Extensive Chemotherapy Research Articles

Design and implementation of a home-based online exercise program for individu-als surviving cancer

Starting point: Pediatric individuals with acute lymphoblastic leukemia undergo extensive chemotherapy treatment and, as a result, suffer from fatigue and, therefore, a decrease in their daily physical activity level, even after the cessation of the treatment. The symptoms of post-treatment thus disable the participation of the children in sports and games, which play a major role in childhood and adolescence. Group: Thirteen 5- to 15-year-old individuals surviving cancer with acute lymphoblastic leukemia (1 and 3 years after cancer treatment) were recruited to an 8-week home-based exercise program. Methods: This study aims to present the design and possibilities of implementing a home-based online exercise program for children who have overcome cancer, taking into account their age and the logistical availability of such physical therapy. Results: Thirteen individuals completed the home-based online exercise program, and the success rate of participation ranged from 79.2% to 95.8%. The overall success rate was 85.6%. The design and implementation of a home-based online exercise program in our conditions proved to be advantageous and often the only way to allow individuals surviving cancer to exercise in real-time, as the distance of many families from exercise centers proved to be a significant obstacle in creating habits of regular exercise in children. Conclusions: We demonstrated that individuals surviving cancer and their parents are interested in physical activity interventions and a home-based online exercise program is available and convenient.

Overall survival and cause-specific mortality in a hospital-based cohort of retinoblastoma patients in São Paulo, Brazil.

Studies are lacking on long-term effects among retinoblastoma patients in low- and middle-income countries. Therefore, we examined cause-specific mortality in a retrospective cohort of retinoblastoma patients treated at Antonio Candido de Camargo Cancer Center (ACCCC), São Paulo, Brazil from 1986 to 2003 and followed up through December 31, 2018. Vital status and cause of death were ascertained from medical records and multiple national databases. We estimated overall and cause-specific survival using the Kaplan-Meier survival method, and estimated standardized mortality ratios (SMRs) and absolute excess risk (AER) of death. This cohort study included 465 retinoblastoma patients (42% hereditary, 58% nonhereditary), with most (77%) patients diagnosed at advanced stages (IV or V). Over an 11-year average follow-up, 80 deaths occurred: 70% due to retinoblastoma, 22% due to subsequent malignant neoplasms (SMNs) and 5% to non-cancer causes. The overall 5-year survival rate was 88% consistent across hereditary and nonhereditary patients (p = .67). Hereditary retinoblastoma patients faced an 86-fold higher risk of SMN-related death compared to the general population (N = 16, SMR = 86.1, 95% CI 52.7-140.5), corresponding to 42.4 excess deaths per 10,000 person-years. This risk remained consistent for those treated with radiotherapy and chemotherapy (N = 10, SMR = 90.3, 95% CI 48.6-167.8) and chemotherapy alone (N = 6, SMR = 80.0, 95% CI 35.9-177.9). Nonhereditary patients had only two SMN-related deaths (SMR = 7.2, 95% CI 1.8-28.7). There was no excess risk of non-cancer-related deaths in either retinoblastoma form. Findings from this cohort with a high proportion of advanced-stage patients and extensive chemotherapy use may help guide policy and healthcare planning, emphasizing the need to enhance early diagnosis and treatment access in less developed countries.

Critical reappraisal of prognostic indicators for 949 mucinous appendiceal neoplasm patients.

The standard of care for treatment of an appendiceal mucinous neoplasm with peritoneal dissemination is cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). These two treatments are combined in the operating room. A crucial requirement for benefit long-term is proper patient selection. Clinical and histopathologic prognostic indicators are used, along with the patient's fitness for surgery, to select patients to receive CRS and HIPEC. This study seeks to identify the reliable prognostic indicators for four different groups of patients. They are (1) the low-grade appendiceal mucinous neoplasms (LAMN) with a complete CRS, (2) the mucinous appendiceal adenocarcinomas (MACA) with complete CRS, (3) MACA with lymph node metastases (MACA-LN) with complete CRS, and (4) all histologic subtypes with incomplete cytoreduction. The prognostic indicators were evaluated for their impact on overall survival in these four groups of patients. The completeness of cytoreduction (CC) score statistically significantly showed survival differences in all three histologic subtypes. The peritoneal cancer index (PCI) showed significance with LAMN and MACA-LN but not with MACA and not with incomplete CRS. The prior surgical score (PSS) was a prognostic indicator that predicted the outcome with LAMN, MACA-LN, and incomplete CRS patients but not with the MACA group. Patients who were symptomatic or who had extensive systemic chemotherapy before CRS had a significantly reduced survival. The utility of prognostic indicators varied greatly within our four different groups of appendiceal mucinous neoplasms. CC score was always a reliable prognosticator. Surprisingly, PCI was not.

