Radiation therapy for cancer is potentially associated with reduced growth of concomitant abdominal aortic aneurysm.

PURPOSE: Co-prevalence of abdominal aortic aneurysm (AAA) and cancer poses a unique challenge in medical care since both diseases and their respective therapies might interact. Recently, reduced AAA growth rates were observed in cancer patients that received radiation therapy (RT). The purpose of this study was to perform a fine-grained analysis of the effects of RT on AAA growth with respect to direct (infield) and out-of-field (outfield) radiation exposure, and radiation dose-dependency. METHODS: A retrospective single-center analysis identified patients with AAA, cancer, and RT. Clinical data, radiation plans, and aneurysm diameters were analyzed. The total dose of radiation to each aneurysm was computed. AAA growth under infield and outfield exposure was compared to patients with AAA and cancer that did not receive RT (no-RT control) and to an external noncancer AAA reference cohort. RESULTS: Between 2003 and 2020, a total of 38 AAA patients who had received well-documented RT for their malignancy were identified. AAA growth was considerably reduced for infield patients (n = 18) compared to outfield patients (n = 20), albeit not significantly (0.8 ± 1.0 vs. 1.3 ± 1.6 mm/year, p = 0.28). Overall, annual AAA growth in RT patients was lower compared to no-RT control patients (1.1 ± 1.5 vs. 1.8 ± 2.2 mm/year, p = 0.06) and significantly reduced compared to the reference cohort (1.1 ± 1.5 vs. 2.7 ± 2.1 mm/year, p < 0.001). The pattern of AAA growth reduction due to RT was corroborated in linear regression analyses correcting for initial AAA diameter. A further investigation with respect to dose-dependency of radiation effects on AAA growth, however, revealed no apparent association. CONCLUSION: In this study, both infield and outfield radiation exposure were associated with reduced AAA growth. This finding warrants further investigation, both in a larger scale clinical cohort and on a molecular level.

Cancer, cancer treatment and aneurysmatic ascending aorta growth within a retrospective single center study.

Background: Multi-morbidity poses a substantial challenge for health care in an aging population. Recent studies did not provide evidence for general side effects of anti-cancer therapy regarding the growth rate of coincident abdominal aortic aneurysms, although it was suggested that specific therapeutic substances might accelerate growth. Aneurysm pathology, however, differs with respect to localization. Hence, we present the first ever analysis on the association of cancer and cancer therapy with growth alteration of aneurysms of the ascending aorta (AscAA). Patients and methods: A retrospective single-center identification of AscAA+cancer patients was performed in the institutional picture archiving and communication system (PACS). Included were all patients with ≥2 CT angiograms over ≥6 months and additional malignancy. Clinical data and aneurysm diameters were retrieved and analyzed for an association of cancer (stratified by tumor entity) or cancer therapy (stratified by several classes of chemotherapeutic agents and radiation therapy) with annual growth rate, respectively. Statistics included t-test, Wilcoxon test, and a linear regression model accounting for initial AscAA diameter and type of treatment. Results: From 2003 to 2021, 151 patients (median age 70 years; 85% male) with AscAA and coincident 163 malignancies were identified. Prostate (37%) and hematologic cancer (17%) were most frequent. One-hundred-eleven patients (74%) received chemotherapy and 75 patients (50%) had radiation. After exclusion of six patients with an initial AscAA diameter >55 mm, the average annual AscAA growth rate was 0.18±0.64 mm/year, with only 12 patients experiencing a growth rate >1mm/year. Neither tumor entity nor radiation or chemotherapy - alone or in combination - were significantly associated with an alteration of the annual AscAA growth rate. Likewise, a subanalysis for singular chemotherapeutic agents did not reveal a specific association with AscAA growth alteration. Conclusions: Growth rates of AscAA are low in this cohort with coincident malignancy. Cancer and/or chemotherapy or radiation are not associated with an alteration of the annual growth rate. Additional control examinations seem unnecessary.

Radiation and Chemotherapy are Associated with Altered Aortic Aneurysm Growth in Patients with Cancer: Impact of Synchronous Cancer and Aortic Aneurysm.

