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Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy
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Introduction: Adjuvant anti-cancer systemic therapy (SACT) following lung resection improves overall survival in stage II/II non-small cell lung cancer (NSCLC). The Getting It Right First Time (GIRFT) National Specialty Report for Lung Cancer recommends centres publish adjuvant SACT rates for National benchmarking and proposes a target of >40% of eligible patients undergo SACT. We report a regional audit into the uptake of adjuvant SACT in Greater Manchester (GM). Method(s): A retrospective case review of all patients undergoing curative-intent NSCLC surgery with a pathological stage of II/III from 01/01/21 to 30/04/21. Data collected included patient demographics, uptake of adjuvant SACT, reasons for no adjuvant SACT and tolerance and complications of SACT. Result(s): 58 patients underwent surgical resection within the audit period and were eligible for adjuvant SACT. Median age was 70 years (range 45 - 81) and 60% were female. 47% (27/58) commenced adjuvant SACT;41% (24/58) were treated with chemotherapy and 7% (4/58) were treated with tyrosine kinase inhibitors. 58% (14/24) of patients that commenced adjuvant chemotherapy completed 4 cycles. Carboplatin/Vinorelbine was the commonest regimen (82%, 18/22). There were no grade III-V complications and no chemotherapy-related deaths. Dose reduction due to toxicity was required in 14% (3/22). The reasons adjuvant systemic therapy was not given were patient choice in 32% (10/31), poor physical health such that risks outweighed benefits in 42% (13/31), and other reasons (e.g. need to treat synchronous primary tumours) in 26% (8/31). COVID-19 was not recorded as a cause for adjuvant omission/ dose reduction. Conclusion(s): This data provides national benchmarking information for adjuvant SACT in NSCLC and suggests the target of >40% is achievable and appropriate. Interventions that improve patient fitness pre- and post-operatively might increase adjuvant SACT uptake. This regional audit will be extended to review all eligible patients in 2021 and further data will be presented. Disclosure: No significant relationships.Copyright © 2023 Elsevier B.V.
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Introduction: Loop diuretics are the first-line treatment for volume overload in acute decompensation of congestive heart failure (AHF). Loop diuretic resistance is common due to pharmacologic tachyphylaxis. Therefore, thiazide and thiazide-like diuretics are often used as add-on therapy to combine two different pharmacologic mechanisms. This systemic review and meta-analysis aimed to synthesize the current evidence on the efficacy and safety of metolazone and other thiazide-like diuretics in AHF. Method(s): PRISMA guidelines were followed in conducting this systematic review. PubMed, Scopus, PubMed Central, and Embase databases were searched using relevant keywords for studies published before 5 Jan 2022. and title screening was performed, followed by full-text screening using the Covidence software. Data were extracted, and analysis was done using Cochrane Review Manager (RevMan v5.1). The results were reported in odds ratio and mean difference with 95% confidence intervals. Result(s): Out of 2999 studies identified by database search, eight studies met the inclusion criteria (2 RCTs and 6 cohort studies). Pooled analysis using a random-effects model showed no difference in mean difference among the metolazone group and control group for 24 hours total urine output (MD 69.32, 95% CI -638.29 to 776.94;n = 551;I2 = 84%), change in urine output in 24 hours (MD -284.09, 95% CI -583.99 to 15.81;n = 345;I2 = 0%), 48 hours total urine output (MD -465.62, 95% CI -1302.22 to 370.99;n = 242;I2 = 0%) and urine output at 72 hours (MD -13.24, 95% CI -90.88 to 64.40;n = 205;I2 = 0%). However, studies with furosemide only in the comparator arm, 24 hours of total urine outcome favored metolazone (MD 692.70, 95% CI 386.59 to 998.82;n = 334;I2 = 0%). There was no difference between the two groups in the rate of adverse events, loss of weight, mortality, or readmission rates. Conclusion(s): Metolazone therapy in diuretic resistant AHF may improves urine output and facilitates achieving a net negative balance. Thus, metolazone and thiazide-like diuretics can be used as add-on therapy in acute decompensation of heart failure, especially in diuretic resistance.Copyright © 2023 The Author(s)
