8, PTEN were assessed on 4µm serial sections stained using a multiplex TSA protocol, with S100, pan-cytokeratin and DAPI acting as landmarks, on a Ventana Discovery platform prior to scanning on a Versa 3 platform with Halo image analysis. Prostate zones were defined at 500µm intervals either side of the prostate capsule. Univariate and multivariate (hierarchical clustering, UMap clustering) expression analysis and correlation with clinic-pathological features was conducted within R. Results: The PNI epithelial cells within each spatial zone of the prostate are significantly different to each other (Kruskal-Wallis test p < 2.2x10−16 except for MTC01 p = 5.3x10−10). In comparison with the local tumour lesion, PNI epithelial cells localised within 1000µm of the prostate edge and outside the tumour lesion, have undergone a migrational switch, gaining features associated with an activated metastatic phenotype, with increased expression of amoeboid signalling (EphA2, pEphA2s897, pMLC2) and mitochondrial defects (loss of Complex I and IV, gain of mitochondrial mass (TOMM20)). Patients clustering by multivariate expression trends across the prostate regions showed 4 distinct patient groups, with PNI epithelial cells in patient group 1 & 2 displaying a more epithelial to mesenchymal (EMT) phenotype, especially in the first 1000µm inside the prostate organ. Conclusions: Cells within PNI close to the edge of the prostate have features consistent with a switch to migrational/metastatic activation in contrast to the more indolent cell type found deeper within the tumour. Further characterisation of this localised migrational upregulation will help in understanding the transition from a localised to a metastatic phenotype.
    • Locoregional therapies in patients with intrahepatic cholangiocarcinoma: A systematic review and pooled analysis

      Edeline, J.; Lamarca, Angela; McNamara, Mairead G; Jacobs, Timothy; Hubner, Richard A; Palmer, D.; Groot Koerkamp, B.; Johnson, P.; Guiu, B; Valle, Juan W; et al. (2021)
      Background: Locoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design. Methods: Identification of studies reporting outcomes of patients treated with LRT for iCC was performed using PubMed and Embase. Pooled weighted means were calculated for progression-free survival (PFS) and overall survival (OS); meta-analysis of proportions was used for estimation of pooled response rate. Results: 6325 entries were reviewed; 93 studies were eligible, representing 101 cohorts and 3990 patients: 15 cohorts (645 patients) for ablation, 18 cohorts (541 patients) for EBRT, 27 cohorts (1232 patients) for SIRT, 22 cohorts (1145 patients) for TACE, 16 cohorts (331 patients) for HAI and 3 cohorts (96 patients) not pooled. 74% of the studies were retrospective, 99% non-randomised. The pooled mean weighted OS was 30.2 months (95% confidence interval (CI): 21.8-38.6) for ablation, 18.9 (14.2-23.5) for EBRT, 14.1 (12.1-16.0) for SIRT, 15.9 (12.9-19.0) for TACE and 21.3 (15.4-27.1) for HAI. The pooled complete response rate was 93.9% for ablation. When analysed together, SIRT, TACE and HAI had a pooled mean weighted OS of 15.7 months, and 25.2 months for patients treated in first-line with concomitant systemic chemotherapy. Conclusions: Available literature on LRT for iCC was heterogeneous and of insufficient quality to make strong recommendations. Ablation achieved satisfactory outcomes, and may be recommended when surgery is not feasible.
    • Locoregionally recurrent breast cancer: incidence, risk factors and survival.

      Clemons, Mark; Danson, Sarah; Hamilton, T; Goss, P; Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, UK. clemonde@breathemail.net (2001-04)
      Locoregional recurrence (LRR) after therapy for early breast cancer is common. Patients with LRR can suffer both local consequences and symptoms of metastatic disease, as LRR is an independent predictor of subsequent distant metastases. Much of the available data on LRR is derived from small, single institution, retrospective studies, so marked differences in the incidence rates for LRR, it's risk factors and subsequent systemic recurrence are reported. The purpose of this review was to try and collate this data in a format that would be useful for both clinicians and their patients.
    • Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors.

      Ranson, Malcolm R; Middleton, Mark R; Bridgewater, John; Lee, Siow Ming; Dawson, Martin J; Jowle, Debra; Halbert, G; Waller, Sue; McGrath, Helen; Gumbrell, Lindsey; et al. (2006-03-01)
      PURPOSE: A major mechanism of resistance to temozolomide involves the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer. EXPERIMENTAL DESIGN: Lomeguatrib was administered at dose levels of 10 to 40 mg/m2 days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m2 on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination. RESULTS: Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m2 days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months. CONCLUSION: This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.
    • Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial

      Caimi, P. F.; Ai, W.; Alderuccio, J. P.; Ardeshna, K. M.; Hamadani, M.; Hess, B.; Kahl, B. S.; Radford, John A; Solh, M.; Stathis, A.; et al. (2021)
      Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody-drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. Methods: We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0-2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov, NCT03589469. Findings: Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9-56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine.
    • The long road towards cancer prevention: 4 steps backward and 8 forward.