OBJECTIVE: The purpose of this study was to assess the associations between malignancy, therapeutic regimens, and aorto-iliac aneurysm (i.e., abdominal aortic aneurysm [AAA]) growth rates. METHODS: A retrospective single centre analysis identified patients with an AAA plus cancer. Patients who had two or more computed tomography angiograms over six months or more and additional malignancy were included. Clinical data and aneurysm diameters were analysed. AAA growth under cancer therapy (chemotherapy or radiation) was compared with a non-cancer AAA control cohort and to meta-analysis data. Statistics included t tests and a linear regression model with correction for initial aortic diameter and type of treatment. RESULTS: From 2003 to 2020, 217 patients (median age 70 years; 92% male) with 246 aneurysms (58.8% AAA) and 238 malignancies were identified. Prostate (26.7%) and lung (15.7%) cancer were most frequently seen. One hundred and fifty-seven patients (72.3%) received chemotherapy, 105 patients (48.4%) radiation, and 79 (36.4%) both. Annual AAA growth (mean ± standard deviation) was not statistically significantly different for cancer and non-cancer patients (2.0 ± 2.3 vs. 2.8 ± 2.1 mm/year; p = .20). However, subgroup analyses revealed that radiation was associated with a statistically significantly reduced mean aneurysm growth rate compared with cancer patients without radiation (1.1 ± 1.3 vs. 1.6 ± 2.1 mm/year; p = .046) and to the non-cancer control cohort (1.7 ± 1.9 vs. 2.8 ± 2.1 mm/year; p = .007). Administration of antimetabolites resulted in statistically significantly increased AAA growth (+ 0.9 mm/year; p = .011), while topoisomerase inhibitors (- 0.8 mm/year; p = .17) and anti-androgens (- 0.5 mm/year; p = .27) showed a possible trend for reduced growth. Similar observations were noted for iliac aneurysms (n = 85). Additionally, the effects persisted for chemotherapy combinations (2.6 ± 1.4 substances/patient). CONCLUSION: Patients with cancer and concomitant aortic aneurysms may require intensified monitoring when undergoing specific therapies, such as antimetabolite treatment, as they may experience an increased aneurysm growth rate. Radiation may be associated with reduced aneurysm growth.

Concomitantly discovered visceral artery aneurysms do rarely grow during cancer therapy.

Visceral artery aneurysms (VAA) are a rare entity of arterial aneurysms with the imminent threat of rupture. The impact of cancer and chemotherapy on the growth of VAAs is unknown. A retrospective dual center cohort study of patients with concomitant VAA and different types of cancer was conducted and the impact of various chemotherapeutic agents on VAA growth was studied by sequential CT analysis. For comparison, a non-cancer all comer cohort with VAAs and no cancer was studied to compare different growth rates. The primary endpoint was aneurysm progress or regression >1.75 mm. Chi-square test, Fisher's exact test and Mann-Whitney test was used for statistical comparison. In the 17-year-period from January 2003 to March 2020, 59 patients with 30 splenic artery aneurysms, 14 celiac trunk aneurysms, 11 renal artery aneurysms and 4 other VAA and additional malignancy were identified. 20% of patients suffered from prostate cancer, the rest were heterogeneous. The most prevalent chemotherapies were alkylating agents (23%), antimetabolites (14%) and mitose inhibitors (10%). Eight patients had relevant growth of their VAA and one patient showed diameter regression (average growth rate 0.1 ± 0.5 mm/year). Twenty-nine patients with 14 splenic, 11 RAAs (seven right) and 4 celiac trunk aneurysms were available in the non-cancer comparison cohort (average growth rate 0.5 ± 0.9 mm/year, p = 0.058). However, the growth rate of patients receiving operative treatment for relevant VAA growth was significantly higher (p = 0.004). VAAs grow rarely, and rather slow. Cancer and/or chemotherapy do not significantly influence the annual growth rate. Additional control examinations seem unnecessary.

Pre-operative cellular dissociation grading in biopsies is highly predictive of post-operative tumour stage and patient outcome in head and neck squamous cell carcinoma.

BACKGROUND: Pre-operative treatment planning in head and neck squamous cell carcinoma (HNSCC) is mainly dictated by clinical staging, which has major shortcomings. Histologic grading is irrelevant due to its lack of prognostic impact. Recently, a novel grading termed Cellular Dissociation Grade (CDG) based on Tumour Budding and Cell Nest Size was shown to be highly prognostic for resected HNSCC. We aimed to probe the predictive and prognostic impact of CDG in the pre-operative biopsies of HNSCC. METHODS: We evaluated CDG in n = 160 pre-therapeutic biopsies from patients who received standardised treatment following German guidelines, and correlated the results with pre- and post-therapeutic staging data and clinical outcome. RESULTS: Pre-operative CDG was highly predictive of post-operative tumour stage, including the prediction of occult lymph node metastasis. Uni- and multivariate analysis revealed CDG to be an independent prognosticator of overall, disease-specific and disease-free survival (p < 0.001). Hazard ratio for disease-specific survival was 6.1 (11.1) for nG2 (nG3) compared with nG1 tumours. CONCLUSIONS: CDG is a strong outcome predictor in the pre-treatment scenario of HNSCC and identifies patients with nodal-negative disease. CDG is a purely histology-based prognosticator in the pre-therapeutic setting that supplements clinical staging and may aide therapeutic stratification of HNSCC patients.