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Background: Several pro- and anti-inflammatory cytokines involved in COVID-19 and it is reasonable to speculate that their removal from blood might limit organ damage. Hemoperfusion with CytoSorb is a technique developed to adsorb molecules in the middle molecular weight range (up to 55 kDa). Studies in vitro and in vivo have shown that HP is highly effective in clearing blood from a number of cytokines. Method(s): We report a case series of 9 consecutive COVID-patients admitted to our COVID Intensive Care Unit (ICU). Five of them were treated with HP using CytoSorb (T), due to the heavy emergency overload it was impossible to deliver blood purification in the other 4 patients (C), who were also considered as potential candidates by the attending medical team. All patients had pneumonia and respiratory failure requiring continuous positive airway pressure. Different antibacterial prophylaxes, antiviral, and anti-inflammatory therapies including steroids were delivered. Result(s): Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. CRP decreased in both groups, but to a greater extent after HP. Lymphocytopenia worsened in control patient but not in treated patient after HP. Procalcitonin increased in 2 of the not treated patients. In all survived patients (n = 4) HP reduced pro-inflammatory cytokines, as IL-6, TNF-alpha, and IL-8. Notably, a striking effect was observed on IL-6 levels that at the end of the second session were decreased by a 40% than before the first treatment. Serum levels of IL-8 and TNF-alpha were lowered within normal range. In all patients the treatment was safe and there were no complications. Conclusion(s): Our study suggests a potential efficacy of HP in an early phase of viral infection not only for improving survival in the treated patients but also by the remodeling treatment-associated cytokine levels.
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Background & Aim: The pro-angiogenic, immunoregulatory and anti- inflammatory properties of MSCs are being exploited for the development of cellular therapies, including the treatment of graft versus host disease (GvHD), inflammatory bowel disease and COVID-19. SNBTS have developed a GMP process to bank umbilical cord MSCs (UC-MSCs) whereby we can reliably bank 100 vials of 10 million P2 UC-MSCs per cord. Each of these vials can be extensively expanded and stored for specific applications. The ultimate aim of the bank is for off-the-shelf clinical use, e.g., in GvHD or as an adjuvant therapy in Islet transplantations. Methods, Results & Conclusion(s): During process development, different basal media and supplements were screened for proliferation and MSC marker expression. Cells grown in promising media combinations were then tested for tri-lineage differentiation (identity), their chemokine/cytokine expression and T-cell inhibition (function) assessed. Medium selected for further GMP development and scale up was ultimately determined by all round performance and regulatory compliance. GMP-like UC-MSCs were shown to have immune-modulatory activity in T-cell proliferation assays at 4:1 or 16:1 ratios. Co-culture of UC-MSCs and freshly isolated leukocytes, +/- the immune activating agent LPS, show a dose dependent survival effect on leukocytes. In particular, neutrophils, which are normally very short lived in vitro demonstrated increased viability when co-cultured with UCMSCs. The survival effect was partially reproduced when UC-MSC were replaced with conditioned medium or cell lysate indicating the involvement of soluble factors. This improved neutrophil survival also correlates with results from leukocyte migration studies that demonstrate neutrophils to be the main cell type attracted to MSCs in in vitro and in vivo. Genetic modification of UC-MSC may improve their therapeutic potential. We have tested gene editing by CRISPR/Cas9 technology in primary UC-MSCS. The CXCL8 gene, highly expressed in UC-MSC, was targeted in isolates from several different donors with editing efficiencies of 78-96% observed. This translated to significant knockdown of CXCL8 protein levels in resting cells, however after stimulation levels of CXCL8 were found to be very similar in edited and non-edited UC-MSCs. This observation requires further study, but overall the results show the potential to generate future banks of primary UC-MSCS with genetically enhanced pro-angiogenic, immunoregulatory and/or anti-inflammatory activities.Copyright © 2023 International Society for Cell & Gene Therapy
