Unresectable Disease Research Articles

A unique case of unresectable metastatic gastric squamous cell carcinoma treated with combined nivolumab and capecitabine/oxaliplatin complicated by immunotherapy induced pure red cell aplasia

Gastric Squamous Cell Carcinoma is an extremely rare type of gastric cancer, with an incidence of 0.04-0.07% among all gastric cancers [1]. The treatment for this malignancy has focused on surgical resection with adjuvant chemotherapy. Treatment for unresectable metastatic disease has varied, with most regimens taken from management of traditional gastric adenocarcinoma and other GI malignancies with varied success. Here, we will explore a case of a patient diagnosed with metastatic gastric squamous cell carcinoma treated with combination nivolumab and capecitabine with oxaliplatin regimen having a complicated course involving medication induced pure red cell aplasia.

Outcomes of Head and Neck Neurogenic Tumors.

Lateral neck mass managementfrequently challenges surgeons. Nerve tissue neoplasmsare an uncommon cause of such nodules. Neurogenic tumors form a tiny percentage of the head and neck neoplastic lesions. Considering the number of nerves in this area, it is surprising that such neoplasms are not more frequently seen. A retrospective study was conducted on all patients who presented to the National Cancer Institute of Cairo, Egypt, with head and neck neurogenic neoplasms. During the last 10 years at the National Cancer Institute of Egypt (2006-2015), 40 cases of neurogenic tumors of the head and neck were treated atthe head and neck unit. Patients' ages ranged from two to 78 years with a mean age of 34.7 years. Childhood neurogenic tumors accounted for nine cases (22.5%) only in this study. Male patients diagnosed with these tumors comprised 16 cases, while female patients comprised 24 cases, with a female-to-male ratio of 1.5:1. Patient presentation depends on the biological behavior of the tumor; for instance, some of them present by slowly growing painless well-circumscribed mobile swelling, and others present by rapidly growing swelling with neurological deficit. Clinical picture and imaging studies such as CT and MRI raise suspicion andmay help delineatesuch tumors, but a definitive diagnosis is obtained by tissue biopsy. Surgery is the mainstay of treatment in most head and neck neurogenic tumors, whereas adjuvant therapy is of limited benefit in some types of neurogenic tumors.The five-year survival rate was60%for the malignant group, while death was reported in six out of 15 cases (40%). Conclusion: Most neurogenic head and neck tumorsare benign.Accurate preoperative assessment and a high degree of suspicion are the initial steps in the management. Proper treatment involves complete surgical excision; however, debulking procedures have an important role. Malignant neurogenic tumorsare aggressive and are treated with combined radical surgical resection and radiation. Chemotherapy is tried for locally advanced unresectable or metastatic disease.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

Real-world treatment patterns and clinical outcomes in patients with stage III NSCLC in Korea: The KINDLE study.

KINDLE-Korea is part of a real-world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC). The KINDLE was an international real-world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE-Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. A total of 461 patients were enrolled. The median age was 66 years (range: 24-87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)-based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.

Management and outcomes of children with rhabdomyosarcoma in a low-to-middle-income country: A first report from Chris Hani Baragwanath Academic Hospital, South Africa

BackgroundStudies done in South Africa show that Rhabdomyosarcomas (RMS) comprises 6 % of childhood malignancies. Very few centres in South Africa (SA) have reported their management and outcomes of children with RMS, and as such, it is difficult to compare outcomes and come up with management protocols befitting our environment. AimTo describe the management and outcomes of children with RMS at Chris Hani Baragwanath Academic Hospital (CHBAH). SettingThe Departments of Paediatric Surgery and Paediatric Oncology. MethodsA retrospective review of clinical records of patients below 18 years of age with RMS, managed from 01 January 2008 to 31 December 2017. ResultsFifty-eight patients had RMS, 77 % embryonal and 21 % alveolar subtypes. Primary tumour site was favourable in 48 %, and unfavourable in 45 %. Thirty-three patients (57%,) had surgery for the primary tumour, whilst 25 patients (43 %) did not have surgery. Post-operative clinical groups were 29 % group I, 9 % group II, 43 % group III, and 19 % group IV. The overall 5-year survival was 55%. Predictors for a good outcome included early disease stage at presentation, favourable site, embryonal subtype, and surgery for the primary tumour. ConclusionThe 5-year survival of 55 % from this study is low when compared to high income countries but is comparable to middle income countries. The main factor contributing to mortality is patients presenting with unresectable advanced disease in unfavourable sites. Surgical resection plays a major role in improving outcomes. Level of evidenceIV

