Incurable Cancer Research Articles

Definition of Palliative Surgery in Cancer Care: A Systematic Review.

Palliative surgery is commonly performed in cancer centers worldwide. Yet, there is little agreement on the definition of palliative surgery or its relevant outcomes. This systematic review sought to characterize the definitions of palliative surgery and outcomes for patients with cancer undergoing thoraco-abdominal procedures. Following PRISMA guidelines, we conducted a search using PubMed, EMBASE and CINAHL databases to identify English-language publications between August 1, 2005, and December 31, 2023 reporting palliative thoraco-abdominal procedures for patients with cancer. Definitions of palliative surgery were coded and analyzed using an inductive approach. Outcomes were classified according to an outcome measures hierarchy. Among 92 articles met inclusion criteria and four themes emerged in how palliative surgery was defined throughout the literature: prognosis (incurable cancer diagnosis), purpose (intent to treat symptoms or improve quality of life), procedure type (specific operative interventions), or persistent disease following surgery (incomplete cytoreduction). Survival (90%) and perioperative complications/morbidity (72%) were the most commonly reported outcomes, whereas symptom relief, quality of life, and sustainability of success were infrequently reported. Definitions of palliative surgery vary across studies of patients with cancer undergoing thoracic or abdominal procedures and measured outcomes often do not align with the intent of surgery.

Integration of palliative rehabilitation in cancer care: a multinational mixed method study

BackgroundIncurable cancer is a major contributor to societal suffering and disability, and palliative rehabilitation is recommended to be integrated within and between cancer services at all healthcare levels. However, little knowledge exists on how integration of palliative rehabilitation in cancer is understood and achieved in clinical practice. INSPIRE (Integrated short-term palliative rehabilitation to improve quality of life and equitable care access in incurable cancer) is a large European-funded project that aims to promote quality of life through a novel rehabilitation model for people disabled by advanced cancer.AimTo compare the existing integration of palliative rehabilitation in cancer within official documents and in clinical practice across five European countries including United Kingdom, France, Denmark, Norway, and Italy.MethodsMixed methods study with a concurrent research design, comprising a document analysis (N = 23), stakeholder interviews (N = 22), and an online survey (N = 225). Data from each sub-study were analysed separately before results were merged.ResultsThere was limited integration of palliative rehabilitation in cancer in official documents and in clinical practice, though some indicators of integration, including participation in multidisciplinary teams and adherence to standardised pathways, were identified in the survey. Notably, integration of palliative rehabilitation in cancer in clinical practice was observed within limited organisations in secondary healthcare systems, without widespread adoption. Although palliative rehabilitation in cancer as a concept was sparingly used by stakeholders, they recognised the need for a comprehensive approach including multidisciplinary teams that aligns with the individual patient’s needs and goals. Moreover, the ambiguous distinction between the terms ‘palliative rehabilitation’ and ‘palliative care’, insufficient funding, lack of well-defined care pathways and competence gaps among healthcare professionals represented barriers to integration of palliative rehabilitation in cancer into clinical practice.ConclusionIntegration of palliative rehabilitation in cancer was limited in the five EU partnership countries investigated. Clarifying the concept of palliative rehabilitation, including adoption of the concept into official documents and delineating it from palliative care, is essential for more successful integration. This can possibly be achieved by addressing the barriers identified and fostering close collaboration across disciplines.

Anticipatory grief - A neglected phenomenon among relatives of patients with incurable cancer: A qualitative study

PurposeTo explore the experience of being a relative to a patient with incurable cancer and the relatives’ perceived need for support. MethodA qualitative design with a critical hermeneutics approach was applied. In total, 15 semi-structured individual interviews with relatives of patients with incurable cancer were conducted and analysed through a Paul Ricœur-inspired analysis. FindingsThree themes emerged: (1) being in a paradoxical waiting position, (2) the complex need for a respite during the illness and (3) the importance of person-centred information and continuity. The themes highlight how relatives are in a vulnerable position experiencing anticipatory grief while waiting for the patient's death. They have ambivalent feelings because of the tension between the need to be supportive and the need for a respite from the illness. However, they do not want to centre their needs and remove the attention from the patient. Their needs change over time and increase the longer the cancer has lasted. In addition, the relatives need person-centred information and continuity among healthcare professionals. ConclusionRelatives of patients with incurable cancer are in a vulnerable position, with a range of complex and varied needs for support. This underscores the importance of healthcare professionals being aware of anticipatory grief and the management of relatives’ needs to avoid complicated grief and its consequences.