Advancements in Photothermal Therapy Using Near-Infrared Light for Bone Tumors.

Bone tumors, particularly osteosarcoma, are prevalent among children and adolescents. This ailment has emerged as the second most frequent cause of cancer-related mortality in adolescents. Conventional treatment methods comprise extensive surgical resection, radiotherapy, and chemotherapy. Consequently, the management of bone tumors and bone regeneration poses significant clinical challenges. Photothermal tumor therapy has attracted considerable attention owing to its minimal invasiveness and high selectivity. However, key challenges have limited its widespread clinical use. Enhancing the tumor specificity of photosensitizers through targeting or localized activation holds potential for better outcomes with fewer adverse effects. Combinations with chemotherapies or immunotherapies also present avenues for improvement. In this review, we provide an overview of the most recent strategies aimed at overcoming the limitations of photothermal therapy (PTT), along with current research directions in the context of bone tumors, including (1) target strategies, (2) photothermal therapy combined with multiple therapies (immunotherapies, chemotherapies, and chemodynamic therapies, magnetic, and photodynamic therapies), and (3) bifunctional scaffolds for photothermal therapy and bone regeneration. We delve into the pros and cons of these combination methods and explore current research focal points. Lastly, we address the challenges and prospects of photothermal combination therapy.

New advances in the treatment of chondrosarcoma under the PD-1/PD-L1 pathway.

Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common subtypes. Chondrosarcoma, a relatively prevalent malignant bone tumor that originates from chondrocytes, is characterized by endogenous cartilage ossification within the tumor tissue. Despite the use of aggressive treatment approaches involving extensive surgical resection, chemotherapy, and radiotherapy for patients with osteosarcoma, chondrosarcoma, and chordoma, limited improvements in patient outcomes have been observed. Furthermore, resistance to chemotherapy and radiation therapy has been observed in chondrosarcoma and chordoma cases. Consequently, novel therapeutic approaches for bone sarcomas, including chondrosarcoma, need to be uncovered. Recently, the emergence of immunotherapy and immune checkpoint inhibitors has garnered attention given their clinical success in various diverse types of cancer, thereby prompting investigations into their potential for managing chondrosarcoma. Considering that circumvention of immune surveillance is considered a key factor in the malignant progression of tumors and that immune checkpoints play an important role in modulating antitumor immune effects, blockers or inhibitors targeting these immune checkpoints have become effective therapeutic tools for patients with tumors. One such checkpoint receptor implicated in this process is programmed cell death protein-1 (PD-1). The association between PD-1 and programmed cell death ligand-1 (PD-L1) and cancer progression in humans has been extensively studied, highlighting their remarkable potential as biomarkers for cancer treatment. This review comprehensively examines available studies on current chondrosarcoma treatments and advancements in anti-PD-1/PD-L1 blockade therapy for chondrosarcoma.

Evaluation of Histomorphological Changes in Breast Cancer Post-Neoadjuvant Chemotherapy.

Breast cancer, a leading cause of global female mortality, demands comprehensive diagnostic and therapeutic strategies. This study delves into the nuanced realm of post-neoadjuvant chemotherapy breast cancer specimens, emphasizing the imperative need for pathologists to discern stromal and nuclear alterations adeptly. The investigation, encompassing 100 female patients with a mean age of 47.5years, elucidates the demographic and clinicopathological parameters. Predominantly presenting as palpable lumps (85%), invasive ductal carcinoma emerged as the predominant histological type (98%). The primary focus of the study revolves around the morphological changes post-neoadjuvant chemotherapy, with a meticulous qualitative analysis encompassing stromal elements (fibrosis, elastosis, calcification) and nuclear features (pyknosis, hyperchromasia). Notably, the response to chemotherapy, classified by the International Union against Cancer criteria, delineates a substantial pathological complete response (55%), partial response (35%), and limited non-response (10%). The therapeutic landscape includes a majority of cases undergoing extensive chemotherapy cycles, primarily featuring the cyclophosphamide, doxorubicin, and paclitaxel regimen. Remarkably, this investigation unveils fibrosis (63%) and elastosis/collagenization (51%) as prevalent stromal changes, while pyknosis (58%) and hyperchromasia (48%) dominate nuclear alterations. In conclusion, this retrospective study provides a comprehensive overview of post-neoadjuvant chemotherapy breast cancer specimens, shedding light on the intricate interplay of clinical parameters, treatment responses, and histopathological changes. The findings underscore the pivotal role of pathologists in accurately diagnosing and grading tumors in the evolving landscape of breast cancer management.

