Good Initial Response Research Articles

P142 Restriction of use of high cost drugs for the treatment of rheumatoid arthritis by CCGs in England

Abstract Background/Aims It became apparent at a session at the 2019 BSR Annual Conferene that some CCGs were restricting the number of high cost drugs (HCDs) that were permitted to be prescribed for an individual with rheumatoid arthritis. Further HCDs could only then be prescribed by utilising an Individual Funding Request. We were interested to explore how common this was and what the restrictions were in different areas. Methods The websites of all CCGs in England were scrutinised between March and July 2020 for local guidelines for the use of HCDs in patients with rheumatoid arthritis (RA). The results were tabulated and mapped. Results Of 134 CCGs in England, 69 (51%) had no expressed restriction on numbers of HCDs provided that NICE thresholds were observed. 10 (7%) had a pathway limiting the drugs to 6, 49 (33%) restricted to 4 and a further 9 (7%) restricted to 3. Dates of guidance implementation varied from 07/2017 to 07/2020 with the vast majority being 2018 and 2019. Geographically, the restrictions were not uniform. The CCGs restricting to 3 HCDs were all in London except for one, Oxford. Those restricting to 4 were mainly from the South East, North West and East. Those restricting to 6 HCDs were in the Liverpool area. Largely unrestricted areas were the North East, the South West, the Midlands and the majority of Yorkshire. The majority of CCGs gave no explanation for the restriction of HCDs. Where stated, the reason given was that it had not been shown to be cost effective. Conclusion Restricting the number of HCDs may deprive some patients of effective drugs that have been NICE approved contrary to NICE guidance. There are currently 5 different modes of action (MOA) of HCDs (TNFi, B cell depletion, IL6i, CTLA4 and JAKi) for the treatment of moderately or severely active RA, therefore in some areas not even all MOAs may have been tried. There is no reliable way of predicting a patient's response to an individual drug, so it is necessary to trial and observe. Non-responders will require more treatment changes. Many patients have secondary failure of drugs after initial good response, so trying other drugs with the same MOA is a logical progression. Over a long disease course, patients will need many different interventions and access to the widest possible range is important. Whilst there are lower response rates for HCDs in biologic inadequate response phase III studies, responders can be observed after only 3 months of treatment. Restricting the number of drug choices is also likely to affect clinical practice, as less effective drugs could be continued unnecessarily for fear of running out of choices. Disclosure D. Walker: Honoraria; Gilead Sciences Ltd, Ely Lilly Pharmaceuticals, Pfizer Pharmaceuticals. Grants/research support; Gilead Sciences Ltd. S. Robinson: None. J. Barry: Corporate appointments; Gilead Sciences Ltd. P. Punter: Corporate appointments; Gilead Sciences Ltd. S. Kearns: Corporate appointments; Gilead Sciences Ltd.

Predictors of Myocardial Recovery Following LVAD-Mediated Reverse Remodeling and Device Removal: Insights from RESTAGE-HF

<h3>Purpose</h3> The RESTAGE-HF multicenter study demonstrated high rates of myocardial recovery by implementing protocolized HF pharmacological therapy, LVAD optimization and regular cardiac function monitoring. The purpose of this study was to identify the pre-implant and early post-implant predictors of myocardial recovery sufficient to allow LVAD explantation. <h3>Methods</h3> We studied 36 HeartMate II LVAD patients with advanced non-ischemic cardiomyopathy, cardiomegaly, age <60yo and chronic HF history <5 years who completed the RESTAGE-HF study protocol. LVAD explantation took place when patients met the following criteria with the LVAD reduced to minimum speed: LVEF >45%, left ventricular end diastolic diameter (LVEDD) <60mm, end systolic diameter <50mm, PCWP ≤15mmHg, cardiac index >2.4 L/min/m2. Univariate and stepwise multivariable logistic regression were used to determine independent effects of pre-implant and early post-implant clinical, laboratory, echocardiographic and hemodynamic parameters on resultant myocardial recovery sufficient for explantation. <h3>Results</h3> Nineteen patients (53%) met the reverse remodeling criteria and underwent LVAD explantation. On both multivariable and univariate analysis ethnicity, post LVAD pre-discharge on pump LVEDD <6.0cm and (an unloaded) change in LVEDD after LVAD implantation >0.75cm were associated with subsequent explantation. Additionally pre-LVAD PA Systolic Pressure <55mmHg and PA Diastolic Pressure <27mmHg and post LVAD pre-discharge on pump LVEF >33% and LVESD <4.7cm were also associated with explantation by univariate analysis (Table 1). <h3>Conclusion</h3> In this multi-center study ethnicity and a good initial response to unloading (LVEDD on pump pre discharge <6.0cm and reduction in LVEDD >0.75cm) were identified as predictors of myocardial recovery sufficient for subsequent LVAD removal. Larger scale prospective studies are required to validate these findings that could inform patient management.

