tbuckley/cabot-search huggingface dataset:
Alter between gut bacteria and blood metabolites and the anti-tumor effects of Faecalibacterium prausnitzii in breast cancer.
Authors: Ji Ma, Lingqi Sun, Ying Liu, Hui Ren, Yali Shen, Feng Bi, Tao Zhang, Xin Wang
Journal: Journal of Clinical Oncology (2020)

e12575 Background: The aim was to evaluate the changes of 16S rDNA sequencing and LC-MS metabolomics in breast cancer and explore the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. Methods: We performed the 16S rDNA sequencing of gut bacteria and the LC-MS metabolomics analysis of blood samples in 25 breast cancer patients and 25 benign breast disease controls. Correlation analysis of significant flora and metabolites were processed, including correlation coefficient calculation, matrix heat map analysis, cluster analysis, correlation network analysis, and scatter plot analysis. We screened for intestinal flora that may participate in breast cancer development and try to test and verify. CCK-8, apoptosis and transwell assays were explored to detect the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. Western blot was used to analyze the changes of IL-6/STAT3 pathway by Faecalibacterium prausnitzii. Results: Total 49 significantly different flora and 26 different metabolites were screened between two groups, and the correlation was calculated. Relative abudance of Firmicutes and Bacteroidetes were decreased, while relative abundance of verrucomicrobla, proteobacteria and actinobacteria was increased in breast cancer group. Differentially expressed metabolites were mainly enriched in pathways such as linoleic acid metabolism, retrograde endocannabinoid signaling, biosynthesis of unsaturated fatty acids, choline metabolism in cancer and arachidonic acid metabolism. Lipid upregulation was found in breast cancer patients, especially phosphorocholine. The abundance of Faecalibacterium was reduced in breast cancer patients, which was negatively correlated with various phosphorylcholines. Moreover, Faecalibacterium prausnitzii, the most well-known species in Faecalibacterium genus, could inhibit the secretion of IL-6 and the phosphorylation of JAK2/STAT3 in breast cancer cells. Faecalibacterium prausnitzii also suppressed the proliferation and invasion and promoted the apoptosis of breast cancer cells, while these effects disappeared after adding recombinant human IL-6. Conclusions: Flora-metabolites combined with the flora-bacteria (such as Faecalibacterium combined with phosphorocholine) might a new detection method for breast cancer. Faecalibacterium may be helpful for prevention of breast cancer. Faecalibacterium prausnitzii suppresses the growth of breast cancer cells through inhibition of IL-6/STAT3 pathway.
Metaplastic breast cancer: A retrospective analysis over 14 years.
Authors: Pooja Gogia Bhasin, Gopal R Desai
Journal: Journal of Clinical Oncology (2020)

e13066 Background: Metaplastic breast carcinoma (MBC), a rare entity, is known to be an aggressive form of breast cancer. With few published reports and scant literature, there are no current guidelines for this type of cancer. The aim of the study is to describe the patient characteristics, pathologic features, treatment and clinical outcomes of the patients with MBC at our institution. Methods: A retrospective analysis of patient charts with histologically confirmed MBC from 2001 to 2014 was done. Clinical information was abstracted from the medical records. Medical records were reviewed for patient age, tumor size, nodal status, tumor grade, hormone receptor status, treatment, recurrence rates and survival characteristics. Results: Twenty-three patients were identified with a median age at diagnosis of 59 years (range 42-91 years). The median tumor size was 2.1 cm (range 0.4-4.5 cm). Most tumors were grade 3 (73.9 %). None of the patients had metastatic disease at presentation. 17 patients were node negative (74%). 13 patients (56.5 %) were triple negative. 6 patients (26 %) underwent mastectomy and 17 underwent lumpectomy. 16 out of 23 patients underwent post-operative radiation therapy. The 5-year disease free survival was 73.9 % and 5-year overall survival was 82.6%. The tumor size was more than or equal to 2.4 cm in all the patients with recurrence. 60 % of the patients with recurrence were triple negative and 20% were Her2 neu positive. 33.33 % patients were poorly differentiated on histology. Conclusions: Based on our analysis and review of literature, MBC has higher tumor grade, hormone receptor negativity and lesser nodal involvement on presentation. Various studies have shown that tumor size is often large on presentation. In our study, tumor size was modest on presentation. Hence, our survival rates are better than seen with other studies. As per our analysis and as demonstrated by other studies, tumor size is an independent risk factor for recurrence. Other ominous factors for recurrence are triple negative hormone status and poorly differentiated tumor as seen in our case. Further studies and clinical trials comparing with infiltrating ductal carcinoma are needed to understand this rare breast cancer.
Post-traumatic stress symptoms in hematopoietic stem cell transplant (HCT) recipients.
Authors: Sarah Griffith, Alyssa L. Fenech, Ashley Nelson, Joseph A. Greer, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2020)