Cytosolic nucleic acid sensors and interferon beta-1 activation drive radiation-induced anti-tumour immune effects in human pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIG-I/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genome-wide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-κB for radiation-induced IFNB1 activation. We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-κB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-κB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiation-induced immune effects when exposed to single-dose protons or photons. Our findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy.

Survival Analysis and Correlates with Molecular Epidemiology: 10-Year Retrospective Series of High-Grade Glioma in Pakistan.

High-grade gliomas are malignant, recurring primary central nervous system (CNS) tumors requiring extensive postoperative chemotherapy and radiation treatment. Isocitrate dehydrogenase (IDH), 1p19q, and ATRX mutations significantly influence survival and response to chemotherapy, as seen in many extensive studies from the Global North. This study aims to report data from the local region regarding progression-free survival and overall survival in light of molecular characteristics. A 10-year retrospective series was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, with 285 patients presenting from 2008 to 2018. Prospective follow-up data was collected, and complete molecular profiles were available for patients presenting from 2010 onwards. Survival analysis was conducted through the Kaplan-Meier method, with log-rank reported. 70.53% (201) of patients were male, with a mean age at diagnosis of 43.33 ± 15.1 years. 265 patients within the cohort completed postoperative radiotherapy, while 141 patients underwent chemotherapy (procarbazine, lomustine, and vincristine, or temozolomide). Mean survival, in months, within the cohort was as follows: glioblastoma (14.1), anaplastic astrocytoma (27.5), and anaplastic oligodendroglioma (39.8). Survival curves showed a lower survival for IDH wild-type (P < 0.0001), ATRX mutated (P = 0.029), and 1p19q non-deleted (P = 0.008) tumors from Pakistan. Our findings quantified long-term survival outcomes for high-grade glioma from Pakistan, analyzing the various treatment patterns. Of particular importance, molecular sub-classification significantly predicted survival outcomes for IDH, ATRX, and 1p19 co-deletion mutations. Expanding brain tumor epidemiology will benefit assessing the efficacy of regional oncological centers and establishing standards of care.

Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma

Glioblastoma (GBM), the most common primary brain tumor in adults, is characterized by low survival rates and a grim prognosis. Current treatment modalities, including extensive surgical resection, chemotherapy, and radiation therapy, often yield limited success due to the brain’s sensitivity, leading to significant side effects. Exciting advancements in immunotherapy have recently shown promise in treating various types of tumors, raising hopes for improved outcomes in brain tumor patients. One promising immunotherapy approach is chimeric antigen receptor (CAR) T-cell therapy, which recognizes surface proteins on targeted tumor cells and redirects cytotoxicity towards specific targets. This review aims to discuss the existing research and future prospects for CAR T-cell immunotherapy in treating glioblastoma.

Distinct molecular features and potential therapeutic strategies for spinal cord gliomas.