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Background: Patients with non-small cell lung cancer (NSCLC) treated with adjuvant vinorelbine-platinum chemotherapy experience neutropenia, which may lead to early termination of treatment. However, evidence suggests that survival is superior in patients who complete four cycles of chemotherapy [1]. Granulocyte colony stimulating factor (GCSF) prophylaxis is used to prevent neutropenia. During the COVID pandemic, the threshold for initiating prophylaxis was lowered to reduce need for hospital attendance with the concomitant risk of hospital-acquired infection [2]. We evaluated whether GCSF prophylaxis supported completion of chemotherapy in patients treated at St Bartholomew's Hospital. Method(s): Data was retrospectively collected on the 112 patients with NSCLC who received adjuvant vinorelbine-platinum chemotherapy (total 349 cycles) in the period Jan 2017- Jul 2022. GCSF prophylaxis was prescribed at physician discretion. chi2 tests were carried out using SPSS 28. Result(s): A significantly higher proportion of patients who received GCSF prophylaxis completed four cycles of chemotherapy (chi2=5.120, p=0.024). These patients also experienced a lower incidence of grade 3 or 4 neutropenia (chi2=6.801, p=0.009). Over 5 years, 2/112 (1.75%) patients died, both from neutropenic sepsis;neither of these patients received prophylactic GCSF. GCSF prophylaxis was not associated with increase in the incidence of thromboembolic events (chi2=1.462, p=0.442). Conclusion(s): GCSF is safe and effective as primary prophylaxis in NSCLC patients receiving adjuvant chemotherapy. Use of GCSF will reduce proportion of post-operative patients considered too high risk for chemotherapy due to concerns about neutropenia. Disclosure: No significant relationships. [Figure presented]Copyright © 2023 Elsevier B.V.
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Background/Objectives: COVID-19 still represents a lifethreatening disease in individuals with a specific genetic background. We successfully applied a new Machine Learning method on WES data to extract a set of coding variants relevant for COVID- 19 severity. We aim to identify personalized add-on therapy. Method(s): A subset of identified variants, "actionable" by repurposed drugs, were functionally tested by in vitro and in vivo experiments. Result(s): Males with either rare loss of function variants in the TLR7 gene or L412F polymorphism in the TLR3 gene benefit from IFN-gamma, which is specifically defective in activated PBMCs, restoring innate immunity. Females heterozygous for rare variants in the ADAMTS13 gene and males with D603N homozygous polymorphism in the SELP gene benefit from Caplacizumab, which reduces vWF aggregation and thrombus formation. Males with either the low-frequency gain of function variant T201M in CYP19A1 gene or with poly-Q repeats >=23 in the AR gene benefit from Letrozole, an aromatase inhibitor, which restores normal testosterone levels, reducing inflammation and which rescues male golden hamsters from severe COVID-19. Conclusion(s): By adding these commonly used drugs to standard of care of selected patients, the rate of intubation is expected to decrease consistently, especially in patients with high penetrance rare genetic markers, mitigating the effect of the pandemic with a significant impact on the healthcare system.
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Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.
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The proceedings contain 9 papers. The topics discussed include: dulaglutide and NAFLD risk reduction;correlation between plasmatic long pentraxin PTX3 and nodular thyroid disease: a preliminary report;the fructose-bisphosphate aldolase a act as autoantigen in primary autoimmune hypophysitis;cortisol deficiency in Lenvatinib treatment;side effects of mitotane treatment: a retrospective study in 35 patients with adrenocortical carcinoma in adjuvant therapy;non-functioning pituitary adenoma: do predictor factors exist?;incidence and features of adrenal crisis in a series of 133 patients with Addison's disease;serological evidence and self-reported outcomes in patients with adrenal insufficiency during the first waves of COVID-19 in the North-East Italy;and persistent effects of spironolactone after its withdrawal in patients with hyperandrogenic skin disorders.