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells.

Simple SummaryNon-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted EGFR tyrosine kinase inhibitors (TKI) therapy. To support malignant features associated with cancer development and therapy resistance, the cancer cells adapt their metabolic rate and pathways. As an example, aerobic glycolysis, where the cells use glycolysis in the presence of oxygen, is frequently seen. Here we show that targeting aerobic glycolysis represents a promising strategy in cancer therapeutics. Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

Quiste Renal Infectado: Reporte de Caso

Descripción del caso clínico: Presentamos el caso atípico de una paciente con diagnóstico de quiste renal infectado.&#x0D; Relevancia: Aunque la presencia de quistes renales solitarios suele ser más común de lo que parece, que estos se compliquen al grado de infectarse es poco común, aún más si no se asocian a ninguna enfermedad quística.&#x0D; Implicaciones clínicas: El diagnóstico de un quiste renal es principalmente por medio de estudios de imagen y su infección es rara, normalmente asociada a enfermedad poliquística renal. Los pacientes suelen no responder bien a la antibioticoterapia convencional, por lo que suelen necesitar drenaje y altas dosis de antibióticos.&#x0D; Conclusiones: Los casos reportados de quiste renal infectado son muy limitados y suelen asociarse a una enfermedad de base, por lo que es importante investigar dicha enfermedad en estos pacientes. Aunque los pacientes suelen no responder de primera instancia al tratamiento con antibióticos, después del drenaje y administración de antibióticos a largo plazo suelen presentar un buen pronóstico con ausencia de complicaciones.

Infected renal cyst: A case report

Clinical case description: We present herein an atypical case of a patient diagnosed with an infected renal cyst.&#x0D; Relevance: Although the presence of solitary renal cysts is more common than expected, they rarely become infected, especially when not associated with a cystic disease.&#x0D; Clinical implications: Renal cyst diagnosis is mainly made through imaging studies. Infection is rare and normally associated with polycystic kidney disease. Patients do not usually respond well to conventional antibiotic therapy and end up needing drainage and high doses of antibiotics.&#x0D; Conclusions: There are few case reports of infected renal cyst and they tend to be associated with an underlying pathology, which is important to establish. Even though patients do not usually have a good initial response to antibiotic therapy, they generally have a favorable outcome, with no complications, after drainage and long-term antibiotic administration.

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway.

Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer. However, little attention has been paid to the role of endothelial cells in the development of docetaxel resistance in prostate cancer. Here, we sought to investigate the function and mechanism of endothelial cells involving in the docetaxel resistance of prostate cancer. We found that endothelial cells significantly promoted the proliferation of prostate cancer cells and decreased their sensitivity to docetaxel. Mechanistically, basic fibroblast growth factor (FGF2) secreted by endothelial cells leads to the upregulation of ETS related gene (ERG) expression and activation of the Akt/mTOR signaling pathway in prostate cancer cells to promote docetaxel resistance. In summary, these findings demonstrate a microenvironment-dependent mechanism mediating chemoresistance of prostate cancer and suggest that targeting FGF/FGFR signaling might represent a promising therapeutic strategy to overcome docetaxel resistance.

Philadelphia Chromosome-Positive (Ph+) Childhood Acute Lymphoblastic Leukemia: Good Initial Steroid Response Allows Early Prediction of a Favorable Treatment Outcome