2056 Background: Spinal cord gliomas (SCG) are rare primary CNS tumors with varied prognosis. Standard treatment remains poorly defined, as no clear survival advantage exists with extensive resection, radiation, or chemotherapy. Mounting evidence suggests that tumors from different regions of the CNS harbor unique molecular signatures. In a retrospective study, we comprehensively characterized molecular alterations to identify potential therapeutic strategies in the largest cohort of SCG reported to date. Methods: We performed centralized pathology review and analyzed SCG with next-generation sequencing of DNA (592 gene NextSeq or WES, Novaseq), RNA (WTS, NovaSeq) and pyrosequencing (MGMT promoter methylation, MGMTme). We estimated tumor microenvironment cell infiltration by quanTIseq &amp; Epithelial-Mesenchymal Transition (EMT) by RNAseq. We used X2/Fisher’s-exact/Mann-Whitney U tests for comparison &amp; determined significance (p &lt; 0.05), adjusting for multiple comparison by the Benjamini-Hochberg method (q &lt; 0.05). Results: We analyzed 39 surgically accessible SCG (19 high grade, 17 low grade, 3 NOS); ependymomas were excluded. The most common alterations were mutations in H3F3A (31%), TP53 (25%), ATRX (21%), NF1 (18%) &amp; BRAF fusion (19%). H3F3A mutations occurred exclusively in high grade SCG (63%, q &lt; 0.05) while BRAF fusions occurred exclusively in low grade SCG (60%, p &lt; 0.05). TP53 mutations were more prevalent in high grade SCG (50% vs. 8%, p &lt; 0.05). Compared to intracranial gliomas (n = 6732), SCG harbor significantly more frequent H3F3A (31% vs. 1.6%), KRAS mutations (10% vs. 0.7%) &amp; BRAF fusions (19% vs. 0.7%) but less frequent TERT (4.3% vs. 66%) &amp; PTEN (0 vs. 27%) mutations or EGFR amplification (0 vs. 28%) (all q &lt; 0.05). SCG rarely harbor the canonical intracranial alterations IDH1 (2.6% vs. 17%), EGFRvIII (0 vs. 17%) or MGMTme (19% vs. 47%) (p &lt; 0.05). SCG have greater penetration of immune infiltrates of DCs (median cell fraction/MCF: 13% vs. 9%), T regs (positive percent: 47% vs. 26%) &amp; B cells (MCF: 9% vs. 7%), with less penetration of monocytes (MCF: 0 vs. 2%) (q &lt; 0.05). EMT score associates with high grade glioma in intracranial disease (q &lt; 0.05) but does not recapitulate in SCG (p &gt; 0.05). Conclusions: Clinical management of SCG is currently drawn from experience with intracranial gliomas. Our results identify unique molecular features of SCG suggesting an underlying biology distinct from intracranial gliomas. In SCG, H3F3A mutations are exclusive to high grade while BRAF fusions are exclusive to low grade; SCG rarely harbor canonical intracranial alterations such as IDH1, EGFR or MGMTme; and SCG have greater penetration of DCs with less penetration of monocytes. We provide a biological explanation for limited effectiveness of current therapies in SCG with potential implications for chemotherapy, targeted and immunotherapy. Our work underscores the need for investigations dedicated uniquely to SCG.

A 3-year study of Candida infections among patients with malignancy: etiologic agents and antifungal susceptibility profile.

Opportunistic fungal infections by Candida species arise among cancer patients due to the weakened immune system following extensive chemotherapy. Prophylaxis with antifungal agents have developed the resistance of Candida spp. to antifungals. Accurate identification of yeasts and susceptibility patterns are main concerns that can directly effect on the treatment of patients. Over a period of three years, 325 cancer patients suspected to Candida infections were included in the current investigation. The clinical isolates were molecularly identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). All strains, were examined for in vitro susceptibility to the amphotericin B, itraconazole, fluconazole, and anidulafungin according to the CLSI M27 document. Seventy-four cancer patients had Candida infections (22.7%). Candida albicans was the most common species (83.8%). Antifungal susceptibility results indicated that 100% of the Candida isolates were sensitive to amphotericin B; however, 17.6%, 9.4%, and 5.4% of clinical isolates were resistant to anidulafungin, fluconazole, and itraconazole, respectively. The findings of the present work shows a warning increase in resistance to echinocandins. Since all fluconazole resistance isolates were obtained from candidemia, we recommend amphotericin B as the first line therapy for this potentially fatal infection.

Localized Nanoparticle-Mediated Delivery of miR-29b Normalizes the Dysregulation of Bone Homeostasis Caused by Osteosarcoma whilst Simultaneously Inhibiting Tumor Growth.

Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localized delivery of miR-29b-which is shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and cervicaltumor growth-can suppress osteosarcoma tumors whilst simultaneously normalizing the dysregulation of bone homeostasis caused by osteosarcoma. Thus, the therapeutic potential of microRNA (miR)-29b is studied to promote bone remodeling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. A formulation of miR-29b:nanoparticles are developed that are delivered via a hyaluronic-based hydrogel to enable local and sustained release of the therapy and to study the potential of attenuating tumor growth whilst normalizing bone homeostasis. It is found that when miR-29b is delivered along with systemic chemotherapy, compared to chemotherapy alone, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in osteolysis thereby normalizing the dysregulation of bone lysis activity caused by the tumor.