Optical confinement in the nanocoax: coupling to the fundamental TEM-like mode.

The nanoscale coaxial cable (nanocoax) has demonstrated optical confinement in the visible and the near infrared. We report on a novel nanofabrication process which yields optically addressable, sub-µm diameter, and high aspect ratio metal-insulator-metal nanocoaxes made by atomic layer deposition of Pt and Al2O3. We observe sub-diffraction-limited optical transmission via the fundamental, TEM-like mode by excitation with a radially polarized optical vortex beam. Our experimental results are based on interrogation with a polarimetric imager. Finite element method numerical simulations support these results, and their uniaxial symmetry was exploited to model taper geometries with both an electrically large volume, (15λ)3, and a nanoscopic exit aperture, (λ/200)2.

Clinical and genetic characterization of de novo double-hit B cell precursor leukemia/lymphoma.

The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex.

Calcium (Ca(2+)) is a secondary messenger in cells and Ca(2+) flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca(2+) flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca(2+) flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca(2+) flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.

Aluminum Nanowire Arrays via Directed Assembly.

Freestanding and vertically-oriented metal nanowire arrays have potential utility in a number of applications, but presently lack a route to fabrication. Template-based techniques, such as electrodeposition into lithographically defined nanopore arrays, have produced well-ordered nanowire arrays with a maximum pitch of about 2 µm; such nanowires, however, tend to cluster due to local attractive forces. Here, we modify this template fabrication method to produce well-ordered, vertically-oriented, freestanding Al nanowire arrays, etched from an underlying Al substrate, with highly tunable pitch. In addition, optical measurements demonstrated that the nanowires support the propagation of surface plasmon polaritons.

Increasing dietary selenium elevates reducing capacity and ERK activation associated with accelerated progression of select mesothelioma tumors.

To study the effect of the micronutrient selenium on malignant mesothelioma (MM) progression, we cultured four different MM cell lines in media containing increasing amounts of sodium selenite (30, 50, and 80 nmol/L). Increasing selenium levels increased density-dependent proliferation and mobility for CRH5 and EKKH5 but not AB12 and AK7. Comparing these cell lines revealed that extracellular regulated kinase (ERK) phosphorylation was sensitive to a selenium increase in CRH5 and EKKH5 but not AB12 and AK7 cells. Stable expression of a dominant-negative mutant ERK eliminated the effects of increasing selenium. Because ERK is redox sensitive, we compared the MM cell lines in terms of glutathione levels and the capacity to reduce exogenous hydrogen peroxide. Increasing selenium levels led to higher glutathione and reducing capacity in CRH5 and EKKH5 but not AB12 and AK7. The reducing agent N-acetylcysteine eliminated the effects of selenium on ERK activation, proliferation, and mobility. Mice fed diets containing increasing levels of selenium (0.08, 0.25, and 1.0 ppm) showed increased tumor progression for CRH5 but not AB12, MM cells, and in vivo N-acetylcysteine treatment eliminated these effects. These data suggest that the effects of dietary selenium on MM tumor progression depend on the arising cancer cells' redox metabolism, and the tumors able to convert increased selenium into a stronger reducing capacity actually benefit from increased selenium intake.

Calpastatin prevents NF-κB-mediated hyperactivation of macrophages and attenuates colitis.