"Treatable not curable": trade-offs in the use of treatment-oriented language with patients who have incurable cancer.

Treatment-oriented language is used by physicians to convey to patients that treatment is available for their cancer (eg, "our usual treatment for this is…," "we can treat this," "your cancer is still treatable"). For patients who have incurable cancer, especially for patients with a poor prognosis or who are at the end of life, it is important to understand how physicians conceptualize and use this "everyday" clinical language. We conducted a qualitative interview study with a multidisciplinary group of physicians (n = 30) who may care for patients with cancer at different points in their clinical course, from diagnosis to end of life. Physicians report a wide range of reasons for using treatment-oriented language in conversations with patients who have incurable cancer. However, physicians also reported concerns that this language can be ambiguous, can convey unintended positive prognostic information, and can shift attention away from important matters such as the non-curative nature of treatment or the inevitability of death. On the basis of these concerns, physicians should (1) consider whether their aims in using treatment-oriented language can be better achieved using other evidence-based communication strategies, and (2) recognize and proactively mitigate potential adverse effects of treatment-oriented language, which may manifest much later in the patient's clinical course.

Efficacy of palliative hemostatic radiotherapy for tumor bleeding and pain relief in locally advanced pelvic gynecological malignancies.

The appearance of symptomatic tumor-related vaginal bleeding and pain in advanced incurable cancer patients with pelvic gynecological malignancies remains atherapeutic challenge in oncological treatment. The aim of our analysis was to evaluate the efficacy and safety of palliative hemostatic radiotherapy. We retrospectively identified patients who had received palliative hemostatic radiotherapy (RT) at our institution between 2011 and 2023 and evaluated acute toxicity, local control, cessation of bleeding, and pain relief. In total, 40patients with amedian planning target volume of 804 cm3 were treated with amedian total dose of 39 Gy in 13fractions, resulting in 6‑month and 1‑year local control rates of 66.9 and 60.8%, respectively. No higher-grade (>gradeIII) acute RT-induced toxicity appeared. Complete cessation of bleeding was achieved in 80.0% of all patients after amedian of 16days and pain relief was documented in 60.9% at first follow-up. 37.5% of the women required ablood transfusion and 25% an additional tamponade with local hemostatic agents. Successful stopping of bleeding was significantly less frequent in patients receiving anticoagulation concurrently with radiation and in the case of infield re-irradiation. Patients with ahigher total RT dose had cessation of bleeding significantly more often, with acut-off value of at least EQD2 (α/β = 10) = 36 Gy. The applied RT technique and planning target volume had no significant influence on the occurrence of bleeding cessation. Palliative hemostatic radiotherapy for locally advanced pelvic gynecological malignancies is safe and effective in achieving high control rates of hemostasis in tumor bleeding and pain relief.

