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Efficacy and Safety of Ripretinib in Advanced Gastrointestinal Stromal Tumors within an Expanded Access Program: A Cohort Study.
No full textRipretinib, a novel tyrosine kinase inhibitor used in advanced gastrointestinal stromal tumors (GIST) resistant to standard therapies, was assessed in the United Kingdom (UK) within an Expanded Access Program (EAP). A retrospective review of patients treated between January 2020 and October 2021 within the ripretinib EAP in our Institution was conducted. Clinician-documented and mRECIST 1.1 assessments were collected. The primary endpoints were progression-free survival (PFS) and time to treatment discontinuation (TTD). Treatment beyond progression (TBP), overall survival (OS), objective response rates and safety data were also analyzed. Survival curves were constructed using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were performed. All analyses were performed with R software. Overall, forty-five patients were included. After a median follow-up of 24.2 (95% CI 19.7-29.7) months, the median PFS of the group receiving 150 mg ripretinib once daily (OD) was 7.9 (95% CI 5.6-19.3) months. In the cohort of 22 patients with dose escalation upon tumor progression to 150 mg ripretinib twice daily (BD), the median PFS from BD was 5.4 (95% CI 2.8-9.3) months. Overall, median PFS and OS values for patients on ripretinib were 9.7 (95% CI 8.3-18.1) and 14.0 (95% CI 9.9-NA) months, respectively. TTD was similar to PFS. TBP was observed in about one third of all patients. Objective responses to ripretinib OD and BD treatments were observed in 16.7% and 10.0% of the patients, respectively. No new safety signals were identified. In conclusion, patients with advanced GIST receiving ripretinib in the UK within the EAP reported prolonged benefits, in line with the recent phase III clinical trials
A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.
No full textBACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC
Longitudinal Assessment of Tumor-Infiltrating Lymphocytes in Primary Breast Cancer Following Neoadjuvant Radiation Therapy.
No full textPURPOSE: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials. METHODS AND MATERIALS: We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes. RESULTS: Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART. CONCLUSIONS: This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials
Using proton beam therapy to reduce the toxicity of treatment for breast cancer
No full textBackground and purpose
Proton beam therapy (PBT) can deliver radiation dose that conforms more closely to the target than photon treatment, sparing organsat-risk {OAR) thereby reducing late effects of radiotherapy (cardiac disease or second malignancy) in breast cancer survivors. Potential benefits are greater when conventional radiotherapy delivers higher mean heart dose (MHD) or dose to contralateral breast (CB) such as internal mammary nodal treatments or unfavourable anatomy e.g. pectus excavatum (PEx). In PBT the linear energy transfer (LET), increases steeply at the end-of-range and relates to the relative biological effectiveness (RBE). These physical differences from photons could have clinical implications for beam arrangement.
The aims of this thesis were to identify which patients might benefit most from breast PBT, define beam arrangement(s) that minimise potential clinical risks of variable RBE and to develop eligibility and technical specifications for a randomised controlled trial of PBT versus photons (PARABLE).
Methods
OAR doses were compared between PBT and photon techniques for irradiating breast and nodal targets in PEx patients and those requiring a simultaneous integrated boost (SIB). Risks of developing a subsequent CB cancer were calculated. PBT plans using different beam arrangements were prepared. LET distributions and RBE-weighted doses were calculated using variable RBE models. Patients at greater risk of radiation-related cardiac disease were defined for inclusion into PARABLE considering age, pre-existing cardiac risks and MHD. A radiotherapy trial quality assurance (RTTQA) document was developed with multidisciplinary input. Results
In PEx patients PBT reduced MHD by a mean of 3.4 Gy compared to volumetric modulated arc therapy and, in a mixed cohort, the median MHD contribution from a SIB was 0.3 Gy lower using PBT. In patients <40 years, PBT could decrease the risk of CB cancer six-fold. Higher LET was observed in OARs for single beam PBT plans. For PARABLE, a simplified model-based approach was developed for eligibility and RTTQA specifications agreed.
Conclusions
PBT has scope to reduce toxicity by reducing MHD, particularly in PEx patients. When using PBT, more than one beam is
recommended. A MHD risk-adapted eligibility criterion and RTTQA document are in use in a national breast PBT trial
Discordance in Recommendation Between Next-Generation Sequencing Test Reports and Molecular Tumor Boards in India.
No full textPURPOSE: Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports. In this study, we analyze the discordance between these recommendations and the rationales behind the discordances, in a non-high-income setting, with international input to evaluate the necessity of MTB in clinical practice. METHODS: We collated data from MTB that were virtually hosted in Chennai, India. We included patients with malignancies who had NGS reports on solid tissue or liquid biopsies, and excluded those with incomplete data. MTB forms and NGS reports of each clinical case were analyzed and evaluated for recommendation concordance. Concordance was defined as an agreement between the first recommendation in the MTB forms and the therapeutic recommendations suggested in the NGS report. Discordance was the absence of the said agreement. The rationales for discordance were identified and documented. RESULTS: Seventy MTB reports were analyzed with 49 cases meeting the inclusion criteria. The recommendation discordance was 49% (24 of 49). Discordant recommendations were mainly due to low level of evidence for the drug (75% of cases). CONCLUSION: The discordance between MTB and NGS vendor recommendations highlights the clinical utility of MTB. The educational experiences provided by this initiative are an example of how virtual academic collaborations can enhance patient care and provider education across geographic borders
Introduction of day-case robotic liver surgery: a case series from a tertiary hepatobiliary and pancreatic centre.