Calpain enzymes proteolytically modulate cellular function and have been implicated in inflammatory diseases. In this study, we found that calpain levels did not differ between intestinal tissues from inflammatory bowel disease (IBD) patients and healthy controls, but IBD tissues showed increased levels of the endogenous calpain inhibitor, calpastatin (CAST). To investigate the role of CAST in the immune system during IBD, mice were x-ray irradiated, reconstituted with either CAST-knockout (KO) or wild-type (WT) bone marrow, and subjected to dextran sulfate sodium-induced colitis. CAST-KO recipients with induced colitis exhibited more severe weight loss, bloody diarrhea, and anemia compared with WT controls. Histological evaluation of colons from KO recipients with colitis revealed increased inflammatory pathology. Macrophages purified from the colons of KO recipients had higher IL-6, TNF-α, and IFN-γ mRNA levels compared with WT controls. Mechanistic investigations using small interfering RNA and KO bone marrow to generate CAST-deficient macrophages showed that CAST deficiency during activation with bacterial pathogen associated molecular patterns, including heat-killed Enterococcus faecalis or CpG DNA, led to increased IκB cleavage, NF-κB nuclear localization, and IL-6 and TNF-α secretion. Thus, CAST plays a central role in regulating macrophage activation and limiting pathology during inflammatory disorders like IBD.

Controlling Exciton/Exciton Recombination in 2-D Perovskite Using Exciton-Polariton Coupling.

In this paper, we demonstrate that exciton/exciton annihilation in the 2D perovskite (PEA)2PbI4 (PEPI)─a major loss mechanism in solar cells and light-emitting diodes, can be controlled through coupling of excitons with cavity polaritons. We study the excited state dynamics using time-resolved transient absorption spectroscopy and show that the system can be tuned through a strong coupling regime by varying the cavity width through the PEPI layer thickness. Remarkably, strong coupling occurs even when the cavity quality factor remains poor, providing easy optical access. We demonstrate that the observed derivative-like transient absorption spectra can be modeled using a time-dependent Rabi splitting that occurs because of transient bleaching of the excitonic states. When PEPI is strongly coupled to the cavity, the exciton/exciton annihilation rate is suppressed by 1 order of magnitude. A model that relies on the partly photonic character of polaritons explains the results as a function of detuning.

Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany.

BACKGROUND: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials. METHODS: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels. RESULTS: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival. CONCLUSION: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.

Fowlpox-based survivin vaccination for malignant mesothelioma therapy.

Survivin protein is an attractive candidate for cancer immunotherapy since it is abundantly expressed in most common human cancers and mostly absent in normal adult tissues. Malignant mesothelioma (MM) is a deadly cancer associated with asbestos or erionite exposure for which no successful therapies are currently available. In this study, we evaluated the therapeutic efficacy of a novel survivin-based vaccine by subcutaneous or intraperitoneum injection of BALB/c mice with murine fiber-induced MM tumor cells followed by vaccination with recombinant Fowlpox virus replicons encoding survivin. Vaccination generated significant immune responses in both models, leading to delayed tumor growth and improved animal survival. Flow cytometry and immunofluorescence analyses of tumors from vaccinated mice showed CD8(+) T-cell infiltration, and real-time PCR demonstrated increased mRNA and protein levels of immunostimulatory cytokines. Analyses of survivin peptide-pulsed spleen and lymph node cells from vaccinated mice using ELISPOT and intracellular cytokine staining confirmed antigen-specific, interferon-γ-producing CD8(+) T-cell responses. In addition pentamer-based flow cytometry showed that vaccination generated survivin-specific CD8(+) T cells. Importantly, vaccination did not affect fertility or induce autoimmune abnormalities in mice. Our results demonstrate that vaccination with recombinant Fowlpox expressing survivin improves T-cell responses against aggressive MM tumors and may form the basis for promising clinical applications.

A Multicenter Collaborative to Improve Postoperative Pain Management in the NICU.

OBJECTIVES: This quality improvement initiative aimed to decrease unrelieved postoperative pain and improve family satisfaction with pain management. METHODS: NICUs within the Children's Hospitals Neonatal Consortium that care for infants with complex surgical problems participated in this collaborative. Each of these centers formed multidisciplinary teams to develop aims, interventions, and measurement strategies to test in multiple Plan-Do-Study-Act cycles. Centers were encouraged to adopt evidence-based interventions from the Clinical Practice Recommendations, which included pain assessment tools, pain score documentation, nonpharmacologic treatment measures, pain management guidelines, communication of a pain treatment plan, routine discussion of pain scores during team rounds, and parental involvement in pain management. Teams submitted data on a minimum of 10 surgeries per month, spanning from January to July 2019 (baseline), August 2019 to June 2021 (improvement work period), and July 2021 to December 2021 (sustain period). RESULTS: The percentage of patients with unrelieved pain in the 24-hour postoperative period decreased by 35% from 19.5% to 12.6%. Family satisfaction with pain management measured on a 3-point Likert scale with positive responses ≥2 increased from 93% to 96%. Compliance with appropriate pain assessment and numeric documentation of postoperative pain scores according to local NICU policy increased from 53% to 66%. The balancing measure of the percentage of patients with any consecutive sedation scores showed a decrease from 20.8% at baseline to 13.3%. All improvements were maintained during the sustain period. CONCLUSIONS: Standardization of pain management and workflow in the postoperative period across disciplines can improve pain control in infants.