Among 4,760 acute lymphoblastic leukemia (ALL) patients enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were analyzed for presenting features and treatment outcome to identify specific prognostic factors. Treatment stratification was based on initial cell mass and early response as determined by blast count in peripheral blood after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate on day 1. All patients were treated by similar intensive Berlin-Frankfurt-Münster (BFM) protocols. The median age of Ph+ patients was 7.5 years, the median white blood cell count (WBC) was 75 × 109/L, 77% of patients had common ALL, and 29% coexpressed myeloid markers. After a median observation time of 4.2 years, 29 of 61 patients are alive (survival probability [pSUR] at 4 years, 0.49; standard error [SE], 0.06), and 24 of 61 are in first complete remission (CR1; probability of event-free survival [pEFS] at 4 years, 0.38; SE, 0.06). Twenty (35%) of 57 evaluable patients had ≥1,000 leukemic blasts per microliter of blood on day 8 of induction (defined as prednisone-poor-response [PPR]). These patients were older (10.0v 6.88 years; P = .02) and had a higher WBC (144v 29 × 109/L; P = .0016) as compared with patients with prednisone good response (PGR; <1,000 blasts/μL at day 8). Only 2 of 20 patients (10%) with PPR remained in CR1 and alive: 6 patients with PPR did not survive after allogeneic bone marrow transplantation (BMT) due to recurring disease (n = 3) and toxicity (n = 3), and 12 nontransplanted patients died due to progression (n = 5) or relapse (n = 7). In contrast, 26 (70%) of the 37 patients with PGR are alive. Of 18 patients transplanted by allo-BMT, 1 relapsed (now in CR2) and 4 died after BMT. Among the 19 patients with PGR treated by chemotherapy alone, 8 remained in CR1 and 11 relapsed, of which 4 are in CR2 or CR3. The prednisone response emerged as the only independent prognostic factor for survival in Cox regression analysis. Thus, two thirds of Ph+ childhood ALL cases can be identified early by PGR, which, when treated with intensive BFM chemotherapy, with or without BMT, have a significantly lower risk of treatment failure. With a median continuous complete remission (CCR) time of 4.1 years, pEFS for PGR is 0.55 (SE, 0.08) compared with 0.10 (SE, 0.07) in patients with PPR (P = .0001). PGR is also an indicator for treatment responsiveness and durable second remission after relapse, which in turn may provide a second chance for BMT.© 1998 by The American Society of Hematology.

Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis

BackgroundAndrogen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAFs-derived exosomes involving in metastasis of PCa after ADT.MethodsPCa cells were co-cultured with exosomes derived from 10 nM dihydrotestosterone (DHT)-treated (simulating the high androgen level of prostate cancer microenvironment) or ethanol (ETOH) -treated (simulating the castration level of prostate cancer microenvironment after ADT) CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot.ResultsCompared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increased migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway.ConclusionsCAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa.

Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome

BackgroundApproximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant.MethodsThis is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m2 per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed.DiscussionThe study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols.Trial registrationThis trial was prospectively registered to the Clinicaltrial.gov (NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/) and Clinical Trials Registry of India (CTRI/2019/04/018517 dated 09/04/2019).

Extraskeletal Ewing's Sarcoma with CD7 Positivity and T-cell Receptor/Immunoglobulin Rearrangement Masquerading as T-lymphoblastic Lymphoma

Background: Extraskeletal Ewing's Sarcoma (EES) may harbor more than one tumor-specific genetic abnormality, leading to diagnostic difficulties. Case report: We report a nine-year-old boy with recurrent mass of his right thigh. Tumor cells were round, with scant cytoplasm, finely dispersed chromatin, and inapparent, small nucleoli. The initial misdiagnosis was T-lymphoblastic lymphoma due to CD7 and TCR/Ig monoclonal rearrangement. As it expressed NKX2.2 and harbored an EWSR1-FLI1 fusion transcript, the diagnosis was changed to EES. The child underwent EES therapy with good initial response, but had a subcutaneous relapse at 22 months. Conclusion: In addition to typical genetic alterations, Ewing sarcoma can also express CD7 and TCR/Ig rearrangement, which are not limited to lymphoma.

S1915 Esophageal Actinomycosis Presenting as Persistent Dysphagia in an Immunocompromised Host