The Association between Breast Cancer Related Lymphedema and Area Deprivation Index.

Lymphedema affects up to 34% of patients after breast cancer treatment but remains underdiagnosed and undertreated. Here, we use area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, to determine how socioeconomic status may affect risk for and diagnosis of breast cancer-related lymphedema. Records of patients who underwent surgical treatment of breast cancer between 2017-2020 were examined. Patients' nine-digit ZIP codes were utilized to determine their deprivation level as a national ADI percentile, and those fitting into the most and least deprived quartiles were compared with evaluate lymphedema risk factors and incidence. A total of 1,333 breast cancer patients were included, 812 (61%) of whom resided within the most disadvantaged ADI quartile nationally, and 521 within the least disadvantaged quartile. The most deprived group had higher rates of diabetes, obesity, and regional breast cancer, and received more extensive surgeries (7.5% modified radical mastectomy vs 1.9%, p < 0.001) and chemotherapy compared with the least disadvantaged quartile. The most disadvantaged cohort were more often at extreme risk of lymphedema utilizing the Risk Assessment Tool Evaluating Lymphedema Risk (9.1% versus 2.5%, p < 0.001); however, the incidence of lymphedema diagnoses was not significantly higher (13% vs 12%, p > 0.9). Logistic regression showed that the most deprived ADI quartile had 44% lower odds of a lymphedema diagnosis in comparison to the least deprived quartile. Residing in more socioeconomically disadvantaged neighborhoods is associated with lower odds of a lymphedema diagnosis, despite higher rates of risk factors for lymphedema, suggesting significant underdiagnosis in this population.

Tumor-Homing and Immune-Reprogramming Cellular Nanovesicles for Photoacoustic Imaging-Guided Phototriggered Precise Chemoimmunotherapy.

Many studies have focused on developing effective therapeutic strategies to selectively destroy primary tumors, eliminate metastatic lesions, and prevent tumor recurrence with minimal side effects on normal tissues. In this work, we synthesized engineered cellular nanovesicles (ECNVs) with tumor-homing and immune-reprogramming functions for photoacoustic (PA) imaging-guided precision chemoimmunotherapy. M1-macrophage-derived cellular nanovesicles (CNVs) were loaded with gold nanorods (GNRs), gemcitabine (GEM), CpG ODN, and PD-L1 aptamer. The good histocompatibility and tumor-homing effect of CNVs improved drug retention in the bloodstream and led to their enrichment in tumor tissues. Furthermore, the photothermal ability of GNRs enabled PA imaging-guided drug release. GEM induced tumor immunogenic cell death (ICD), and CpG ODN promoted an immune response to the antigens released by ICD, leading to long-term specific antitumor immunity. In addition, the PD-L1 aptamer relieved the inhibitory effect of the PD1/PD-L1 checkpoint on CD8+ T-cells and augmented the immunotherapeutic effect. The synergistic innate and adaptive immune responses enhanced the antitumor effect of ECNVs. In summary, this nanoplatform integrates local targeted photothermal therapy with extensive progressive chemotherapy and uses ICD to reshape the immune microenvironment for tumor ablation.

LEISH2b - A phase 2b study to assess the safety, efficacy, and immunogenicity of the Leishmania vaccine ChAd63-KH in post-kala azar dermal leishmaniasis.

