Role of protein kinase C in inhibition of renin release caused by vasoconstrictors

It was the aim of the present study to get insight into some of the intracellular mechanisms by which the vasoconstrictor hormones angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine (NE) inhibit renin release from renal juxtaglomerular cells. To this end a primary cell culture from rat renal cortex was established that consisted of 50% juxtaglomerular cells. The cultured juxtaglomerular cells contained prominent renin granules closely resembling those in the intact kidney and responded to a number of stimuli of renin release. By using these cultures, we found that ANG II (10(-7) M), AVP (10(-6) M), and NE (10(-5) M) inhibited renin release and increased the calcium permeability of the plasma membrane of the cultured cells. Both the effects on renin release and on calcium permeability could be diminished or even be abolished by the calcium channel blocker verapamil (Vp) (10(-5) M). ANG II, AVP, and NE led to an increased formation of diacylglycerol (DAG), a well-known stimulator of protein kinase C (PKC). Moreover, a direct stimulation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) (10(-8)-10(-6) M) also inhibited renin release and increased the calcium permeability of the cell membrane. Similar to ANG II, AVP, and NE, the effects of TPA on calcium permeability and renin release could be diminished by Vp. In conclusion, these results point toward a common mechanism by which vasoconstrictors inhibit renin release from renal juxtaglomerular cells: ANG II, AVP, and NE activate a phospholipase C, which generates DAG.(ABSTRACT TRUNCATED AT 250 WORDS

Prognostic value of PD-L1 expression on tumor cells combined with CD8+ TIL density in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND/AIM:mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT). PATIENTS AND METHOD:We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0-40% vs. 41-100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated. RESULTS:Median OS was 14 months (range: 3-167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1neg/CD8low) and type IV (PD-L1pos/CD8low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively. CONCLUSION:Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT

Retrospektive Analyse von Patienten mit einem lokal-fortgeschrittenem nicht-kleinzelligen Lungenkarzinom die von 2006 bis 2016 mit einer primären Radiochemotherapie in der Klinik und Poliklinik für Strahlentherapie und Radioonkologie LMU behandelt wurden

Das Lungenkarzinom ist verantwortlich für die meisten Krebstoten in Deutschland und weltweit. Der Behandlungsstandart von Patientinnen und Patienten mit inoperablen lokal fortgeschritte-nen nicht-kleinzelligen Lungenkarzinome ist die definitive Radiochemotherapie, gefolgt von einer Durvalumab-Erhaltungstherapie abhängig vom PD-L1 Status. Das Gesamtüberleben und progressionsfreie Überleben der so behandelten Patienten variiert jedoch immens. Zur Individualisierung der Therapieplanung ist es darum wichtig die Möglichkei-ten der Prognosestellung zu verbessern. In der Arbeit „Survival score to characterize prognosis in inoperable stage III NSCLC after chemoradiotherapy” wurde ein einfach anwendbarer Prognosescore basierend auf den grundlegenden Patientendaten zu Alter, Geschlecht, Tabakkonsum, Histologie und Atelektase, jeweils bei Diagnosestellung in einer retrospektiven Kohorte mit 99 Patienten entwickelt und in einer prospektiven Patientenkohorte validiert. Die Bedeutung der bildgebenden Nachsorge nach einer definitiven Radiochemotherapie ist für Patienten mit lokal fortgeschrittenem, inoperablem Lungenkarzinom unangefochten. In „How much primary tumor metabolic volume reduction is required to improve outcome in stage III NSCLC after chemoradiotherapy? A single-centre experience” wurde in einer Kohorte mit 60 Patienten der Rückgang des metabolischen Primärtumorvolumens in einem post-therapeutischen PET/CT im Vergleich zu jenem vor einer Radiochemotherapie erfasst. Eine Reduktion von mindestens 80% zeigte hierbei einen signifikanten positiven Einfluss auf das Gesamtüberleben. Somit wurden zwei Verfahren zur genaueren Prognosestellung von NSCLC Patienten im inoperablem UICC-Stadium III entwickelt

Longitudinal changes of blood parameters and weight in inoperable stage III NSCLC patients treated with concurrent chemoradiotherapy followed by maintenance treatment with durvalumab