7505 Background: Patients admitted for HCT, an intensive and potentially curative therapy for hematologic malignancies, experience a prolonged, isolating hospitalization and endure substantial physical and psychological symptom burden. However, data are limited regarding long-term post-traumatic stress (PTSD) in HCT survivors and its risk factors. Methods: We conducted a secondary analysis examining longitudinal data from 250 patients who underwent autologous and allogenic HCT. We used the Post-Traumatic Stress Checklist (PTSD-CL) to assess for PTSD symptoms at six months post-HCT. We used the Functional Assessment of Cancer Therapy—Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale to assess quality of life (QOL), depression, and anxiety symptoms at the time of admission for HCT, at week-2 during hospitalization, and at six months post-HCT. We used multivariate regression models to assess factors associated with PTSD symptoms, modeling QOL, depression, and anxiety symptoms separately given their collinearity. Results: The mean age was 56.3 (SD = 13.3). The rate of clinically significant PTSD symptoms at six months post-HCT was 18.9% and these patients experienced hypervigilance (92.3%), avoidance (92.3%), and intrusion (76.9%) symptoms. Among patients without clinically significant PTSD symptoms, 24.5% and 13.7% had clinically significant hypervigilance and avoidance symptoms, respectively. Lower QOL at time of HCT admission (B = -0.04, P = 0.004), and being single (B = -3.35, P = 0.027) were associated with higher PTSD symptoms at six months post-HCT. Higher anxiety at time of HCT admission (B = 1.34, P &lt; 0.001), change in anxiety during HCT hospitalization (B = 0.59, P = 0.006), and being single (B = -3.50, P = 0.017), were associated with higher PTSD symptoms at six months. In a separate model, younger age (B = -0.13, P = 0.017), being single (B = -3.58, P = 0.018), and higher baseline depression symptoms were also associated with higher PTSD symptoms at six months (B = 0.97, P &lt; 0.001). Conclusions: Approximately one fifth of patients undergoing HCT experienced clinically significant PTSD symptoms at six months post-transplant. Patients’ baseline QOL and psychological symptoms emerged as important predictors of their risk for PTSD at six months post-HCT. Thus, interventions to prevent and treat PTSD symptoms in HCT recipients are clearly warranted.
Prognostic value of the TGFß1 rs4803455 single nucleotide polymorphism and its association with prophylactic cranial irradiation in small cell lung cancer.
Authors: Pablo Ayala de Miguel, María Valle Enguix-Riego, Jon Cacicedo, Blas David Delgado, Marco Pérez, Juan Manuel Praena-Fernández, Laura Quintana Cortés, Pablo Borrega, Eleonor Rivin del Campo, Jose Lopez Guerra
Journal: Journal of Clinical Oncology (2020)

e21038 Background: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta- 1 (HSPB1) and Transforming growth factor (TGFß1) and survival have been investigated. Methods: A prospective multicenter study of 94 SCLC patients treated between 2013 and 2016 was conducted. Several variables clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFß1 gene and 5 of HSPB1 gene) variables were analyzed. Results: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (BID in 42%). Forty-seven percent received concomitant platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis PCI and the TGFß1 SNP rs4803455 showed a statistically significant association with OS and local control. Patients with the CA genotype of the TGFß1 SNP rs4803455 showed worse OS (HR 2.53; IC 1.22-5.21; p = 0.012) and higher local recurrence (HR 2.26; IC 1.01-5.08;p = 0.048). A combined analysis showed that those patients receiving PCI and carrying the rs4803455:CA genotype had a statistically significant lower OS (p &lt; 0.001) and disease-free survival (p &lt; 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Conclusions: Genetic analysis showed that the CA genotype of TGFß1 SNP rs4803455 was associated with worse prognosis in SCLC patients and could be considered as a potential biomarker for OS.
A site-specific approach to improved antibody-drug conjugates.
Authors: James Italia
Journal: Journal of Clinical Oncology (2020)