Abstract 2406: Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous and extremely aggressive neoplasm. Most patients with PDAC present with symptomatic, surgically unresectable disease at initial diagnosis. Systemic chemotherapy is the standard care for patients diagnosed with unresectable PDAC, despite the dismal survival rate due to disease recurrence. In this context, liquid biopsy based ctDNA monitoring may aid to improve detection accuracy and allow real time disease prognosis. Here we aimed to investigate the utility of ctDNA in longitudinal tumor monitoring to assess treatment response and to predict disease recurrence. We performed targeted NGS sequencing to investigate over 900 mutations (SNVs) and 12 copy number variations (CNVs) in 53 genes, using the Ion S5 Oncomine PanCancer gene panel in 40 PDAC patients with unresectable disease. Serial plasma samples were obtained from patients in the course of 24 months, including samples collected before the first intervention (baseline) as well as within 2 months after initiation of chemotherapy. Patients were followed for a period of up to 2-years from diagnosis through treatment, to death or final follow-up. Genomic DNA from paired plasma-buffy coat samples were sequenced to exclude clonal hematopoiesis. Overall detection of ctDNA alterations in baseline samples was 55% (22/40) with increasingly higher detection rates and mutation loads in advanced disease (88% in stage IV patients). Alterations including SNVs and CNVs were preferentially distributed among 9 genes; mutations in TP53 (45%), KRAS (38%) and SMAD4 (5%) were most commonly identified. To asses response to chemotherapy, the presence of residual ctDNA after clinical intervention was evaluated by comparing total ctDNA MAF (mutant allele frequency) detected in plasma at diagnosis and within 2 months of chemotherapy. 71% (17/24) of patients who reached progressive disease (PD) had detectable baseline mutations and 79% (19/24) had persistent residual mutations at 2 months of treatment. Conversely, 94% (15/16) of non-PD patients had no detectable ctDNA or had a significant reduction in total MAF after 2 months of chemotherapy. Absence of residual ctDNA after 2 months of chemotherapy was associated with a better OS (p=0.031; HR = 3.48). On the other hand, residual ctDNA after 2 months of chemotherapy was associated with a shorter PFS (p=0.042; HR = 3.28). Our study demonstrates that monitoring ctDNA levels derived from plasma provides valuable insights into the therapeutic response in patients with unresectable PDAC, even in the absence of matched tumor genotyping. We found a significant correlation between increased ctDNA levels following the initiation of treatment and poorer survival outcomes. Citation Format: Fabio Pittella Silva, Yasutoshi Kimura, Masayo Motoya, Toru Nakamura, Takeshi Murakami, Kazunori Watanabe, Siew-Kee Low, Yusuke Nakamura. Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2406.

Abstract 699: Targeting radiation-driven invasion and metastasis in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Standard of care includes chemotherapy and radiotherapy (RT) for locally advanced, unresectable disease. Despite radiotherapy being an effective and sometimes curative option for many cancer types, radio-resistance is common, and pre-clinical research in recent years has found that RT can initiate a more aggressive, pro-invasive phenotype in the remaining cells post treatment (1,2). Little is known about the molecular mechanisms responsible for this phenomenon.There is accumulating evidence highlighting a role for the RhoGTPase family in mediating radioresistance and enhanced invasion (2, 3). Understanding their role in PDAC progression may aid the identification of novel chemotherapeutics that could be used alongside RT in the future. We present in vitro data that confirms the pro-migratory effect of RT and importantly indicates a significant increase in metastases formed in a clinically relevant model of PDAC (KPC Pdx1-Cre; KrasG12D/+; Trp53R172H/+) after treatment using a small animal radiation research platform (n=31, p<0.0001). In concurrence with previous literature, we found that PDAC cell motility was dependent on the RhoGTPase pathway, RhoA/ROCK1 (p=0.004). However, post-RT, this dependency was switched to an alternative pathway, CDC42/Rac1/MRCK, indicating a clear change in the balance of RhoGTPase signaling (p=0.002). This switch was confirmed via high-throughput immunofluorescence analysis. To widen this investigation further, we performed an siRNA screen targeting all members of the RhoGTPase family. Preliminary results indicate signaling dependency on Rac2, Rac3 and CDC42 post-RT. Additionally, we have performed RNAseq to investigate pro-invasive gene signatures arising from the acute irradiation of pancreatic cancer cells. This was done at sufficient depth to identify splice variants, with differential transcript expression (DTE) analysis identifying 236 differentially expressed transcripts and the differential transcript usage (DTU) analysis identifying 28 transcripts and 23 genes. Initial functional enrichment analysis found gene signatures relating to cell migration and adhesion, which may be indicative of an invasive phenotype. In conclusion, we present in vitro and in vivo data suggesting RT may promote a more invasive phenotype in PDAC at least in part due to a switch in RhoGTPase signaling. 1. Mueller, A.C., et al., Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer. Cancer Res, 2021. 81(12): p. 3255-3269. 2. Birch, J.L., et al., A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma. Cancer Res, 2018. 78(22): p. 6509-6522. Citation Format: Kathy Mclay, Mathias Tesson, Dion Gilmour, Jennifer P. Morton, Joanna L. Birch. Targeting radiation-driven invasion and metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 699.