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Background: The role of inflammatory cytokines is known in the pathogenesis of organ damage and is also confirmed in the context of COVID-19 disease. The modulation of the cytokine storm seems to determine endothelial protection, which can translate into a reduction of the "capillary leak syndrome", and, consequently, in a better control of the formation of edema and pulmonary infiltrates. CytoSorb stands in this context as a cartridge capable of adsorbing cytokines and allowing a better clinical course. Case Report: A 69 years-old woman with a history of arterial hypertension, diabetes mellitus and CKD, was admitted to ICU for SARS Cov 2 related critical illness staged with chest CT, blood gas analysis and PCR. At the admission, the patient presented with ubiquitous interstitial pneumonia, PaO2 60 mmHg with 90% Airvo2 and PCR 36.67. Therefore, in order to remove inflammatory cytokines, the patient underwent hemoperfusion treatment with the CytoSorb adsorbent cartridge. Method(s): The protocol used is approved by the FDA for the treatment of covid patients and consists of the use of 4 cartridges 12h, 12h, 24h, 24h with measurement for each cycle of PCR, PaO2 and chest CT control. Result(s): During the hemoperfusion whit CytoSorb, respiratory failure improved until the patient was discharged from the ICU on the tenth day, with oxygen support via simple facial mask. Below the progressive values of the PCR, PaO2 and the chest CT control on the twelfth day. Conclusion(s): The hemoperfusion treatment with the CytoSorb adsorbent cartridge proved to be a valid adjuvant therapy in determining a better clinical course both in terms of the need for invasive mechanical ventilation and survival.
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Background/Aims A 72-year-old lady presented in primary care with complaints of generalised body aches, bilateral leg weakness and constitutional symptoms following a first dose of COVID-19 vaccine. Blood tests showed slightly raised inflammatory markers. She was initially diagnosed with polymyalgia rheumatica and was started on 40mg prednisolone with minimal improvement. Methods The examination in the rheumatology clinic was unremarkable. Investigations revealed raised white cell count, consistent with high dose steroid treatment, and elevated monocytes. There was mild improvement in inflammatory markers. The working diagnosis was of self-limiting viral illness. Further testing discovered strongly positive MPO ANCA (115 IU/ml), and the patient received three pulses of 500mg methylprednisolone for suspected vasculitis arranged by the medical team. There was no evidence of renal involvement. The diagnosis made at this point was autoimmune inflammatory disorder with unclear aetiology. At the subsequent clinic visit she reported mild shortness of breath, but no other symptoms suggestive of either vasculitis or connective tissue disease. Repeat ANCA showed significant reduction in MPO titre following pulse steroid treatment. CT of chest, abdomen and pelvis demonstrated a localised lobular/ nodular deformity of the liver. Viral hepatitis screen was negative. CA19-9 was raised at 100 U/ml. Liver biopsy was reported as poorly differentiated carcinoma without specific localising immunohistochemical features. Results The patient underwent hemi-hepatectomy for histologically confirmed pT2pNXM0R0 liver cholangiocarcinoma in a tertiary centre followed by adjuvant chemotherapy with capecitabine. With treatment, her MPO ANCA and CA19-9 levels declined. An interval CT scan of chest, abdomen and pelvis performed ten months after the surgery, showed no recurrence of malignancy. Given the fact that the patient's MPO ANCA fell following the treatment of cholangiocarcinoma, it is likely that positive MPO ANCA is associated with underlying malignancy rather than an active vasculitis. Conclusion This unusual case describes an evolution of the diagnostic process guided by non-specific symptoms and ANCA positivity, arriving at an unexpected diagnosis of malignancy. Although ANCA is a sensitive and specific marker of vasculitides, it can be positive in other conditions particularly hepatitis B, inflammatory bowel disease and autoimmune liver disorders. Malignancy can also be associated with ANCA in the absence of vasculitis. In one study, of 118 ANCA positive patients without ANCA-associated vasculitis, four were found to have malignancy. In a study of 1024 patients who had ANCA tested, 61 patients were found to have malignancy, predominantly haematological and lung cancers. However, after adjustment for sex, age and time of blood draw, no association was found between ANCA status and incidence of cancer. Interestingly, paraneoplastic vasculitis such as polyarteritis nodosa (PAN) has been described in the context of underlying cholangiocarcinoma, and is associated with ANCA rise. Moreover, patients with raised ANCA and PAN also have raised CA 19- 9.