e13009 Background: Antibody based therapeutics have emerged as a highly promising treatment option for various forms of cancer. One such class of emergent antibody therapeutics is antibody-drug conjugates (ADCs), which has experienced remarkable success in the past few decades, including many candidates currently undergoing clinical trials. Despite its promise, developing effective ADCs remains a challenge due to extensive optimization with regard to antibody target identification, conjugate specificity, conjugation chemistry compatibility, heterogeneous side product co-purification, all affecting efficacy, PK/PD characteristics, and toxicity. There is a pressing need to develop alternative strategies for precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates to overcome these limitations and realize the full potential of this highly promising class of therapeutics. Methods: In this study, we demonstrate the feasibility of efficiently incorporating an azide-containing UAA into full-length antibody at different site and facilitate its site-specific functionalization, which provides a facile scale-up compatible route to generate precise antibody-drug conjugates with fine-tuned therapeutic properties. Specifically, we have engineered multiple variants of trastuzumab to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as MMAE/MMAF, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickBio ADCs exhibit high therapeutic efficacy against HER2+ cell lines in vitro as well as in mouse xenograft models. These homogenous ADCs additionally outperform traditional antibody conjugation technologies which lack site-specificity or site-selectivity. Conclusions: The ability to systematically vary the attachment topology between the drug and the antibody is a major strength of this approach and preliminary data suggest that such variation indeed affect ADC performance. BrickBio ADCs are currently in the preclinical stage with further efforts for safety studies underway.
Real-world outcomes of advanced melanoma patients not represented in phase III trials.
Authors: Rawa Ismail, Michiel van Zeijl, Liesbeth De Wreede, Alfonsus Johannes Maria van den Eertwegh, Anthonius De Boer, Maaike van Dartel, Doranne Hilarius, Maureen J.B. Aarts, Franchette Van Den Berkmortel, Marye Boers-Sonderen, Jan Willem de Groot, Geke Hospers, Ellen Kapiteijn, Djura Piersma, Rozemarijn Van Rijn, Karijn Suijkerbuijk, Albert J. ten Tije, Astrid Aplonia Maria Van Der Veldt, John B. A. G. Haanen, Michel W.J.M. Wouters
Journal: Journal of Clinical Oncology (2020)

10042 Background: A large proportion of patients with advanced melanoma is not represented in phase III clinical trials, due to ineligibility. Real-world efficacy evidence of immune- and targeted therapies in these patients is lacking. We aimed to provide insight in survival outcomes of systemically treated patients who were not represented in the phase III trials in order to support clinical decision-making. Methods: Systemically treated ineligible patients with advanced melanoma diagnosed between 2014-2017 were analyzed. Prognostic importance of factors associated with overall survival (OS) was assessed by Kaplan Meier method, Cox regression models, predicted OS probabilities of prognostic subgroups and a conditional inference survival (decision) tree. Results: Of 2,536 systemically treated patients with advanced melanoma, 1,004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria most strongly correlated with survival in ineligible systemically treated patients with ECOG Performance Score (PS) ≥2 vs PS 0-1 (HR 1.95 (95%CI: 1.52-2.5)), symptomatic brain metastases (BM) vs absent BM (HR 1.71 (95%CI: 1.34-2.18)) and LDH &gt; 500 U/l vs normal (HR 1.89 (95%CI: 1.49-2.41)). All other factors for ineligibility were not associated with OS. By combining ECOG PS, BM and LDH, 18 subgroups were created. The 3-year survival probability of patients with ECOG PS ≤1, asymptomatic BM and normal LDH was 35.1%. Patients with ECOG PS of ≥2 with or without symptomatic BM had a mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6% respectively. In the decision tree, the covariate with the strongest predictive distinctive character for survival was LDH, followed by ECOG PS. Prognosis of LDH of &gt; 500 U/L is infaust, although still long-term survival is possible (3-year survival probability of 15.3%). The decision tree showed the prognosis of patients with symptomatic BM can be good if ECOG PS is 0 and patients are aged ≤55 years (mOS of 22.3 months). Conclusions: Patients with advanced melanoma not represented in phase III trials treated with systemic therapy can achieve long term survival. LDH was the strongest predictive factor associated with survival, followed by ECOG PS and symptomatic BM. Other factors for ineligibility were not associated with OS. These results, together with the decision tree, can be used to provide insight in outcomes to facilitate the shared decision-making process when comparative studies are not available.
Infection in patients with acute leukemia during initial induction chemotherapy and its relation to therapeutic efficacy
Authors: Nannan Zhang, Ruijuan Zhang, Linhua Yang, Yang Chen, Jing Xu, Feng Xue, Bin Yin
Journal: BMJ (2017)