INTRODUCTION: Actinomyces are a Gram-positive anaerobic bacterium part of the normal flora of the human oropharyngeal, gastrointestinal and genitourinary tract. Infectious esophagitis caused by actinomyces is rare, with less than 30 cases reported in the English literature. Majority of cases involve immunocompromised patients and those with prior esophageal injury. Herein, we describe a case of a 50-year-old immunocompromised male who presented with complaints of dysphagia and was diagnosed with esophageal actinomycosis through biopsy of suspected lesions. CASE DESCRIPTION/METHODS: A 54 y.o male with a PMH of HIV and DMII presented with dysphagia and odynophagia. He had a recent candidal esophagitis. Patient was compliant with his antiretroviral therapy and had a low HIV viral load. EGD was done and showed a submucosal mass in the lower third of the esophagus (Figure 1). Biopsy showed chronic granulomatous inflammation and micro-abscesses. Culture grew Actinomyces. He was initially treated with PO Cefdinir for 4 weeks without resolution of symptoms, then started on Augmentin, again without any relief. Consensus was to treat with an eight-week course of ertapenem IV. Unfortunately, there was no improvement. Patient was admitted and started on iv Penicillin G. Within 5 days there was marked improvement of his symptoms. He was discharged home on PO penicillin 500mg BID with initial good response. Unfortunately, he has continued to experience intermittent nausea, vomiting, and dysphagia as of this writing. DISCUSSION: Actinomycosis often happens after surgery, trauma, instrumentation or inflammatory processes. Co-infections with Actinobacillus, Eikenella, Fusobacterium and Candida is common. It can mimic malignancy, tuberculosis, or other more common disorders. Thoracic actinomycosis accounts only for 15% of all cases and esophageal infection is rare. Esophagitis, esophageal ulcerations, abscesses, fistulas, sinus tracts and strictures have been described. Around 75% of cases occur in immunocompromised hosts. Dysphagia and odynophagia are the most common complaints. Radiologic findings are nonspecific and EGD with biopsy is always needed. Isolation of the bacteria occurs in a minority of cases but it is the gold standard for diagnosis. Management consists of IV Penicillin followed by oral Penicillin for 6–12 months. Actinomyces remain highly sensitive to Penicillin however if allergy is present, tetracyclines, clindamycin, and macrolides are alternative options. In some cases, surgical drainage may be required.Figure 1.: Non obstructing mass on the lower third of the Esophagus.

Abstract PR05: Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target

Abstract Melanoma is the most life-threatening skin cancer in the world. Advanced melanoma is highly metastatic, commonly develops drug resistance, and causes low survival rate in patients. PLX4032 (vemurafenib), a BRAFV600E inhibitor, is used to treat patients with late-stage melanoma. It showed initial good clinical responses but relapsed due to acquired drug resistance in tumors. The mechanism of PLX4032-induced resistance in melanoma is not well characterized; in particular, whether PLX4032-induced drug resistance in BRAF mutant melanoma would alter lipid metabolism in cancer is not clear. Understanding the status and role of lipid mediators (oxylipins) in melanoma pathology may be crucial for developing effective approach to overcome drug resistance. Our laboratory has demonstrated that plant sesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35 effectively suppressed human A375 BRAFV600E melanoma with acquired drug resistance to PLX4032 in vitro and in xenograft mice. In this study we aimed to identify potential biomarkers associated with the resistant melanoma cells (A375-R) in the context of bioactive lipid mediators and to investigate whether DETD-35/DET effects against drug-resistant melanoma are through regulating their dynamics and contents. MS-based metabolomics was used to comprehensively analyze the oxylipin profiles in A375 and A375-R cells, mouse A375/A375-R tumor tissues, and respective sera with vehicle, drug, or compound treatment. We observed that PLX4032-resistant A375R melanoma cells or tumors produce significant and higher amounts of CYP450 enzyme-derived oxylipins than the parental A375, which were decreased after DETD-35 or DET treatment. This study proposes a role of CYP450-derived oxylipins in PLX4032-resistant melanoma cells and its potential to be a drug target. This abstract is also being presented as Poster B03. Citation Format: Meng-Ting Chang, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR05.

Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review.

Immune thrombocytopenia, often known as immune thrombocytopenic purpura (ITP), has emerged as an important complication of COVID-19. A systematic review was done to analyze the clinical profile and outcomes in a total of 45 cases of new-onset ITP in COVID-19 patients described in literature until date. A comprehensive approach is essential for diagnosing COVID-19-associated ITP after excluding several concomitant factors that can cause thrombocytopenia in COVID-19. Majority of ITP cases (71%) were found to be elderly (> 50 years) and 75% cases had moderate-to-severe COVID-19. Three patients (7%) were in the pediatric age group. Reports of ITP in asymptomatic COVID-19 patients (7%) underscore the need for COVID-19 testing in newly diagnosed patients with ITP irrespective of COVID-19 symptoms amid this pandemic. ITP onset occurred in 20% cases 3 weeks after onset of COVID-19 symptoms, with many reports after clinical recovery. SARS-CoV-2-mediated immune thrombocytopenia can be attributed to the underlying immune dysregulation, susceptibility mutations in SOCS 1, and other mechanisms, including molecular mimicry, cryptic antigen expression, and epitope spreading. No bleeding manifestations were reported in 31% cases at diagnosis. Severe life-threatening bleeding was uncommon. One case of mortality was attributed to intracranial hemorrhage. Secondary Evans syndrome was diagnosed in one case. Good initial response to short course of glucocorticoids and intravenous immunoglobulin has been found with the exception of delayed lag response in one case. Thrombopoietin receptor agonist usage as a second-line agent has been noted in few cases for short duration with no adverse events. In the relatively short follow-up period, four relapses of ITP were found.