Abstract 1692: MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal type of pancreatic neoplasm. Unfortunately, most patients are diagnosed with unresectable or metastatic disease, making current treatments insufficient. As a result, the 5-year survival rate for PDAC is below 10%.Pancreatic neoplasms are primarily initiated by the KRAS mutation, accounting for 95% of cases. However, the progression of PDAC to a highly aggressive and therapy-resistant cancer is accelerated by chronic inflammation. The role of mutant KRAS signaling and NF-κB inflammatory signaling in promoting PDAC progression has been extensively studied. Yet, the transcriptional mechanism of their cooperation remains unclear. Additionally, the interaction between PDAC tumor cells and signals in the tumor microenvironment (TME) is not yet fully understood. Our study demonstrates that the simultaneous activation of KRAS/MAPK and NF-κB by epidermal growth factor (EGF) and TNFα, respectively, increases cell migration as shown through live-cell imaging analysis. An integrated analysis of epigenetic and transcriptomic data (ChIP-seq and RNA-seq) was performed after dual stimulation of both pathways. This revealed a high occupancy of the active mark, H3K27ac at transcription start sites of a subset of genes involved in cell migration and subtype switch. Through gain and loss-of-function studies, FOSL1 and RELA were identified as the key transcription factors. The epigenome mapping of FOSL1 and RELA after the stimulation of both pathways revealed their occupancy at RELA-dominant and FOSL1/RELA co-occupied regions. Inhibitor treatments and loss-of-function studies revealed that RELA binding controls RNA polymerase recruitment for transcription initiation and enhances cell migration. Further analysis of RNA-seq data on PDAC cell lines and cells from patient-derived xenografts highlighted that active inflammatory signaling contributes to a subtype switch from the classical to the more migratory basal subtype. Our study, combined with single-cell RNA-seq analysis of published data, shows that macrophages in the tumor microenvironment supply TNFα that activates NF-κB signaling, leading to changes in cell migration. Our study has provided a comprehensive understanding of the mechanism by which mutant KRAS and inflammatory signaling contribute to the progression of PDAC. These findings could offer a new perspective in the development of mechanism-based therapeutic approaches that can improve the efficacy of chemotherapeutic agents and make tumors more amenable to surgical resection. Citation Format: Joana E. Aggrey-Fynn, Meghana Manjunath, Steven A. Johnsen. MAPK and NF-kappaB signaling converge on the epigenome to transcriptionally activate genes involved in pancreatic cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1692.