Objective
To analyze the infection features, risk factors, and the relationship with the efficacy in patients with acute leukemia during initial induction chemotherapy.


Methods
The clinical data of 200 patients with newly diagnosed acute leukemia from January 2015 to February 2016 in the Second Hospital of Shanxi Medical University were retrospectively analyzed.


Results
The infection rate of patients with acute leukemia under induction chemotherapy was 84.0% (168/200). Among 168 patients with infection, 159 cases (94.6%) had known infection sites, the top three infection sites were the lungs, gastrointestinal tract and the oral cavity. Total 213 strains of pathogens were identified, Gram-negative bacilli accounted for 39.0% (n=83), Gram-positive cocci for 34.3% (n=73), fungi for 23.5% (n=50) and the virus for 3.3% (n=7). Multivariate regression analysis showed that agranulocytosis was the independent risk factor for acute leukemia patients during induction chemotherapy(OR=14.370, 95% CI: 2.576-116.518, P<0.01). The rate of complete remission (CR) and CR with incomplete hematologic recovery (CRi) in infection group was 74.4% (125/168), and the rate of CR + CRi in non-infected group was 87.5% (28/32), and there was no significant difference between the two groups. (χ2=2.564, P=0.109).


Conclusion
During the induction therapy for acute leukemia patients, the rate of infection and the rate of fungal infection are high; lung is the most common site, Gram-negative bacteria is more common; agranulocytosis increases the chance of infection; and the infection may not affect the disease remission rate.


Key words: 
Leukemia; Drug therapy, Combination; Infection; Risk factors
Single-nucleus RNA-seq of frozen archival primary pancreatic ductal adenocarcinoma uncovers multi-compartment intratumoral heterogeneity associated with neoadjuvant treatment.
Authors: William L. Hwang, Karthik Jagadeesh, Jimmy Guo, Hannah I. Hoffman, Orr Ashenberg, Eugene Drokhlyansky, Nicholas Van Wittenberghe, Samouil Farhi, Denis Schapiro, Clifton Rodrigues, Debora Ciprani, Daniel Zollinger, Theodore S. Hong, Andrew Aguirre, Mari Mino-Kenudson, Orit Rozenblatt-Rosen, Carlos Fernandez-del Castillo, Andrew Liss, Tyler Jacks, Aviv Regev
Journal: Journal of Clinical Oncology (2020)