Background Investigating dynamic changes in blood-parameters and weight in patients with locally advanced non-small cell lung cancer (NSCLC) receiving durvalumab maintenance therapy after chemoradiotherapy (cCRT). Laboratory outcomes were determined based on the number of durvalumab administrations received. Methods Twenty-two patients completed platinum-based cCRT followed by maintenance treatment with durvalumab. Different parameters such as hemoglobin (Hb), leukocytes, Lactate dehydrogenase (LDH), C-reactive protein (CRP), body weight and albumin were analyzed before cCRT, after cCRT, 3, 6, 9 and 12 months after starting durvalumab maintenance. Results Sixteen (72.7%) patients were male; twelve (54.5%) and fifteen (68.2%) patients had non-squamous histology and Union for International Cancer Control (UICC) stage IIIB-C disease, respectively. Median follow-up time was 24.4 months; 12- and 18-months- progression-free and overall-survival rates were 55.0% and 45.0 as well as 90.2 and 85.0%, respectively. During maintenance treatment Hb increased by 1.93 mg/dl (17.53%) after 9 months ( p < 0.001) and 2.02 mg/dl (18.46%) after 12 months compared to the start of durvalumab ( p < 0.001). LDH decreased by 29.86 U/l (− 11.74%) after 3 months ( p = 0.022). Receipt of at least 12 cycles of durvalumab was beneficial in terms of Hb-recovery (Hb 6 months: 12.64 vs. 10.86 [mg/dl]; Hb 9 months: 13.33 vs 11.74 [mg/dl]; ( p = 0.03)). Median weight change [kilogram (kg)] was + 6.06% (range: − 8.89 − + 18.75%) after 12 months. The number of durvalumab cycles significantly correlated with total weight gain [kg] (Spearman-Rho-correlation: r = 0.502*). Conclusion In the investigated cohort, no severe hematologic toxicity occurred by laboratory blood tests within 1 year of durvalumab maintenance therapy after cCRT for unresectable stage III NSCLC. Receiving at least 12 cycles of durvalumab appears to have a significant effect on recovery of hemoglobin levels and body weight

First-site-metastasis pattern in patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with or without immune check-point inhibition: a retrospective analysis

&lt;jats:title&gt;Abstract&lt;/jats:title&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Purpose&lt;/jats:title&gt; &lt;jats:p&gt;The aim of this study was to investigate a first-site-metastasis pattern (FSMP) in unresectable stage III NSCLC after concurrent chemoradiotherapy (cCRT) with or without immune checkpoint inhibition (ICI).&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Methods&lt;/jats:title&gt; &lt;jats:p&gt;We defined three patient subgroups according to the year of initial multimodal treatment: A (2011–2014), B (2015–2017) and C (2018–2020). Different treatment-related parameters were analyzed. Observed outcome parameters were brain metastasis-free survival (BMFS), extracranial distant metastasis-free survival (ecDMFS) and distant metastasis-free survival (DMFS).&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Results&lt;/jats:title&gt; &lt;jats:p&gt;136 patients treated between 2011 and 2020 were included with ≥ 60.0 Gy total dose and concurrent chemotherapy (cCRT); thirty-six (26%) received ICI. Median follow-up was 49.7 (range:0.7–126.1), median OS 31.2 (95% CI:16.4–30.3) months (23.4 for non-ICI vs not reached for ICI patients, &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.001).&lt;/jats:p&gt; &lt;jats:p&gt;Median BMFS/ecDMFS/DMFS in subgroups A, B and C was 14.9/16.3/14.7 months, 20.6/12.9/12.7 months and not reached (NR)/NR/36.4 months (&lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.004/0.001/0.016).&lt;/jats:p&gt; &lt;jats:p&gt;For cCRT+ICI median BMFS was 53.1 vs. 19.1 months for cCRT alone (&lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.005). Median ecDMFS achieved 55.2 vs. 17.9 (&lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.003) and median DMFS 29.5 (95% CI: 1.4–57.6) vs 14.93 (95% CI:10.8–19.0) months (&lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.031), respectively.&lt;/jats:p&gt; &lt;jats:p&gt;Multivariate analysis showed that age over 65 (HR:1.629; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.036), GTV ≥ 78 cc (HR: 2.100; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.002) and V20 ≥ 30 (HR: 2.400; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.002) were negative prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS (HR: 1.739; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.027).&lt;/jats:p&gt; &lt;jats:p&gt;After onset of brain metastasis (BM), patients survived 13.3 (95% CI: 6.4–20.2) months and 8.6 months (95% CI: 1.6–15.5) after extracranial-distant-metastasis (ecDM). Patients with ecDM as FSMP reached significantly worse overall survival of 22.1 (range:14.4–29.8) vs. 40.1 (range:18.7–61.3) months (&lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.034) in the rest of cohort. In contrast, BM as FSMP had no impact on OS.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Conclusion&lt;/jats:title&gt; &lt;jats:p&gt;This retrospective analysis of inoperable stage III NSCLC patients revealed that age over 65, V20 ≥ 30 and GTV ≥ 78 cc were prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS. ICI treatment led to a significant improvement of BMFS, ecDMFS and DMFS. ecDM as FSMP was associated with significant deterioration of OS, whereas BM as FSMP was not.&lt;/jats:p&gt; &lt;/jats:sec&gt

Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition

BACKGROUND The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). METHOD AND PATIENTS Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local-regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). RESULTS All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60~Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0-42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7-34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8~months, p = 0.020) and eMFS (8.1~months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8~months (p < 0.001) and 3.6~months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65~years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263-22.942, p = 0.023)). CONCLUSION In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm

Differential role of residual metabolic tumor volume in inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition

BACKGROUND The PET-derived metabolic tumor volume (MTV) is an independent prognosticator in non-small cell lung cancer (NSCLC) patients. We analyzed the prognostic value of residual MTV (rMTV) after completion of chemoradiotherapy (CRT) in inoperable stage III NSCLC patients with and without immune checkpoint inhibition (ICI). METHODS Fifty-six inoperable stage III NSCLC patients (16 female, median 65.0~years) underwent 18F-FDG PET/CT after completion of standard CRT. rMTV was delineated on 18F-FDG PET/CT using a standard threshold (liver SUVmean + 2 × standard deviation). 21/56 patients underwent additional ICI (CRT-IO, 21/56 patients) thereafter. Patients were divided in volumetric subgroups using median split dichotomization (MTV ≤ 4.3~ml vs. > 4.3~ml). rMTV, clinical features, and ICI-application were correlated with clinical outcome parameters (progression-free survival (PFS), local PFS (LPFS), and overall survival (OS). RESULTS Overall, median follow-up was 52.0~months. Smaller rMTV was associated with longer median PFS (29.3 vs. 10.5~months, p = 0.015), LPFS (49.9 vs. 13.5~months, p = 0.001), and OS (63.0 vs. 23.0~months, p = 0.003). CRT-IO patients compared to CRT patients showed significantly longer median PFS (29.3 vs. 11.2~months, p = 0.034), LPFS (median not reached vs. 14.0~months, p = 0.016), and OS (median not reached vs. 25.2~months, p = 0.007). In the CRT subgroup, smaller rMTV was associated with longer median PFS (33.5 vs. 8.6~months, p = 0.001), LPFS (49.9 vs. 10.1~months, p = 0.001), and OS (63.0 vs. 16.3~months, p = 0.004). In the CRT-IO subgroup, neither PFS, LPFS, nor OS were associated with MTV (p > 0.05 each). The findings were confirmed in subsequent multivariate analyses. CONCLUSION In stage III NSCLC, smaller rMTV is highly associated with superior clinical outcome, especially in patients undergoing CRT without ICI. Patients with CRT-IO show significantly improved outcome compared to CRT patients. Of note, clinical outcome in CRT-IO patients is independent of residual MTV. Hence, even patients with large rMTV might profit from ICI despite extensive tumor load

Metabolic patterns on [18F]FDG PET/CT in patients with unresectable stage III NSCLC undergoing chemoradiotherapy ± durvalumab maintenance treatment

PurposeIn patients with unresectable stage III non-small-cell lung cancer (NSCLC), durvalumab maintenance treatment after chemoradiotherapy (CRT) significantly improves survival. So far, however, metabolic changes of tumoral lesions and secondary lymphoid organs under durvalumab are unknown. Hence, we assessed changes on [18F]FDG PET/CT in comparison to patients undergoing CRT alone.MethodsForty-three patients with [18F]FDG PET/CT both before and after standard CRT for unresectable stage III NSCLC were included, in 16/43 patients durvalumab maintenance treatment was initiated (CRT-IO) prior to the second PET/CT. Uptake of tumor sites and secondary lymphoid organs was compared between CRT and CRT-IO. Also, readers were blinded for durvalumab administration and reviewed scans for findings suspicious for immunotherapy-related adverse events (irAE).ResultsInitial uptake characteristics were comparable. However, under durvalumab, diverging metabolic patterns were noted: There was a significantly higher reduction of tumoral uptake intensity in CRT-IO compared to CRT, e.g. median decrease of SUVmax -70.0% vs. -24.8%, p = 0.009. In contrast, the spleen uptake increased in CRT-IO while it dropped in CRT (median + 12.5% vs. -4.4%, p = 0.029). Overall survival was significantly longer in CRT-IO compared to CRT with few events (progression/death) noted in CRT-IO. Findings suggestive of irAE were present on PET/CT more often in CRT-IO (12/16) compared to CRT (8/27 patients), p = 0.005.ConclusionDurvalumab maintenance treatment after CRT leads to diverging tumoral metabolic changes, but also increases splenic metabolism and leads to a higher proportion of findings suggestive of irAE compared to patients without durvalumab. Due to significantly prolonged survival with durvalumab, survival analysis will be substantiated in correlation to metabolic changes as soon as more clinical events are present