Abstract 6528: Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) encompasses malignancies of the mucosal epithelium in the oral cavity, pharynx, and larynx. The lack of effective screening strategies and the typically late stage of detection are contributors to a considerable annual death toll of HNSCC. Additionally, the anatomical proximity of the malignancy to delicate structures of the head and neck leads to tremendous treatment-related morbidity. Therefore, there is great interest in developing life-saving therapies and strategies for treatment de-escalation. The immune checkpoint inhibitor pembrolizumab (αPD-1) has been approved for recurrent or metastatic HNSCC and as a frontline therapy for unresectable disease. However, only about a quarter of patients respond to αPD-1 therapy. The immunosuppressive effect of TGFβ has been widely described as relevant to the HNSCC tumor microenvironment. However, attempts to blockade TGFβ have failed mainly due to the widespread side effects of disrupting a highly promiscuous cytokine. Integrin αvβ6 is a major activator of the inert latent TGFβ into the active, immunosuppressive form. With its high relative specificity to HNSCC tissue, inhibition of αvβ6 could offer a safer approach for disrupting TGFβ to overcome resistance to immune checkpoint blockade. After screening ɑvβ6 expression levels of HNSCC cell lines via flow cytometry, cell lines FaDu and CAL27 were selected for further investigation due to high endogenous ITGB6 expression (FaDu 35.57% cells ITGB6+, CAL27 95.69% cells ITGB6+). The cell lines were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown of αvβ6 using a lentiviral system. Both knockdown and control shRNA cell lines were pretreated with 1 μg/mL of doxycycline for five days to induce the shRNA and subsequently co-cultured with TALL-104 T-cells. Quantitative fluorescence microscopy of the co-culture revealed that the knockdown of αvβ6 substantially increased T-cell killing over 24hrs (FaDu CTRL shRNA 6.72%±2.49 dead vs. FaDu ITGB6 shRNA 12.80%±3.16 dead, p<0.001). However, treatment of FaDu and CAL27 cell lines with active-TGFβ showed no change in PD-L1 expression via flow cytometric analysis. To determine whether the T cell evasive effect of αvβ6 is driven by other immune checkpoints on the cancer cells or by the direct effect that TGFβ has on immune cells, we show the generation of relevant mouse αvβ6 shRNA knockdown cells. These syngeneic in vivo studies will facilitate cytokine profiling to uncover the dynamics of tumor-immune cell interactions in response to αvβ6 inhibition. Citation Format: William J. MacDonald, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Shengliang Zhang, Vida Tajiknia, Connor Purcell, Jillian Strandberg, Nolan Stubbs, Wafik S. El-Deiry. Integrin ɑvβ6 upregulation as a mechanism of T-cell evasion in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6528.

Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.

Unraveling the enigma: A comprehensive review of solid pseudopapillary tumor of the pancreas.

Solid pseudopapillary tumor of the pancreas (SPTP) is a rare neoplasm predominantly observed in young females. Pathologically, CTNNB1 mutations, β-catenin nuclear accumulation, and subsequent Wnt-signaling pathway activation are the leading molecular features. Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies. Surgical resection remains the mainstay treatment. Risk models, such as the Fudan Prognostic Index, show promise as predictive tools for assessing the prognosis of SPTP. Establishing three types of metachronous liver metastasis can be beneficial in tailoring individualized treatment and follow-up strategies. Despite advancements, challenges persist in understanding its etiology, establishing standardized treatments for unresectable or metastatic diseases, and developing a widely recognized grading system. This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic methods, treatment options, and prognostic factors.

Feasibility and efficacy of indocyanine green in monitoring systemic drug leakage during isolated limb perfusion for recurrent melanoma of extremity.

Melanoma is known for its high metastatic potential and aggressive growth. Recurrence is common post-surgery, sometimes leading to unresectable disease. Locally recurrent unresectable melanoma of extremity has been treated with high-dose anticancer chemotherapy via isolated limb perfusion (ILP) to improve local efficacy of drug and salvage limbs. Standard ILP monitoring uses radiolabeled dyes, requiring specialized personnel and involving radiation exposure. In this case, we used indocyanine green (ICG) to track systemic drug leakage during ILP. A 47-year-old gentleman with recurrent malignant melanoma of the left foot, operated twice earlier and treated with adjuvant pembrolizumab, presented with multiple in-transit metastases in the limb. ILP was planned, with 5 mg ICG administered in the perfusion solution along with high-dose melphalan. Stryker's SPI PHI handheld device was employed to visualize ICG during ILP. Absence of fluorescence beyond the involved extremity, such as fingers, ears, and the abdominal wall, indicated no systemic drug dispersion. For control, technetium radiocolloid dye was co-administered, monitored by a precordial gamma probe, confirming no systemic leakage, and validating effectiveness of ICG in leakage monitoring. ICG proves to be a safe, reliable, cost-effective, radiation-free approach for precise systemic drug leakage monitoring during ILP for recurrent melanoma of extremity.

FOLFIRINOX or Gemcitabine Plus Nab-paclitaxel as First Line Treatment in Pancreatic Cancer: A Real-World Comparison.