Survival benefit with checkpoint inhibitors versus chemotherapy is modified by brain metastases in patients with recurrent small cell lung cancer.

Introduction: Small cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear. Methods: In this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival. Results: Among 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59). Conclusion: CPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.

Clinical predictors of survival in patients with relapsed/refractory small-cell lung cancer treated with checkpoint inhibitors: a German multicentric real-world analysis.

Objectives: Small-cell lung cancer (SCLC) is a lung malignancy with high relapse rates and poor survival outcomes. Treatment-resistant disease relapse occurs frequently and effective salvage therapies are urgently needed. Materials and Methods: We aimed to define efficacy and safety of checkpoint inhibitors (CPIs) in a heterogeneous population of relapsed and refractory SCLC patients in a large retrospective multicentric real-world cohort across German tertiary care centers. Results: A total of 111 patients from 11 treatment centers were included. Median age of all patients was 64 years, and 63% were male. Approximately one-third of all patients had poor performance status [Eastern Cooperative Oncology Group (ECOG) ⩾ 2], and 37% had known brain metastases. Patients were heavily pretreated with a median number of prior therapy lines of 2 (range, 1-8). Median follow-up of the entire cohort was 21.7 months. Nivolumab and Nivolumab/Ipilimumab were the most common regimens. Overall disease control rate was 27.2% in all patients and was numerically higher in CPI combination regimens compared with single-agent CPI (31.8% versus 23.8%; p = 0.16). Median overall survival (OS) was 5.8 months [95% confidence interval (CI), 1.7-9.9 months]. The 12- and 24-month survival rates were 31.8% and 12.7%, respectively. The 12-week death rate was 27.9%. Disease control and response rate were significantly lower in patients with liver metastases. Platinum sensitivity (to first-line treatment), metastatic burden, and lactate dehydrogenase (LDH) showed prognostic impact on survival in univariate analysis. Neutrophil-to-lymphocyte ratio (NLR) was a significant and independent predictor of survival in univariate (p = 0.01) and multivariate analyses [hazard ratio (HR), 2.1; 95% CI = 1.1-4.1; p = 0.03]. Conclusion: CPI in patients with relapsed or refractory (R/R) SCLC is of limited value in an overall patient cohort; however, long-term survival, in particular with CPI combination strategies, is possible. Clinical characteristics allow a more differentiated subgroup selection, in particular patients with low NLR showed less benefit from CPI in R/R SCLC.

Specific antioxidant selenoproteins are induced in the heart during hypertrophy.

Selenium (Se) is thought to confer cardioprotective effects through the actions of antioxidant selenoprotein enzymes that directly limit levels of ROS such as hydrogen peroxide (H(2)O(2)) or that reverse oxidative damage to lipids and proteins. To determine how the selenoproteome responds to myocardial hypertrophy, two mouse models were employed: triidothyronine (T3)- or isoproterenol (ISO)-treatment. After 7days of T3- and ISO-treatment, cardiac stress was demonstrated by increased H(2)O(2) and caspase-3 activity. Neither treatment produced significant increases in phospholipid peroxidation or TUNEL-positive cells, suggesting that antioxidant systems were protecting the cardiomyocytes from damage. Many selenoprotein mRNAs were induced by T3- and ISO-treatment, with levels of methionine sulfoxide reductase 1 (MsrB1, also called SelR) mRNA showing the largest increases. MsrB enzymatic activity was also elevated in both models of cardiac stress, while glutathione peroxidase (GPx) activity and thioredoxin reductase (Trxrd) activity were moderately and nonsignificantly increased, respectively. Western blot assays revealed a marked increase in MsrB1 and moderate increases in GPx3, GPx4, and Trxrd1, particularly in T3-treated hearts. Thus, the main response of the selenoproteome during hypertrophy does not involve increased GPx1, but increased GPx3 for reducing extracellular H(2)O(2) and increased GPx4, Trxrd1, and MsrB1 for minimizing intracellular oxidative damage.

Low-dose melphalan in elderly patients with relapsed or refractory acute myeloid leukemia: A well-tolerated and effective treatment after hypomethylating-agent failure.

Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.

Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme.

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.