Radiology quiz- dancing ball

We are presenting an interesting case of Pneumonia, who after good initial response deteriorated with recurrent hemoptysis. On culture of bronchial aspirate, patient had coexisting fungal infection and on repeat bronchoscopy showed a unique and rare picture. There was a dancing ball in RUL which was moving. Patient was initially managed conservatively but finally had to undergo lobectomy to achieve permanent cure.

What's Important: Empathy in Patient Care: Lessons from My Own Knee Story.

What's Important: Empathy in Patient Care: Lessons from My Own Knee Story.

Urinary System Manifestation of IgG4-Related Disease: Clinical, Laboratory, Radiological, and Pathological Spectra of a Chinese Single-Centre Study.

Background IgG4-related disease is a new disease entity, but little attention was drawn to urinary system involvement besides nephritis or nephropathy. Here, we described clinical, radiological, and pathological manifestations of IgG4-related urinary disease (IgG4-RUD) and assess its treatment responses. Methods We conducted a retrospective study enrolling 65 IgG4-RUD patients from an IgG4-related disease (IgG4-RD) cohort of the Peking Union Medical College Hospital. Clinical, laboratory, radiological, pathological data were collected, and treatment response to immunosuppressants were analysed. Results IgG4-related interstitial nephritis (TIN, 32.3%), glomerular nephritis (GN, 7.7%), renal pelvis and ureter involvement (21.5%), abnormal radiology with quiescent clinical presentation (13.8%), and renal parenchymal lesion plus retroperitoneal fibrosis (RPF, 18.5%) were major lesion types of IgG4-RUD. All patients had elevated serum IgG4, 76.9% had hyperglobulinemia, and 92.3% had elevated serum IgE at diagnosis. IgG4-TIN patients presented with renal dysfunction, and 94.3% had low serum complement C3 and IgG4-GN presented with nephrotic syndrome, while renal pelvis and ureter involvement had normal renal function and urinalysis. IgG4-RPF with renal parenchymal involvement presented with acute renal dysfunction and required emergency medical intervention. Renal cortex low-density areas, parenchyma or pelvis nodular mass, bilateral enlargement of the kidney, and renal pelvis and ureter mass/wall thickening were specific image patterns of IgG4-RUD. Infiltration of plasma lymphocytes and storiform fibrosis were histopathological features of IgG4-RUD. Patients showed satisfactory responses to immunosuppressive treatment, but complete recovery of renal function was difficult to achieve in IgG4-TIN. Four patients (6.2%) experienced clinical relapses during the maintenance period. Conclusion IgG4-RUD had diverse lesion types and distinctive manifestations. Radiological examinations were helpful for diagnosis and treatment evaluation. Patients showed good initial response to immunosuppressive treatment but relapses could occur at the maintenance period.

Paclitaxel as a possible continuation maintenance therapy in advanced non-small-cell lung cancer

Background: Understanding the molecular basis of lung cancer has led to the development of targeted agents with a significant clinical benefit. This benefit is confined to patients with specific molecular tumor characteristics. However, chemotherapy represents the backbone of treatment in fit patients and is associated with a significant overall survival prolongation and quality of life improvement. Aim: To evaluate the effect of a continuation maintenance therapy with paclitaxel in advanced NSCLC patients with weekly paclitaxel. Patients and Methods: The current study included patients with advanced non-small-cell lung cancer (NSCLC) (stage IIIB or IV) with performance status ≤ 2 who experienced good initial good response, or stable disease after receiving 4 cycles of paclitaxel carboplatin. Patients were randomized into 2 arms, the first arm received weekly paclitaxel (70 mg/m2) as continuation maintenance therapy for 3 weeks of 4 weeks cycle. The treatment was continued until disease progression or unacceptable toxicity (maintenance arm). The second arm was kept under observation (observation arm). Results: There was a better lung cancer symptoms scale in the maintenance arm. Both times to progression and overall survival for the maintenance arm was higher (P value 0.16 and 0.047, respectively). Treatment-related toxicities were significantly higher in the maintenance arm as compared to the observation arm (P value <0.001). Conclusion: Maintenance with paclitaxel can be a reasonable option in patients with NSCLC who experienced a complete or partial response after initial paclitaxel carboplatin combination.