      Coebergh, Jan-Willem; Martin-Moreno, Jose M; Soerjomataram, Isabelle; Renehan, Andrew G; Department of Public Health, Erasmus MC, Rotterdam, The Netherlands. j.coebergh@erasmusmc.nl (2010-09)
    • Long term follow-up of a phase 2 study examining intratumoral G100 alone and in combination with pembrolizumab in patients with follicular lymphoma

      Flowers, R; Panizo, C; Isufi, I; Herrera, F; Okada, C; Cull, H; Kis, B; Chaves, M; Bartlett, L; Ai, Y; et al. (2018)
    • Long term outcomes of Dynamic Sentinel Lymph Node Biopsy (DSNB) for clinically impalpable (cN0) penile cancer patients- an eUROGEN study

      Pozzi, E.; Cakir, O. O.; Castiglione, F.; Schifano, N.; Hadway, P.; Nigam, R.; Rees, R.; Albersen, M.; Parnham, Arie S; Lau, Maurice W; et al. (2021)
      Introduction & Objectives: Dynamic Sentinel Lymph Node Biopsy (DSNB) is routinely offered to patients presenting with penile cancer ³T1G2 and clinically impalpable inguinal lymph nodes (cN0). We aimed to assess the diagnostic accuracy of DSNB, Cancer Specific Survival (CSS) in patients with positive DSNB and positive LN at further Radical Lymph Node groin Dissection (RLND). Materials & Methods: An eUROGEN retrospective study of 509 penile cancer patients undergoing DSNB. Age, type of primary surgery, complications after DSNB, tumour stage, tumour grade were all reported. Number of true positives, true negatives, false negatives and false positives were recorded. False negative was defined as inguinal lymph node recurrence within 12 months from a previous negative DSNB. Sensitivity and specificity of DSNB were calculated. Kaplan-Meier analysis was used to estimate the 5-years CSS and recurrence free-survival rates among patients with positive DNSB and RLND. Results: Overall, 509 patients with cN0 penile cancer were identified. The median follow-up for local recurrence and CSS were 62.5 months (IQR 28.5-91) and 63.5 months (IQR 26.5-90) respectively. All patients underwent DSNB at the time of primary surgery or as a delayed procedure. A total of 993 groins were studied. 37 patients had positive histology at DSNB. 37 patients underwent further RLND with 34 of them having positive histology at RLND. At DSNB true positives were 37 (7.27%), false negatives 3 (0.59). Sensitivity and specificity were 92.5% and 100% respectively. Multivariable Cox regression analysis identified positive LN histology both at DSNB and at RLND as predictors for reduced CSS (HR 4.59, CI: 2.35-8.95, p<0.0001) and (HR 5.64, p=0.0004). Likewise, positive LN histology at DSNB and RLND was a predictor for reduced recurrence free survival HR 4.04 and HR 6.98 all p<0.0001. At Kaplan-Meier analysis, the 5-years CSS for positive LN histology at DSNB/RLND were 69.7% and 69.6% respectively.
    • Long term outcomes of radical radiotherapy with hypoxia modification with biomarker discovery for stratification: Ten year update of the BCON (Bladder CarbOgen Nicotinamide) phase III randomised trial (ISRCTN45938399)

      Song, Yee Pei; Mistry, Hitesh; Irlam, Joely J; Valentine, Helen R; Yang, Lingjian; Lane, Brian; West, Catharine M L; Choudhury, Ananya; Hoskin, Peter J; Division of Cancer Sciences, The University of Manchester, Manchester, UK; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, U (2021)
      Background: Many muscle invasive bladder cancers are hypoxic which limits efficacy of radiotherapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase III trial, XXXX. We present mature follow up with biomarker prediction of outcome. Patients and methods: XXXX is a prospective phase III multicentre randomised two arm non-blind clinical trial. Randomisation was to a control arm receiving radical radiotherapy alone or with the addition of carbogen (98% O2, 2% CO2) and nicotinamide (CON). Patients with muscle invasive or high grade non muscle invasive bladder cancer were included. Tumour tissue was collected at entry and has been analysed for tumour necrosis, hypoxia (24-gene signature) and basal and luminal tumour molecular subtypes. Overall and disease free survival and relationships with biomarker status outcome are analysed using multivariable Cox regression and log-rank analysis. Results: 333 patients with a median follow up of 10.3 years were analysed. 10-year OS rates were 30% (95% CI 0.23-0.39) in RT+CON patients and 24% (95% CI 0.18-0.33) in the RT alone patients (HR = 0.80; 95% CI: 0.61-1.04; p=0.08). Greatest benefit from CON is seen in patients with tumour necrosis (n=79; 5 yr OS 53% v 33%; HR 0.59; 95% CI 0.36-0.99; p=0.04). The results for high hypoxia gene score (n=75) were 5 yr OS 51% v 34%; HR 0.64; 95% CI 0.38-1.08; p=0.09 and molecular subtype basal (n=70) were 5 yr OS 58% vs 38%; HR 0.58; 95% CI 0.32-1.06; p=0.08. Conclusions: Although the improvement in long term overall survival in the whole population is not statistically significant, patients selected by necrosis and a high hypoxia gene score benefitted from hypoxia modification.
    • Long term patient reported swallowing function following chemoradiotherapy for oropharyngeal carcinoma.

      Dixon, Lynne; Ramasamy, S; Cardale, K; Dyker, K; Garcez, Kate; Lee, Lip W; McPartlin, Andrew J; Murray, P; Sen, M; Slevin, Nicholas J; et al. (2018-06-21)
      Limited data are available to inform on long term swallowing outcomes following concurrent chemoradiotherapy for oropharyngeal carcinoma. The aims of this study are to determine long term patient-reported swallowing outcomes across two large UK centres in routine clinical practice and identify associated factors.