DDEL-02. PRECLINICAL EFFICACY OF IL13RΑ2-TARGETING POLYPEPTIDE-DRUG CONJUGATE (SELF-DEPOTTM ONCOPDC) IN GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are currently incurable cancers. Systemic chemotherapy shows limited efficacy because of the intact blood-brain barrier. Convection-enhanced delivery (CED) offers promise by concentrating high doses of chemotherapeutics directly within these tumors. However, drugs administered via CED often face challenges in confirming precise target delivery and are quickly cleared by increased interstitial fluid flow and drug efflux transporters. This highlights the urgent need for innovative drugs that demonstrate target specificity and prolonged retention capabilities. Intrinsically disordered polypeptides (IDPs), derived from tropoelastin, self-assemble into water-insoluble structures with extended retention properties triggered by body temperature. IL13Rα2, differentially amplified in U87MG GBM and SF8628 DIPG cells, serves as a target for therapeutic intervention. An IL13Rα2-targeting IDP (XM161) was developed by incorporating IL13Rα2 binding sequences into the IDP domains. XM161 demonstrated high selectivity in binding to IL13Rα2, with Kd values of 1,786 nM for IL13Rα1 and 12.8 nM for IL13Rα2. Conjugation of XM161 with SN38, a potent topoisomerase I inhibitor, resulted in XM161-SN38, which remained in a dissolved state up to 50°C but formed insoluble aggregates above 27°C in the presence of cerebrospinal fluid. XM161-SN38 exhibited strong cytotoxicity against U87MG and SF8628 cells, with IC50 values of 14.2 nM and 0.48 nM, respectively. Importantly, XM161-SN38 demonstrated efficacy in overcoming Temozolomide resistance in T98G GBM cells, with IC50 values of 3.35 nM compared to 10.87 nM for unconjugated SN38. In orthotopic xenograft models established in BALB/cSlc-nu/nu male mice using U87MG-Luc2 cells, three doses (3 x 0.95 μg SN38 equivalents) of XM161-SN38 delivered via CED were well tolerated and significantly extended median survival to over 65 days, providing a notable survival benefit compared to untreated controls (42 days) and Topotecan-treated group (42.5 days). These findings validate the feasibility and therapeutic potential of XM161-SN38 for GBM treatment. Ongoing studies are underway to investigate the safety and pharmacokinetics of XM161-SN38 in tumor-naive mouse brains.

IMMU-69. THERAPEUTIC WINDOW ENABLING ERADICATION OF RESIDUAL GLIOMA STEM CELLS BY INTRACRANIAL NK CELL THERAPY FOLLOWING TEMOZOLOMIDE-INDUCED TUMOUR DEPOPULATION – A POSSIBLE ROLE OF CYTOTOXIC EXTRACELLULAR VESICLES

Abstract Glioblastoma (GBM) is an incurable brain cancer, where dismal outcomes result from disease recurrence driven by tumour-initiating glioma stem cells (GSCs). GSCs survive and expand in the brain after surgery, radiation and temozolomide (TMZ) amidst weak immune and natural killer (NK) cell surveillance. Efficient NK cell-mediated killing of GBM cells occurs at high effector to target ratios precluding effective eradication of large tumour remnants, as enforced by clinical trials with autologous NK cells in an adjuvant setting. Here we explore in a human GSC xenograft model whether tumor depopulation using high dose Temozolomide (TMZ) could create a window of curative opportunity for endogenous or exogenous NK cells. We observed that while subcutaneous (sc) xenografts of patient derived GSCs are infiltrated by endogenous functional (NCR1+) NK cells in SCID mice, the corresponding intracranial (ic) tumours remained NK cell depleted. Notably, while TMZ caused near complete regression of intracranial GSC xenografts this was followed by inevitable recurrence of drug-resistant lesions. To explore whether direct delivery of NK cells into depopulated intracranial tumours would change the lethal course of the disease, mice were injected with GSCs intracranially, and upon tumour formation were treated with a sequence of TMZ (systemically), at 2, 7, 14, and 21 days later with irradiated NK92MI cells. Remarkably, this combined therapy completely obliterated recurrent disease at 2 and 7 days but not beyond 14 days. To assess whether NK92MI cells could be replaced by their derived extracellular vesicles (NK-EVs), the latter were injected i.c. post TMZ in GSC xenograft bearing mice. A single injection of NK-EVs resulted in tumour eradication in some but not all mice. Thus, chemotherapy-dependent tumour depopulation may create a unique window of opportunity for curative NK-mediated immunotherapy in GBM.