Background: The leishmaniases are neglected tropical diseases caused by various Leishmania parasite species transmitted by sand flies. They comprise a number of systemic and cutaneous syndromes including kala-azar (visceral leishmaniasis, VL), cutaneous leishmaniasis (CL), and post-kala-azar dermal leishmaniasis (PKDL). The leishmaniases cause significant mortality (estimated 20 - 50,000 deaths annually), morbidity, psychological sequelae, and healthcare and societal costs. Treatment modalities remain difficult. E.g., East African PKDL requires 20 days of intravenous therapy, andfrequently relapsing VL is seen in the setting of HIV and immunodeficiency. We developed a new therapeutic vaccine, ChAd63-KH for VL / CL / PKDL and showed it to be safe and immunogenic in a phase 1 trial in the UK, and in a phase 2a trial in PKDL patients in Sudan. Methods: This is a randomised double-blind placebo-controlled phase 2b trial to assess the therapeutic efficacy and safety of ChAd63-KH in patients with persistent PKDL in Sudan. 100 participants will be randomly assigned 1:1 to receive placebo or ChAd63-KH (7.5 x10 10vp i.m.) at a single time point. Follow up is for 120 days after dosing and we will compare the clinical evolution of PKDL, as well as the humoral and cellular immune responses between the two arms. Discussion: Successful development of a therapeutic vaccine for leishmaniasis would have wide-ranging direct and indirect healthcare benefits that could be realized rapidly. For PKDL patients, an effective therapeutic vaccination used alone would have very significant clinical value, reducing the need for extensive hospitalization and chemotherapy. Combining vaccine with drug (immuno-chemotherapy) might significantly increase the effective life of new drugs, with lower dose / abbreviated regimens helping to limit the emergence of drug resistance. If therapeutic benefit of ChAd63-KH can be shown in PKDL further evaluation of the vaccine in other forms of leishmaniasis should be considered. Clinicaltrials.gov registration: NCT03969134.

DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers

BackgroundLittle is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC).MethodsWe performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations.ResultsLandscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers.ConclusionThese findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

First experience with 224Radium-labelled microparticles (radspherin) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study).

3599 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by combining extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). However, median time to recurrence is short (11-12 months) and there is a need for novel therapies to prevent subsequent PM. Radspherin consists of the α-emitting radionuclide radium-224 (224Ra), half-life 3.6 days, adsorbed to a suspension of biodegradable calcium carbonate microparticles, designed to give short-range radiation to the serosal peritoneal surface, aiming to kill remaining free cancer cells and small tumor cell clusters. Methods: A first-in-man phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin was injected in the abdominal cavity through a catheter 2 days after CRS-HIPEC. Dose escalation at increasing dose levels of 1-2-4-7-MBq, repeated injection and expansion cohorts evaluated the safety and tolerability of Radspherin, explored maximal tolerated dose and biodistribution by using single photon-emission computed tomography/computed tomography (SPECT/CT) imaging. Results from the planned safety interim analysis after completion of the dose-limiting toxicity (DLT) period are presented. Results: Twenty-three patients were enrolled, dose escalation cohort (14), repeated cohort (3) and expansion cohort (6). Nineteen patients were treated in Oslo/ 4 in Uppsala. Twelve patients had synchronous PM Stage IV and 11 metachronous PM (Stage II (6), Stage III (5). Disease-free interval 15 months (3-39); males (7), females (16); median age 64 years (28-78). Peritoneal cancer index was median 7 (3-19), operation time 395 minutes (194-515) and hospital stay 12 days (7-37). Accordion ≥3 grade events (6); including anastomotic leaks (2); abscess (1); drains (2) and missed lesion (1), all reported as serious adverse events (SAEs). The 7MBq dose was selected as recommended dose as no DLT was observed. A total of 185 treatment emergent adverse effects (TEAE) were recorded, most were of low grade and considered related to CRS and/or HIPEC. Few patients (7) had TEAEs considered related to a combined impact of Radspherin and CRS-HIPEC. The biodistribution of Radspherin showed a relatively even peritoneal distribution, and no patients had compartments of the abdominal cavity without radioactivity (cold spots), and low number had hot spots. Long-term safety, dosimetry and first efficacy results of Radspherin will be reported after 12 months follow up period. Conclusions: All dose levels of Radspherin were well tolerated with DLT not reached. No deaths occurred and no SAEs were considered related to Radspherin. The biodistribution of Radspherin showed good peritoneal distribution of the radiolabeled microparticles. Clinical trial information: 2018-002803-33.