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Introduction: Critically ill COVID-19 patients undergoing cytokine storm are believed to have a worse prognosis and increased fatality rate. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAIDs) that might prove beneficial for the early management of COVID-19 due to its immunomodulatory effects. This study aimed to assess the efficacy and safety of the early use of ibuprofen to attenuate the severity of the course of COVID-19 and improve outcomes in patients diagnosed with a moderate case of COVID-19 disease. Method(s): This randomized, double-blinded prospective study was conducted from January, 2022 to May, 2022, which included a total sample size of 180 patients with moderate cases of COVID-19. The number of patients transferred to intensive care was used as a primary outcome with a proposed large effect size (0.8), alfa =0.05, and power=0.80, so 90 cases were included in each group. Secondary outcomes were inflammatory markers: C-Reactive Protein (CRP), serum ferritin, and interleukin-6 (IL-6), duration of hospital stay, and need for ICU admission. Result(s): One hundred eighty patients with moderate case of COVID-19 disease were divided in a 1: 1 ratio to receive ibuprofen (IG) or paracetamol (CG). The average age of the included patients was almost 41 years. Statistically significant differences were reported between both groups in terms of improvement in cough symptoms and lymphopenia in IG compared to CG (p= 0.034 and p= 0.044, respectively). Regarding secondary outcomes, statistically, significant differences were reported between the study's groups in terms of the mean number of patients transferred to the ICU in IG compared to the CG (p =0.0.047) and duration of hospitalization (p =0.013), with no significant differences (p > 0.9999) in the occurrence of side effects. Concerning the follow-up of the cytokine storm marker, there was a statistically significant reduction in serum cytokine marker compared to the baseline value (P < 0.05) in the same group. No statistically significant differences were observed when comparing both groups together in terms of serum ferritin level (p =0.570), serum IL-6 level (p =0.580), and CRP level (p =0.401). Conclusion(s): It can be concluded that early use of ibuprofen as adjuvant therapy in COVID-19 management is effective and safe to attenuate the severity of diseases and improve outcomes. Trial Registration: Project manager for the Pan African Clinical Trial Registry PACTR202202880140319. Registered 9th February, 2022-Retrospectively registered, (https://pactr.samrc.ac.za/).Copyright © 2023 Sobhy et al.
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Background: Natural killer (NK) cells play a critical role in control of viral infections. However, empirical evidence thus far has been unclear on the role of NK cells in pathogenesis and control of SARS-CoV-2 infection with some research suggesting NK cell accumulation as beneficial while others indicate it as deleterious. To address this crucial deficit in understanding, we employed a non-human primate infection model with a validated experimental NK cell depletion technique. Method(s): A total of 12 experimentally naive (75% female) cynomolgus macaques (CM) of Cambodian origin were used in this study. Six CM were NK cell-depleted using an anti-IL-15 neutralizing antibody, while six controls received placebo, prior to intranasal and intratracheal challenge with the SARS-CoV-2 Delta variant at a TCID50 of 1X105. The cohort was monitored for five weeks with scheduled blood, colorectal (CR) biopsies, and lymph node (LN) collections. Total envelope and sub-genomic viral loads (VL) were measured in the nasal cavity, throat, and bronchoalveolar lavage (BAL). 23-color flow cytometry, pathology, and 27-plex inflammatory analyte Luminex analyses were conducted. Statistical tests used were Mann-Whitney U and Spearman's Correlation. Result(s): Control CM exhibited an increase in the frequency of circulating NK cells, reaching a peak at 10 days post-infection (DPI) and returning to baseline by 22DPI. Simultaneously, NK cells expressing activation and tissue retention marker, CD69, also significantly increased. Cytotoxic NK cells were positively associated with VL (r=0.66;p=0.02), suggestive of a virus-induced mobilization. Total experimental NK cell ablation was verified in blood, CR, and LN of NK celldepleted CM, which had higher VL compared to controls in all tissues evaluated, reaching significance at 10DPI (p=0.01) and demonstrated a longer duration of viremia. Although Luminex measures were similar in plasma, BAL samples from NK cell-depleted CM had universally higher concentrations of inflammatory mediators, most notably a 25-fold higher concentration of IFN-alpha compared to controls. Lung pathology scores were also higher in NK cell-depleted CM with increased evidence of fibrosis, syncytia, pneumocyte hyperplasia, and endothelialitis. Conclusion(s): Overall, we find significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data suggest adjunct therapies for infection could largely benefit from NK cell-targeted approaches.