4633 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease and existing molecular subtypes do not inform clinical decisions. Previously identified bulk transcriptomic subtypes of PDAC were often unintentionally driven by “contaminating” stroma. RNA extraction from pancreatic tissue is difficult and prior single-cell RNA-seq efforts have been limited by suboptimal dissociation/RNA quality and poor performance in the setting of neoadjuvant treatment. We developed a robust single-nucleus RNA-seq (sNuc-seq) technique compatible with frozen archival PDAC specimens. Methods: Single nuclei suspensions were extracted from frozen primary PDAC specimens (n = 27) derived from patients with (borderline)-resectable PDAC who underwent surgical resection with or without neoadjuvant chemoradiotherapy (CRT). Approximately 170,000 nuclei were processed with the 10x Genomics Single Cell 3’ v3 pipeline and gene expression libraries were sequenced (Illumina HiSeq X). Results: Distinct nuclei clusters with gene expression profiles/inferred copy number variation analysis consistent with neoplastic, acinar, ductal, fibroblast, endothelial, endocrine, lymphocyte, and myeloid populations were identified with proportions similar to corresponding multiplexed ion beam imaging. Non-negative matrix factorization revealed intra-tumoral heterogeneity shared across patients. Neoplastic cells featured eight distinct transcriptional topics characterized by developmental (epithelial, mesenchymal, endoderm progenitor, neural progenitor) and environmental (anabolic, catabolic, cycling, hypoxic) programs. CAFs exhibited four different transcriptional topics (activated/desmoplastic, myofibroblast, neurogenic, osteochondral). Differential gene expression and gene set enrichment analyses demonstrated that CRT was associated with an enrichment in myogenic programs in CAFs, activation pathways in immune cells, and type I/II interferons in malignant cells. CRT was also associated with a depletion in developmental programs within malignant cells. Conclusions: We uncovered significant intratumoral heterogeneity and treatment-associated differences in the malignant, fibroblast, and immune compartments of PDAC using sNuc-seq. Deconvolution of clinically-annotated bulk RNA-seq cohorts and characterization of intercellular interactions with receptor-ligand analysis and spatial transcriptomics are ongoing.
Neurotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.
Authors: Muhammad Zain Farooq, Sheeba Habeeb Ba Aqeel, Prasanth Lingamaneni, Shristi Upadhyay Banskota, Rayli Pichardo, Mahrukh Siddiqui, Trilok Shrivastava, Ankit Mangla
Journal: Journal of Clinical Oncology (2020)

e15096 Background: Immune checkpoint inhibitors (ICI) are associated with multiple immune related adverse events (irAE). Moderate to severe neurotoxicity is reported in less than 1% of all patients treated with ICI. We performed a systematic review and meta-analysis to assess neurotoxicity associated with anti-PD-1/PD-L1 and anti-CTLA4 therapy. Methods: The Embase, Ovid, Pubmed and Scopus database were comprehensively searched by two independent reviewers, from inception to 2019, to include Phase II and III clinical trials reporting neurotoxicity with the combination of, or monotherapy with anti-PD-1/PD-L1 and/or anti-CTLA4 therapies. Our primary outcome was assessment of neurologic irAE of all grades. We divided neurotoxicity into two groups: peripheral nervous system (PNS) including peripheral neuropathy (PeN), fatigue, Guillain-Barre syndrome (GBS), myelitis; and central nervous system (CNS) including stroke, myasthenia gravis (MG), encephalopathy/encephalitis, altered mental status (AMS), decreased appetite and headache. Statistical heterogeneity was quantified using I 2 statistics and publication bias was assessed with Eggers regression test. The estimates were reported as odds Ratio (OR) with 95% confidence intervals (CI) using random effect model. Results: A total of 2,876 full text articles retrieved in the initial database search were analyzed according to PRISMA guidelines. The final analysis included 39 trials, evaluating 10,595 patients in the control arm and 13,110 patients in the immunotherapy arm. All-grade neurotoxicity events with ICI were significantly lower compared to placebo or standard of care (OR 0.55, 95% CI 0.38-0.81, I 2 96.82%, P &lt; 0.001). Only significant CNS irAE observed was fatigue (OR 0.82, CI 0.71-0.96, I 2 81.75%, P &lt; 0.001). Other CNS irAE including AMS (OR 1.318, 95% CI 0.86-2.0, I 2 0%, P = 0.442), encephalopathy/encephalitis (OR 1.36, 95% CI 0.38-4.96, I 2 0%, P = 0.82) and seizures (OR 1.96, 95% CI 0.64-6.02, I 2 0%, P = 0.56) had statistically non-significant increased risk in ICI group. Only one case of myelitis was reported in placebo group. The ICI arm had statistically significant lower rates of PeN (OR 0.28, CI 0.16-0.49, I 2 87.31, P &lt; 0.001). One trial reported 1 patient with MG and 5 trials reported 1 patient each of GBS in the ICI arm. Conclusions: Our meta-analysis concludes that use of ICI is associated with lower rate of neurotoxicity overall. Fatigue and PeN are lower with ICI compared to standard of care or placebo. Although, CNS irAE are increased with ICI, they do not reach statistical significance.