Advanced pancreatic cancer has a poor prognosis and a 5-year survival rate <5%; thus, treatment of patients with advanced unresectable or metastatic disease is challenging. Current guidelines recommend either gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FOL) as first-line treatment. Data on both efficacy and toxicity of FOL versus GnP in metastatic cancer are limited. This study aimed to compare the two chemotherapy regimens in terms of efficacy and toxicity in a real-world setting. This retrospective propensity score matching study reviewed the medical records of 123 consecutive patients with advanced or metastatic pancreatic cancer who received either GnP or FOL between March 2013 and January 2019 in Guglielmo da Saliceto Hospital, Piacenza. Fifty patients (40.65%) received FOL, administered in an attenuated dose, and seventy-three patients (59.35%) received GnP. After a propensity matching score, 100 patients were retrospectively evaluated. In the final matched cohort, there was no difference in neoadjuvant therapy, radiotherapy, and surgery performed before the first-line therapy between the two groups. Progression-free survival and overall survival were comparable between the two groups and no difference was found in the percentage of toxicity. There was no difference in outcomes between patients who received FOL and those who received GnP. Unexpectedly, no greater FOL-related toxicity was found, probably due to the dose reduction.

SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.

A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic HER2-negative breast cancer

BackgroundZilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer.Patients and methodsEligible patients had locally advanced, unresectable, or metastatic HER2− breast cancer with Eastern Cooperative Group performance status of 0–2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV.ResultsStudy patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response.ConclusionThe combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.Trial Registration: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.

Clinical outcomes in borderline and locally advanced pancreatic cancer with the addition of low-dose-rate brachytherapy to standard of care therapy

PURPOSESurgical resection remains the only curative therapy for pancreatic cancer. Unfortunately, many patients have borderline or unresectable disease at diagnosis due to proximity of major abdominal vessels. Neoadjuvant chemotherapy and radiation are used to down-stage, however, there is a risk that there will be a positive/close surgical margin. The CivaSheet is a low-dose-rate (LDR) brachytherapy device placed at the time of surgery to target the area of highest risk of margin positivity. The purpose of this study is to assess the clinical value of brachytherapy in addition to standard-of-care therapy in pancreatic therapy. METHODS AND MATERIALSBetween 2017 and 2022 patients with borderline and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and radiation followed by surgical resection were included. There were 2 cohorts of patients: (1) Those who had the LDR brachytherapy device placed at the time of surgery and (2) those who did not. Sixteen of 19 (84%) patients who had brachytherapy were enrolled in a prospective clinical trial (NCT02843945). Patients were matched for comorbidities, cancer staging, and treatment details. The primary outcome was progression-free survival (PFS). RESULTSThirty-five patients were included in this analysis, 19 in the LDR brachytherapy group and 16 in the comparison cohort. The 2-year PFS was 21% vs. 0% (p = 0.11), 2-year OS was 26% vs. 13% (p = 0.43), and the pancreatic cancer cause-specific survival was 84% vs. 56% (p = 0.13) in favor of the brachytherapy patients. CONCLUSIONSUse of LDR brachytherapy at the time of resection shows a trend towards improved progression free and overall survival for patients with borderline or locally advanced pancreatic cancer treated with neoadjuvant chemoradiation.

Do children with Osteosarcoma benefit from Pulmonary Metastasectomy? - A Systematic Review Of Published Studies and 'Real world' Outcomes.

To critically examine the evidence-base for survival benefit of Pulmonary metastasectomy (PM) for Osteosarcoma (OS) in the paediatric population. PM for OS is recommended as standard of care in both paediatric and adult treatment protocols. Recent results from the PulMiCC trial demonstrate no survival benefit from Pulmonary Metastasectomy (PM) in Colorectal Cancer in adults. A systematic review was undertaken according to PRISMA guidelines. Medline, Embase and 2 clinical trials registers were searched for ALL STUDIES detailing paediatric OS patients (<18y) undergoing PM with a comparison cohort group that did not receive PM. Eleven studies met inclusion criteria dating from 1984 - 2017. All studies were retrospective and none directly compared PM versus No PM in paediatric patients as its main objective(s). Three-year survival rates ranged from 0-54% for PM and 0-16% for no PM. No PM patients were usually those with unresectable disease and/or considered to have a poor prognosis. All studies were at high risk of bias and there was marked heterogeneity in the patient selection. There is a weak evidence-base (Level IV) for a survival benefit of PM for OS in paediatric patients likely due to selection bias of 'favourable cases'. The included studies many of which detailed outdated treatment protocols were not designed in their reporting to specifically address the questions directly. A randomised controlled trial - whilst ethically challenging in a paediatric population - incorporating modern OS chemotherapy protocols is needed to crucially address any 'survival benefit'.