No full textBACKGROUND: Liver surgery is associated with a significant hospital stay regardless the type of liver resection. A large incision is essential for open liver surgery which is a major factor in the course of the patient's recovery. For patients with small parenchyma liver lesions requiring surgical resection, robotic surgery potentially offers the opportunity to transform the patient's post-operative course. A day-case robotic liver resection pathway was formulated and implemented at our institution when patients were planned for discharge within 24 h of admission for liver surgery. METHODS: Single surgeon case series of cases performed at a tertiary hepatobiliary and pancreatic centre between September 2022 and November 2023. The inclusion criteria were non-anatomical wedge resections, < 2 anatomical segmental resections, left lateral hepatectomy and minimally invasive surgery. RESULTS: This is the first series of robotic day-case minor liver resection in the United Kingdom. 20 patients were included in this case series. The mean operative time was 86.6 ± 30.9 min and mean console time was 58.6 ± 24.5 min. Thirteen patients (65%) were discharged within 24 h of surgery. The main cause of hospitalisation beyond 24 h was inadequate pain relief. There were no Clavien-Dindo grade III or above complications, no 30-day readmission and 90-day mortalities. CONCLUSION: This case series demonstrates that robotic day-case liver resection is safe and feasible. Robust follow-up pathways must be in place to allow for the safe implementation of this approach, to monitor for any complications and to allow intervention as required in a timely manner
The response of the Eukaryotic replisome to DNA quadruplex structures
No full textSequences that can form DNA secondary structures, such as G-quadruplexes (G4s) and intercalated-Motifs (iMs), are abundant in the human genome and play a range of physiological roles. However, they can pose a challenge to the replication machinery and in turn threaten genome stability. Multiple lines of evidence suggest G4s interfere with replication, but the underlying mechanism of stalling and how this contributes to their roles in disease remains unclear. Moreover, there is a lack of evidence as to how iMs affect the replisome. In this study, I have reconstituted replication of physiologically derived structure-forming sequences to find that a single G4 or iM is sufficient to arrest DNA replication. I describe a range of approaches to attempt to detect the formation of secondary structures within the context of duplex DNA, many of which are widely used in the literature but proved unsuccessful in the context of this project. A novel technique, using solid-state nanopores to detect structures on a single molecule level, reveals that structures form as a consequence of replication. A combination of genetic and biophysical characterisation establishes that structure forming capacity is a key determinant of replisome arrest. Mechanistically, replication fork arrest is caused by impaired synthesis, resulting in helicase-polymerase uncoupling. Significantly, iMs also induce breakage of nascent DNA. Stalled forks can be rescued by a specialised helicase, Pif1, but not Rrm3, Sgs1, Chl1 or Hrq1. Finally, I address how the replicative helicase, CMG, responds differently to different types of DNA secondary structures, and is eventually able to bypass a pre-existing G4, iM or hairpin structure. Altogether, this study provides a potential mechanism for quadruplex structure formation and resolution during replication and highlights G4s and iMs as endogenous sources of replication stress, which may explain their genomic instability and mutation frequencies in cancer
tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice.
No full textINTRODUCTION: Amyloid beta (Aβ) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aβ accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aβ-induced neurovascular and cognitive dysfunction. METHODS: Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later. RESULTS: Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid. DISCUSSION: These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution. HIGHLIGHTS: Amyloid beta (Aβ) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aβ. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aβ and tPA reconstitution may be of therapeutic value
Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.
No full textPineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors
Inverse planning of lung radiotherapy with photon and proton beams using a discrete ordinates Boltzmann solver.
No full textObjective. A discrete ordinates Boltzmann solver has recently been developed for use as a fast and accurate dose engine for calculation of photon and proton beams. The purpose of this study is to apply the algorithm to the inverse planning process for photons and protons and to evaluate the impact that this has on the quality of the final solution.Approach.The method was implemented into an iterative least-squares inverse planning optimiser, with the Boltzmann solver used every 20 iterations over the total of 100 iterations. Elemental dose distributions for the intensity modulation and the dose changes at the intermediate iterations were calculated by a convolution algorithm for photons and a simple analytical model for protons. The method was evaluated for 12 patients in the heterogeneous tissue environment encountered in radiotherapy of lung tumours. Photon arc and proton arc treatments were considered in this study. The results were compared with those for use of the Boltzmann solver solely at the end of inverse planning or not at all.Main results.Application of the Boltzmann solver at the end of inverse planning shows the dose heterogeneity in the planning target volume to be greater than calculated by convolution and empirical methods, with the median root-mean-square dose deviation increasing from 3.7 to 5.3 for photons and from 1.9 to 3.4 for proton arcs. Use of discrete ordinates throughout inverse planning enables homogeneity of target coverage to be maintained throughout, the median root-mean-square dose deviation being 3.6 for photons and 2.3 for protons. Dose to critical structures is similar with discrete ordinates and conventional methods. Time for inverse planning with discrete ordinates takes around 1-2 h using a contemporary computing environment.Significance.By incorporating the Boltzmann solver into an iterative least squares inverse planning optimiser, accurate dose calculation in a heterogeneous medium is obtained throughout inverse planning, with the result that the final dose distribution is of the highest quality