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Background: Adjuvant chemotherapy has been an integral component of breast cancer care for decades. Advances in supportive care have been made, but despite this, infective complications of therapy remain a significant toxicity concern. Case Presentation: A premenopausal patient presented to the emergency department during the third wave of the Covid-19 pandemic with sepsis after a second course of adjuvant docetaxel-cyclophosphamide chemotherapy. Overnight she developed tetraplegia. An urgent MRI cervical spine revealed a pre-vertebral, vertebral, and epidural abscess. This was treated with an emergency C4-C7 posterior cervical laminectomy and decompression. Her inpatient care involved a protracted ICU admission followed by rehabilitation. She remains tetraplegic and requires continued inpatient care over a year after presentation. Restricted pandemic-related hospital visiting has compounded the impact of her illness. Conclusion: Infective complications of adjuvant breast cancer chemotherapy remain an issue despite advances in supportive care. This case highlights the devastating, life-altering impact that these complications can have as emphasized by the inclusion of the patient's perspective. Copyright © 2022.
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Background Development of immunotherapy/molecular targeted therapy has significantly increased survival/QoL in advanced stages of NSCLC. Aim(s): to analyze outcome predictors, surrogate outcomes, and PROMs after neoadjuvant immunotherapy for initially unresectable NSCLC. Methods Initially unresectable NSCLC (2014-2021) patients who received immunotherapy +/- platinum-based chemo and/or radiotherapy evaluated after response (reduction of primary tumor and/or mediastinal lymphadenopathy/control of distant metastatic disease underwent surgical resection). PROMs were recorded using EORTC QLQ-29. Results 19 underwent salvage surgery after ICI. 14 had partial response (73.6%), 5 stable disease. Diagnosis was achieved by endobronchial ultrasound (EBUS) in 8 (42.1%), fine-needle aspiration biopsy (FNAB) in 7 (36.8%), metastasis biopsy in 4 (21.0%). 11 (57.9%) were treated with neoadjuvant platinum-based chemo before or with ICI, 1 (5.2%) pemetrexed before ICI, 5 (26.3%) radiotherapy for metastatic control. 3 (15.7%) had ICI adverse effects. Radiotherapy was never used preoperatively for pulmonary/mediastinal disease. 7 (36.8%) received adjuvant therapy (5 [26.3%] pembrolizumab, 1 [5.2%] pemetrexed, 1 [5.2%] pemetrexed + pembrolizumab). 4 (21.0%) had local relapse (no systemic relapse). Median OS was 19 months (range: 2-57.4). At 2 months, 94.7% were alive (6 months: 89.5%;31 months: 79.5%). 2 (10.5%) had local recurrence. 2 (10.5%) died due to recurrence, 1 (5.2%) to COVID. 4 (21.0%) relapsed (median DFS: 5.3 months [range: 2.2-13.0]). PROMs were reviewed retrospectively at 30 days/1 year with significant decrease in coughing, side effects of treatment, surgery-related problems. [Formula presented] Conclusions Radical surgical resections following definitive immunotherapy/immune-chemotherapy in selected initially unresectable NSCLC are feasible and safe (low surgical-related mortality and morbidity). Symptoms and surgery-related outcomes were lower with higher QoL due to a selected group of highly motivated patients. Legal entity responsible for the study The authors. Funding Ministero della Salute. Disclosure All authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
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Lobectomy with pulmonary artery (PA) angioplasty in locally advanced lung cancer is an alternative to pneumonectomy. It is feasible, oncologically effective and the procedure of choice in patients with recurrent hemoptysis and limited pulmonary reserves. We present a case of a successful left upper lobectomy with PA resection and reconstruction by an autologous pericardial patch.Copyright © 2022 EDIZIONI MINERVA MEDICA.