A Diagnosis of Choriocarcinoma in a Parturient Presenting With Intracranial Hemorrhage

Choriocarcinoma in a viable pregnancy is uncommon. The diagnosis can easily be missed when there is an explanation for the clinical symptoms that the cancer can mimic. We present the case of a primigravid patient whose choriocarcinoma was initially missed as a result of seemingly obvious explanations for her atypical history and disease manifestation. The patient is a Caucasian female at 30 weeks and 5 days of gestation who presented with persistent headaches and new-onset tonic-clonic seizures found on brain magnetic resonance imaging (MRI) to have a left intracranial hematoma, a 5 mm midline shift, and multiple foci of restricted diffusion. Cerebral angiogram demonstrated arteriovenous malformations (AVMs). The fetus was emergently delivered 1 week into hospitalization for non-reassuring fetal heart tracings in the setting of maternal lethargy secondary to continued AVM hemorrhage. The patient’s hospital course was complicated by four episodes of intracranial bleeding and edema requiring neurosurgical intervention. Three weeks after hospitalization she was discharged to a rehabilitation center, shortly after which placental biopsy demonstrated choriocarcinoma. MRI after readmission demonstrated extensive metastatic disease and human chorionic gonadotropin (hCG) levels were greater than 225,000 mIU/mL. Despite two additional neurosurgical procedures and extensive chemotherapy the patient died 3 months after initial presentation. Choriocarcinoma is extremely rare in viable pregnancies, but it should be considered when a parturient presents with intracranial bleeding. A high level of suspicion and serial serum hCG levels may lead to early and potentially life-saving multidrug chemotherapy. With a broader differential, earlier hCG measurement, and earlier treatment, our patient may have survived.

Update 2021: Management of Small Cell Lung Cancer.

Accounting for 14% of lung cancer, small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid proliferation, early spread, and poor survival. We provide an overview of recent advances regarding SCLC pathogenesis, subtypes, and treatment development through literature review of key trials. There are no validated biomarkers or approved targeted treatments for this overly heterogeneous disease, but recent analyses have identified some promising targets and four major subtypes which may carry unique therapeutic vulnerabilities in SCLC. Treatment wise, only a third of patients present with limited stage SCLC, which can be managed with a combined modality approach with curative intent (usually chemo-radiotherapy, but in some eligible patients, surgery followed by systemic treatment). For advanced or extensive stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard front-line treatment, with modest improvement in overall survival. In the second-line setting, for disease relapse ≤ 6 months, topotecan, lurbinectedin, and clinical trials are reasonable treatment options; for disease relapse>6 months, original regimen, topotecan or lurbinectedin can be considered. Moreover, Trilaciclib, a CD4/CD6 inhibitor, was recently FDA-approved to decrease the incidence of chemotherapy-related myelosuppression in SCLC patients. While modest improvements in survival have been made especially in the metastatic setting with chemo-immunotherapy, further research in understanding the biology of SCLC is warranted to develop biomarker-driven therapeutic strategies and combinational approaches for this aggressive disease.

Pain, numbness, or both? Distinguishing the longitudinal course and predictors of positive, painful neuropathic features vs numbness after breast cancer surgery.

Both positive (burning, stabbing, and allodynia) and negative (numbness) neuropathic symptoms may arise after surgery but likely contribute differently to patients' postoperative pain experience. Numbness has been identified as divergent from positive neuropathic symptoms and therefore excluded from some neuropathic assessment tools (Neuropathic Pain Scale for PostSurgical patients [NeuPPS]). In this prospective longitudinal study of patients undergoing breast surgery, we aimed to delineate the time course of numbness and its coincidence with NeuPPS and to contrast the association of surgical, psychosocial, and psychophysical predictors with the development of negative vs positive neuropathic symptoms. Patients reported surgical area sensory disturbances at 2 weeks and 3, 6, and 12 months postoperatively. Association of baseline demographic, surgical, psychosocial, and psychophysical factors with NeuPPS and numbness across time was investigated using generalized estimating equation linear and logistic regression. Numbness was consistently reported by 65% of patients; positive neuropathic symptoms were less common, often decreasing over time. Neuropathic Pain scale for PostSurgical patients and numbness co-occurred in half of patients and were both associated with greater clinical pain severity and impact, younger age, axillary surgery, and psychosocial factors. More extensive surgery and chemotherapy were only associated with numbness. Conversely, other chronic pain, lower physical activity, perioperative opioid use, negative affect, and lower baseline pressure pain threshold and tolerance were only associated with NeuPPS. Patients reporting numbness alone did not endorse substantial clinical pain. Differentiation of predictors, prevalence, and time course of numbness vs NeuPPS in breast surgical patients revealed important distinctions, suggesting that their independent assessment is worthwhile in future studies of postsurgical pain.