Expected benefits and concerns regarding virtual reality in caring for terminally ill cancer patients – a qualitative interview study

BackgroundMany palliative cancer patients require inpatient hospital treatment for medical reasons, which contrasts their frequent desire to be at home. Virtual reality (VR) could be a way of bringing the home environment closer to them. First observations have shown benefits from VR for inpatients in palliative care. The aim of this qualitative, descriptive study was to explore the expectations of in-patients suffering from incurable cancer and their relatives about VR, in particular individualized VR images of the patients’ own home.MethodsSemi-structured interviews with inpatients suffering from incurable cancers and their relatives in three medical settings (palliative care, hematology, radiotherapy) of a German university hospital. Qualitative content analysis about expected benefits and concerns regarding VR-videos showing their private home; defining the main topics deductively and the subcategories inductively. We also assessed the patients’ subjective perspective on their remaining time to live to estimate the impact of double awareness on the results. The Patient Advisory Board informed the study protocol and conduct.ResultsWe interviewed 15 patients (8 men; age M = 63.4, SD = 11.34; range 39–82) under palliative care, and four relatives. We organized the interview content in 6 themes (general interest, desired content, non-desired content, expected benefits, concerns, and irregularities) and 26 sub-themes. Most patients and relatives were interested in using VR during hospital treatment. They often preferred viewing nature or tourist sites over seeing their home or family. Reasons could be linked to privacy concerns and the general desire for distraction from the current situation that they specified with their expectation of well-being, a break from the patient-experience, the pursue of curiosity, and the VR evoking fond memories.ConclusionVR seems to be of interest for palliative cancer patients, especially as distraction and relief from their illness. The desired content can be very different, so a choice from a selection of VR-content should be made available. If patients want to see videos of their own home, recordings by relatives instead of study or hospital staff seem to meet the need for privacy.Trial registrationRegistered at Deutsches Register Klinischer Studien; registration number: DRKS00032172; registration date: 11/07/2023. https://drks.de/search/de/trial/DRKS00032172.

Ex-vivo models of post-surgical residual disease in human glioblastoma

Background Glioblastoma is a highly infiltrative, currently incurable brain cancer. To date, translation of novel therapies for glioblastoma from the laboratory into clinical trials has relied heavily on in vitro cell culture and murine (subcutaneous and orthotopic) xenograft models using cells derived from the main bulk of patient tumours. However, it is the residual cells left-behind after surgery that are responsible for disease progression and death in the clinic. A lack of substantial improvements in patient survival for decades suggests commonly used murine xenograft models, a key step before clinical trials, do not reflect the biology of residual disease in patients. Methods To address this, we have developed the ‘Sheffield Protocol’ to generate ex vivo models that reflect both resected, and post-surgical residual disease from the same patient. The protocol leverages parallel derivation of inherently treatment-resistant glioblastoma stem cells (GSCs) from ‘core’ and distant ‘edge’ regions through careful macrodissection of a large en bloc specimen, such as from a partial lobectomy for tumour, followed by tissue dissociation and propagation in serum-free media. Opportunistic en bloc specimen use can liberate the most distant infiltrative cells feasibly accessible from living patients. Results We provide an example illustrating that resected and residual disease models represent spatially divergent tumour subpopulations harbouring distinct transcriptomic and cancer stem cell marker expression profiles. We also introduce the ‘Sheffield Living Biobank’ of glioma models (SLB) that incorporates over 150 GSC lines from 60+ patients, including 44+ resected and residual models, which are available for academic use via MTA. Conclusions These models provide a novel tool to reduce animal xenograft usage by improving candidate drug triage in early preclinical studies and directly replacing animal studies for some therapies that are post-Phase 1+ clinical trial for other cancers/conditions to, ultimately, deliver more effective treatments for post-surgical residual disease in glioblastoma.

The experiences of living with multiple myeloma and a palliative approach to care: A grounded theory study.

Multiple myeloma is an incurable hematologic cancer. A palliative approach to care can be used in conjunction with curative therapy to alleviate suffering, but is underutilized in the hemato- oncology population. The purpose of this study was to explore living with multiple myeloma and individuals' experiences with, and perceptions of a palliative approach in their care. Straussian grounded theory was employed. Ten individuals with multiple myeloma participated between October 2021 and May 2022. A theoretical model depicting the process of living with multiple myeloma was developed. Seven categories emerged from the data, as well as a core category: 'existing in the liminal space between living with and dying from multiple myeloma'. Results demonstrate that a palliative approach to care was inconsistently utilized. The model designed from the participant data offers an explanation of the process of living with multiple myeloma and how a palliative approach to care can be utilized to help these individuals.