JAUNDICE IN PATIENTS WITH GALL BLADDER CANCER- A SURROGATE MARKER OF ADVANCED DISEASE

Background: Gall bladder cancer (GBC) is most common cancer of biliary tract. R0 resection is the most important predictor of survival. Patients with GBC and jaundice do worse than those without jaundice.Methods: Retrospective analysis of prospectively kept data of patients with GBC admitted to the department of Surgical Gastroenterology at a tertiary care hospital in northern India over10 years from 2011 to 2020. Data on patient demography, clinical profile, imaging characteristics, clinical course, staging, and operative procedures was extracted and analyzed to compare the experience of patients with GBC with jaundice and GBC without jaundice.Results: There were 401 patients with GBC; 75 with jaundice and 326 without jaundice. Patients with GBC and jaundice had a significantly higher incidence of pain abdomen, loss of appetite, loss of weight and presence of an abdominal lump, gastric outlet obstruction and hypoalbuminemia, a shorter duration of symptoms, more number of hospital admissions, a less frequent (4% vs 10.7%) incidental diagnosis of GBC and a higher incidence of GB neck tumors (80% vs 20%). In patients with GBC and jaundice detection of metastatic or locally advanced unresectable disease on imaging (31%), laparoscopy (11%) or laparotomy (31%) precluded resection in majority of patients. Only 2.6% patients with GBC and jaundice could undergo definitive surgery as compared to 71.2% of patients without jaundice.Conclusion: Patients with GBC and jaundice are very likely to have advanced, unresectable disease. Chances of complete resection are slim even after extensive preparation requiring more extensive, time-consuming, costly, multidisciplinary interventions.

Immune checkpoint inhibitors in liver transplantation: Current practice, challenges, and opportunities.

Immune checkpoint inhibitors are becoming a mainstay of cancer treatment. While first studied and approved for patients with unresectable disease, due to their efficacy, they are becoming increasingly used in the perioperative period across many cancer types. In patients with HCC, immune checkpoint inhibitors have now become the standard of care in the advanced setting and have shown promising results in the adjuvant setting after liver resection. While these drugs continue to show promise, their role in the peritransplant setting still remains a question. In this review, we explore the current use of this class of medications in patients with HCC, as well as the immunologic role of the pathways that they inhibit. We also identify potential for future research opportunities to better understand the role of these medications.

Are preoperative serum cancer antigen 125 levels a prognostic factor for outcome in epithelial ovarian cancer? A systematic review.

Most patients with epithelial ovarian cancers (EOC) present with advanced-stage disease because of non-specific symptoms and lack of reliable strategies for early diagnosis. Cancer antigen 125 (CA-125) is suggested as a useful prognostic biomarker, its serum level is raised in over 80.0% of patients with EOC. Primary debulking surgery (PDS) followed by chemotherapy is the conventional treatment, but neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) is offered to patients with unresectable disease. There are inconsistencies regarding the role of preoperative CA-125 serum levels to adopt in stratifying patients for treatment choice that offers the most benefit. This review aimed to determine the role of preoperative CA-125 levels in predicting optimal cytoreduction and the association between optimal cytoreduction and survival outcome in patients with EOC. Three electronic databases CINAHL, Cochrane library and PubMed were searched for potentially relevant articles from 2016 to 2021 on the role of preoperative CA-125 levels in predicting optimal cytoreduction and survival in patients with epithelial ovarian carcinomas. In patients who underwent NACT-IDS, a lower preoperative CA-125 value is a predictor of optimal cytoreduction and an increase in preoperative CA-125 value is consistently associated with a decrease in optimal cytoreduction. There was insufficient data to assess overall survival. However, a raised preoperative CA-125 level is poor predictor of chance of achieving optimal cytoreduction and the rate of optimal cytoreduction was a weak predictor of overall survival in women who had primary debulking surgery.