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Sarcomatoid urothelial carcinoma is a rare and aggressive variant. Serum beta-hCG levels are used as a tumor marker in gestational trophoblastic diseases and germ cell tumors, but may also be elevated in high-grade bladder cancers. Here, we report two urothelial carcinoma cases with sarcomatoid differentiation that relapsed early after surgery with elevated serum beta-hCG levels. The first case was a 65-year-old female and the second case was a 67-year-old man with sarcomatoid urothelial carcinoma located in the ureter and renal pelvicalyceal system, both of them relapsed with elevated beta-hCG serum level to 146.8 mIU/ mL and 242 mIU/mL, respectively. They died a few months after initial diagnosis;4.9 and 2.5 months respectively. Both sarcomatoid variant and beta-hCG expression were associated with poor prognosis and advanced stage. However, beta-hCG is not used as a tumor marker in urinary tract cancers yet, and its relationship with variant pathologies has not been clarified. We need multi-centered studies to reveal this relationship.Copyright © 2023, Derman Medical Publishing. All rights reserved.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogenic coronavirus that emerged in late 2019, resulting in coronavirus disease (COVID-19). COVID-19 can be potentially fatal among a certain group of patients. Older age and underlying medical illness are the major risk factors for COVID-19-related fatal respiratory dysfunction. The reason for the pathogenicity of COVID-19 in the older age group remains unclear. Factors, such as coagulopathy, cytokine storm, metabolic disrup-tion, and impaired T cell function, may worsen the symptoms of the disease. Recent literature has indicat-ed that viral infections are particularly associated with a high degree of oxidative stress and an imbalance of antioxidant response. Although pharmacological management has taken its place in reducing the severity of COVID-19, the antioxidants can serve as an adjunct therapy to protect an individual from oxidative damage triggered by SARS-CoV-2 infection. In general, antioxidant enzymes counteract free radicals and prevent their formation. The exact functional role of antioxidant supplements in reducing disease symptoms of SARS-CoV-2 infection remains mostly unknown. In this review, the functional role of natural antioxidants in SARS-CoV-2 infection management is discussed in brief.Copyright © 2022 Bentham Science Publishers.
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Background: To mitigate the risks of chemotherapy associated neutropenia, during the COVID-19 pandemic, all genitourinary (GU) cancer patients treated with chemotherapy at the Princess Margaret Cancer Centre (PMCC) were offered primary prophylaxis with GCSF. We hypothesize that this reduced rates of febrile neutropenia, hospitalizations, healthcare costs and improved overall outcomes, compared to GU cancer patients treated with chemotherapy without GCSF in the 2 years prior to the pandemic. Method(s): We performed a retrospective review of GU cancer patients, receiving curative or palliative intent chemotherapy, with or without primary GCSF prophylaxis between January 2018 and June 2022. GCSF was given either as a single dose or as consecutive doses post chemotherapy. Main outcomes were incidence of febrile neutropenia, hospitalization, health care expenditures as well as disease specific outcomes. Result(s): Overall, 248 patients with prostate cancer (44%), urothelial cancers (33%) germ cell (21%), and rare GU cancers (4%) were identified. Median age was 70 (range 19-91), 92% were male, 65% were ECOG 0/1. Treatment intent was neoadjuvant (13%), adjuvant (20%), or palliative (67%). Main regimens used were docetaxel, cabazitaxel, carboplatin, cisplatin/ etoposide, gemcitabine/cisplatin and BEP. Median follow-up was 10.5 months (0.23-52.3 months). A total of 206/248 received primary GCSF prophylaxis. During chemotherapy, the median white blood cell levels were higher in the GCSF group compared to the non-GCSF group (14.1+/-10+/-9/L vs 2.90+/-10+/-9/L, p<0.0001);and neutropenia rates were markedly lower (2% vs. 93%, P=,0.0001). Hospital admission rates were significantly lower in G-CSF users compared to nonusers (19% vs. 69%, P,0.0001). Symptomatic disease progression 13% was the leading cause of admission in the G-CSF group. Infectious causes such as UTI, pneumonia, COVID-19, and sepsis were seen in only 12% of the G-CSF group compared to 31% in the non-users. G-CSF was generally well tolerated with just 0.97% discontinuing G-CSF. Conclusion(s): During the COVID-19 pandemic, primary prophylactic G-CSF use in GU cancer patients, undergoing chemotherapy significantly lowered rates of both febrile neutropenia and hospitalizations and could be a cost-effective strategy in this patient population that warrants further study.