Factors for Consideration for Hematological Cancer Patients When Planning for Place of Death: A Constructive Grounded Theory Study.

Planning for place of death is considered troublesome for patients with hematological cancer. Qualitative studies have focused on healthcare professionals and caregivers. To date, no study has been conducted from the patient's perspective of planning for place of death in the last year of life. To develop an understanding of how patients with hematological cancer experience planning for place of death in their last year of life. The study used constructivist grounded theory, semistructured interviews, a constant comparison technique, and memoing to collect and analyze data. The 21 participants were attending a cancer center, cancer unit, or hospice in the United Kingdom. This article describes one core category, factors influencing planning for death, within the incurable hematology cancer illness trajectory through the following 2 subcategories: personal factors-driving away, developing a legacy, designing a death plan, and disease determining; and environmental factors-dependent determination, displacement of the home, and discernment of services. This critical study illustrates that planning for place of death is complex and multifaceted in conjunction with an unpredictable incurable illness trajectory. Preferences for the place of death will change over time depending on the illness trajectory experienced by patients with hematological cancer and the level of physical and emotional energy and independence afforded to discuss and plan.

Trigger Point Injections for Myofascial Pain in Terminal Cancer: A Randomized Trial.

The aim of this study was to evaluate the efficacy and safety of a single trigger point injection (TPI) of a local anesthetic for the treatment of myofascial pain syndrome (MPS) in patients with incurable cancer. This multicenter, exploratory, open-label, randomized comparative trial was conducted in five specialized palliative care departments. Hospitalized patients with incurable cancer who had been experiencing pain related to MPS were randomized to receive either a TPI of 1% lidocaine plus conventional care (TPI group) or conventional care alone (control group). The short-term efficacy and occurrence of adverse events were compared between groups. The primary endpoint was the percentage of patients who experienced a reduction in pain scores of ≥ 50%, assessed using an 11-point Numerical Rating Scale, at 3 days post-intervention. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v5.0. Fifty patients were enrolled, and the trial completion rate was 100%. The proportion of patients who experienced an improvement in Numerical Rating Scale pain scores of ≥ 50% was 70.8% (95% confidence interval, 52.4% to 89.2%) in the TPI group and 0.0% in the control group; the difference was statistically significant (p < 0.001). In the TPI group, one case (4.2%) of Grade 1 nausea and one case (4.2%) of Grade 1 somnolence were reported. A single TPI of a local anesthetic is safe and efficacious in inducing an immediate reduction in MPS-related pain in patients with incurable cancer.