P0216CHECK POINT INHIBITORS AND CANCER. RENAL ADVERSE EVENTS: CASE SERIES

Abstract Background and Aims The treatment of cancer with check point inhibitors (CPI) has demonstrated significant benefits. CPI initiate antitumor immunity through negative regulatory components in T cells. However, these agents are associated with adverse events related to the immune system that can affect several organs. Initially, a low incidence of renal adverse events was reported, although recent data suggest an incidence between 9.9% and 29%. The objective of the study was to describe a case series that presented renal dysfunction related to CPI treatment. Method 11 patients were studied retrospectively (67% males, mean age 69 ± 13 years), diagnosed with Neoplasms (9 advanced lung cancer, 7 of them metastatic and 2 metastatic melanomas) treated with CPI, who developed renal dysfunction. 5 patients with lung cancer were treated with Pembrolizumab, 3 with Nivolumab and 1 with Pembrolizumab + Ipilimumab combination. Patients with melanoma received Pembrolizumab. In 55% of the cases, immunotherapy was used as first line of antitumor treatment. Demographic and clinical-analytical data were collected, as well as the evolution of renal function. Results The median plasma creatinine prior to receiving treatment with CPI was 0.9 mg/dl [0.67-1.5]. The maximum creatinine reached after treatment with CPI was 2.5 mg/dl [1.8-7.5] with Pembrolizumab, 5.4 mg/dl [3-6.7] with Nivolumab and 4.3 mg/dl with the combination Pembrolizumab + Ipilimumab. Renal dysfunction occurred in the fifth cycle of treatment with Pembrolizumab and in the third cycle with Nivolumab and Pembrolizumab + Ipilimumab. All patients received steroids (1mg/kg) and CPI were permanently discontinued in 3 patients with Pembrolizumab (43%), 1 with Nivolumab (33.3%) and 1 with Pembrolizumab + Ipilimumab (100%). Renal biopsy was performed in 4 patients who initially did not respond to steroids, resulting in acute tubulo-interstitial nephritis (ATIN), 1 of them with granuloma formation and worse renal evolution. All patients recovered renal function partially or totally, except 1 treated with Pembrolizumab who remained with advanced kidney disease. Tumor progression was observed in 3 patients and 2 died. Conclusion CPI have demonstrated significant clinical benefits in the regression and prolonged stabilization of many tumors. The main cause of renal dysfunction after the use of CPI in our patients was the ATIN, with a good initial response to steroids and drug suspension. The presence of granulomas in renal biopsy confers a poor prognosis. It is an increasingly frequent entity in clinical practice, and because of its complicated management, it requires a multidisciplinary approach.

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.

Hemophagocytic Lymphohistiocytosis in Renal Transplant Recipients: A 2-Case Report

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by an excessive immune activation. HLH can be triggered by a variety of events that disrupt immune homeostasis, such as infections and immunosuppression. HLH presents with heterogeneous clinical symptoms and laboratory findings such as pancytopenia, elevated liver enzymes, impaired renal function, and hyperferritinemia. Case presentationsCase 1. A 58-year-old man was admitted because of a high fever and diarrhea. Laboratory findings showed acute renal impairment, pancytopenia, Epstein-Barr virus (EBV) DNA seropositivity with a replication index of 2 million copies/mL, and hyperferritinemia. A diagnosis of HLH was confirmed by bone marrow aspiration. He was treated with etoposide, steroids, and rituximab with initial good response and good kidney function restoration. He was discharged after 31 days but eventually died after 44 days after a disease relapse. Case 2. A 51-year-old kidney transplant recipient was admitted because of a fever of unknown origin. A worsening renal function, pancytopenia, EBV DNA of 4,356,222 copies/mL on blood, D-Dimer 7505 ng/mL, ferritinemia 9180.9 ug/L, and triglycerides 1273 mg/dL were found. Bone marrow aspiration was negative for HLH; a few days later, a diagnosis of HLH was made after a positive bone marrow biopsy. Continuous renal replacement therapy was started in the intensive care unit because of severe lactic acidosis due to sepsis. She died few days later. ConclusionEBV infection could be a trigger for HLH in a renal transplant patient. Hyperferritinemia is useful for differential diagnosis in a septic patient. The outcome is very poor even with prompt treatment.