8105 Radiation-Induced Hyperthyroidism in the Context of Palliative Radiation Therapy

Abstract Disclosure: A. Randhawa: None. G. Palaguachi: None. J.G. Karam: None. Introduction: Palliative radiotherapy, designed to alleviate focal symptoms in advanced, incurable cancer, aims to enhance quality of life with minimal treatment burden. The thyroid gland's susceptibility to neck radiation is known, primarily leading to hypothyroidism. However, hyperthyroidism is a much less frequently reported adverse effect that is poorly understood. This case report highlights an unusual instance of radiation-induced hyperthyroidism. Case Presentation:The patient is a 53 years-old woman with history of Ewing’s sarcoma of the sacrum diagnosed in August 2022, treated initially with chemotherapy (cyclophosphamide, vincristine, etoposide and ifosfamide), but diagnosed with leptomeningeal metastasis and T12/L1 mass in October 2023 when she presented with lower extremities weakness and urinary incontinence. She underwent T12-L1 laminectomy, resection of tumor and fusion, and was started on palliative intent radiation therapy for the brain and C-spine. A month later, she was admitted for altered mental status and was found to be persistently tachycardic at 140 bpm. Thyroid function testing was sent and revealed hyperthyroidism with TSH of 0.07 mIU/L (0.39-4.08), Free T4 of 1.74 ng/dl (0.58-1.64), T4 of 10.7ug/ml (4.4-9.5), T3 of 0.54 ng/ml (0.72-1.35), with undetectable Thyroid Peroxidase Antibodies and Thyroid Stimulating Immunoglobulin level. Thyroid Ultrasound showed a small and homogenous thyroid gland with no discrete nodules. Radioactive Iodine uptake and scan was not obtained because of exposure to iodized contrast during hospital stay. The patient had no available baseline thyroid function tests. She had no recent fever or viral illness. Unfortunately, her clinical condition deteriorated rapidly, and she passed away on the seventh day of admission. Conclusion: While hypothyroidism is a well-established consequence of high-dose irradiation, the mechanisms behind the rarer radiation-induced hyperthyroidism remain unclear. Speculation includes the release of autoantigens from damaged thyroid glands, triggering an immune response and potentially leading to Graves' hyperthyroidism. However, our case more likely represents a hyperthyroid phase in the triphasic sequence of destructive subacute thyroiditis, given the absence of elevated thyroid antibodies, thyroid nodules, and other causes of thyroiditis. Increasing awareness of radiation-induced hyperthyroidism, unraveling its mechanisms, and refining diagnostic strategies such as obtaining baseline and monitoring thyroid function testing are crucial, particularly in the context of palliative therapy, where striking the delicate balance between efficacy and minimizing toxicity is paramount. Presentation: 6/3/2024

Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells.

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM.

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent antitumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

Initial adjustments in the dosage and rest period of gemcitabine plus cisplatin therapy for patients with incurable biliary tract cancer based on baseline estimated glomerular filtration rate (eGFR) values may be crucial for treatment outcomes and the preservation of renal function.

Gemcitabine (GEM) and cisplatin (CDDP) combination therapy (GC therapy) is the standard 1st-line regimen for incurable biliary tract cancers (BTCs). However, the correlation between dynamic changes in renal function and the outcomes of GC therapy remains unclear. This study aimed to clarify the association between renal function alterations and treatment outcomes after GC therapy. We retrospectively examined 44 patients with incurable BTC who underwent GC therapy (January 2015 to December 2022). The patients were stratified according to their baseline estimated glomerular filtration rate (eGFR). Changes in eGFR, overall survival (OS), and progression-free survival (PFS). The median baseline eGFRs were 65.0 mL/min/1.73 m2 (low group, n=22) and 90.7 mL/min/1.73 m2 (high group, n=22). No significant background differences were observed between the groups. During the 1st course, 86.4% and 54.5% of patients in the low and high groups underwent dose adjustments and/or administration postponement, which was found to be significantly greater in the low group. In the high group, eGFR decreased with an increase in the CDDP dose (100 mg =-12.0, 200 mg =-12.7, 300 mg =-25.9, and 400 mg =-25.7 mL/min/1.73 m2). In the low group, eGFR remained stable (100 mg =0.8, 200 mg =7.5, 300 mg =4.5, and 400 mg =-0.3 mL/min/1.73 m2). The decrease in the eGFR in the high group was significantly greater at each CDDP dose. However, the median OS and PFS were longer in the low group (OS: 16.3 vs. 9.2 months, P=0.02; PFS: 5.4 vs. 3.6 months, P=0.02). No significant differences in adverse events were observed between the groups. Adjusting GC therapy based on baseline estimated glomerular eGFR may be pivotal for therapeutic benefits and renal function protection in patients with incurable BTC.

Real-World Outcomes of Incurable Cancer Patients Treated with Unlisted Anticancer Treatments in an Academic Center in Quebec, Canada.

Medical oncology is a rapidly evolving field, with new medications being discovered yearly, contributing to increased survival rates. However, accessing drugs in a timely manner can be challenging. In Quebec, Canada, a physician can prescribe an unlisted anticancer treatment through a regulated pathway under exceptional circumstances. We conducted a quality improvement study describing the outcomes of incurable cancer patients receiving unlisted anticancer therapy at the Jewish General Hospital between 2018 and 2019. Though our study did not include a comparator arm, unlisted anticancer therapies were associated with interesting median progression-free survival (11 months) and overall survival (25 months). Moreover, a large proportion of treatments, 44%, were subsequently reimbursed in the province of Quebec. Given the delay in anticancer drug reimbursement, this pathway is essential for timely access to oncology drugs. Such 'special access' programs will likely become increasingly important as precision medicine becomes the standard of practice.

Symptom severity reported by older adults with cancer and its impact on survival prognostication

IntroductionSymptom burden is a crucial factor for survival prognostication, but older adults may report fewer and less severe symptoms than younger patients. We investigated the impact of age on symptom severity and its prognostic implications in the prognostic model for advanced cancer (PRO-MAC). Materials and MethodsEight hundred forty subjects with incurable cancer, who were reviewed by palliative medicine at a tertiary university hospital, were categorized into four groups based on age: < 65 (young), 65–74 (young-old), 75–84 (old-old), and ≥ 85 (oldest-old) for comparison. The study compared individual symptoms reported on the Edmonton Symptom Assessment System-revised (ESAS-r) and analyzed the significance of each prognostic variable in the PRO-MAC model using multivariate Cox proportional hazards regression analysis for all age categories. We generated the log-rank test for each age group to evaluate the effectiveness of PRO-MAC across age groups. RsultsThe older adults had significantly lower unadjusted mean scores in pain, tiredness, anxiety, wellbeing, and ESAS-r summative score compared to young adults. There was a higher proportion of older adults with no symptoms. The ESAS-r summative score remained a significant prognostic factor only in the young and young-old groups. More participants in the older age groups had dementia, which may impact reporting of symptom severity. Despite these findings, the PRO-MAC model remains applicable across all age groups as a multi-domain 90-day survival prognostication tool. DiscussionSymptom burden, including pain, tiredness, anxiety, wellbeing, as well as summative ESASr scores, are lower in older adults with cancer. This could affect the prognostication of survival using symptom burden. However, a multi-dimensional prognostic model like PRO-MAC remains effective for older adults with advanced cancer. Further research is needed to explore tools that can help older adults express the severity of their symptoms and incorporate this into survival prognostication.

N-Check: nerve check to document chemotherapy-induced peripheral neuropathy (CIPN) in incurable cancer

Chemotherapy-induced polyneuropathy (CIPN) encompasses aspectrum of symptoms ranging from hypoesthesia with impaired gait, stance and fine motor skills to painful dysesthesia and allodynia and significantly impairs the quality of life of those affected. In the present pilot study, quantitative sensory testing (QST) was used to investigate CIPN as acommon adverse effect of cytostatic drugs in patients with incurable cancer. The QST is astandardized examination procedure that is not yet routinely used in cancer patients. It is used to examine thermal and mechanical perception and pain thresholds to record the subjectively experienced pain phenotype. In the N‑Check pilot project, the QST was used before and after tumor-specific, potentially CIPN-inducing treatment and the data collected was compared in apre-post analysis. In addition, the specific effects of CIPN on the health-related quality of life of patients treated primarily with apalliative intention were recorded using the Functional Assessment for Cancer Therapy-General (FACT-G) questionnaire. Overall, the patients showed significant heat hypoalgesia after chemotherapy as asign of damage to small nerve fibers. In addition, there were signs of deterioration of the quality of life. The feasibility of QST in patients with incurable cancer and palliative, neurotoxic chemotherapy was demonstrated in this pilot study.

Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells

Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling. Significantly reduced viability was observed in IRS1-silenced cells even upon EGF stimulation showing the critical role of IRS1 in the EGFR signaling network in both malignant and normal pancreatic cells. This study also demonstrated that EGFR binds directly to IRS1 and at least on two tyrosine sites, Y612 and Y896, IRS1 becomes phosphorylated in response to EGF stimulation. Mechanistically, the EGFR-mediated phosphorylation of IRS1 can further activate the MAPK signaling pathway with the recruitment of GRB2 protein. Collectively, in this study, IRS1 was identified as a crucial regulator in the EGFR signaling suggesting IRS1 as a potential target for more durable responses to targeted PDAC therapy.