Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC.

INTRODUCTION: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. METHODS: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. RESULTS: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively. CONCLUSIONS: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.

What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?

Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer.

Targeted therapies have revolutionized the treatment for many patients with non-small cell lung cancer (NSCLC). Multiple new oral targeted therapies have been approved in the last decade; however, their overall efficacy may be reduced by poor adherence, treatment interruptions, or dose reductions due to adverse events. Most institutions lack standard monitoring protocols for toxicities from these targeted agents. This review describes important adverse events observed in clinical trials and reported by the U.S. Food and Drug Administration for both currently approved and upcoming promising therapies in the treatment of NSCLC. These agents cause a range of toxicities, including dermatologic, gastroenteric, pulmonary, and cardiac toxicities. This review proposes protocols for routine monitoring of these adverse events, both prior to initiation of therapy and while on treatment.

The Development of STING Agonists and Emerging Results as a Cancer Immunotherapy.

PURPOSE OF REVIEW: New therapies are needed to potentiate the effects of current immunotherapies and overcome resistance. The stimulator of interferon genes genes (STING) pathway is an innate immune activating cascade that may enhance current cancer immunotherapies. RECENT FINDINGS: Preclinical data has shown that the addition of a STING agonist enhances the effect of current treatments such as immune checkpoint inhibitor antibodies and radiation therapy. Early phase trials have demonstrated modest efficacy of STING agonists and revealed new mechanistic and technical challenges. STING agonists are a new class of agents that activate the immune response to improve tumor control. A wide range of preclinical experiments, translational data, and ongoing clinical trials support the therapeutic use of STING agonists in patients. Trials to determine optimal drug combinations and novel delivery mechanisms are continuing in development.

Clinical standardized fMRI reveals altered language lateralization in patients with brain tumor.

BACKGROUND AND PURPOSE: Brain tumors affecting language-relevant areas may influence language lateralization. The purpose of this study was to systematically investigate language lateralization in brain tumor patients using clinical language fMRI, comparing the results with a group of healthy volunteers. MATERIALS AND METHODS: Fifty-seven strictly right-handed patients with left-hemispheric-space intracranial masses (mainly neoplastic) affecting either the Broca area (n = 19) or Wernicke area (n = 38) were prospectively enrolled in this study. Fourteen healthy volunteers served as a control group. Standardized clinical language fMRI, using visually triggered sentence- and word-generation paradigms, was performed on a 1.5T MR scanner. Semiautomated analyses of all functional data were conducted on an individual basis using BrainVoyager. A regional lateralization index was calculated for Broca and Wernicke areas separately versus their corresponding right-hemisphere homologs. RESULTS: In masses affecting the Broca area, a significant decrease in the lateralization index was found when performing word generation (P = .0017), whereas when applying sentence generation, the decrease did not reach statistical significance (P = .851). Masses affecting the Wernicke area induced a significant decrease of the lateralization index when performing sentence generation (P = .0007), whereas when applying word generation, the decrease was not statistically significant (P = .310). CONCLUSIONS: Clinical language fMRI was feasible for patients with brain tumors and provided relevant presurgical information by localizing essential language areas and determining language dominance. A significant effect of the brain masses on language lateralization was observed, with a shift toward the contralesional, nondominant hemisphere. This may reflect compensatory mechanisms of the brain to maintain communicative abilities.

Gadofosveset enhanced MR phlebography for detecting pelvic and deep vein leg thrombosis.

BACKGROUND: Deep venous thrombosis is mainly diagnosed by ultrasound today. In some instances diagnosis is challenging and magnetic resonance angiography could be an attractive alternative. Gadofosveset is a blood pool contrast agent with some favourable properties for this purpose. PATIENTS AND METHODS: We investigated eight patients with proven deep venous thrombosis by Gadofosveset enhanced MR phlebography. We performed a 3D gradient-echo sequence with an overall measurement time of 9 minutes and 6 seconds. One minute after injection of Gadofosveset in a concentration of 0.12 ml/kg body weight images were acquired. Thrombi were visualised by their lack of luminal contrast filling. RESULTS: Thrombi were visualised in all patients. In one patient with extended thrombosis a previously undiagnosed ovarian adenocarcinoma was detected additionally. CONCLUSIONS: Deep venous thromboses in lower extremities can be visualised reliably by performing MR phlebography with blood pool contrast agent Gadofosveset. Visualisation of the complete venous system is feasible. This investigation method may be performed in patients difficult to investigate with ultrasound or may be used for planning interventional procedures.

Bond strength of various fluoride-releasing orthodontic bonding systems. Experimental study.

The aim of the study was to compare the shear bond strength of a fluoride-releasing composite resin adhesive (Light Bond, Reliance) and a light-cured resin-reinforced glass ionomer cement (Fuji Ortho LC, GC America) bonded to extracted teeth under different enamel surface conditions. Forty human premolars were divided at random into 4 groups of 10 specimens. Stainless steel brackets were attached to the enamel surface by 1 of the 4 protocols: 1. Fuji Ortho LC, moist non-etched enamel; 2. Fuji Ortho LC, moist etched (37% H3PO4); 3. Light Bond, dry etched (37% H3PO4); 4. Light Bond, dry etched (Etch & Prime 3.0, Degussa). The teeth were stored in deionized water at 37 degrees C for 48 hours. Shear bond strengths was determined at a crosshead speed of 1 mm/min. The residual adhesive on the enamel surface was evaluated with the modified Adhesive Remnant Index (ARI). Analysis of variance (ANOVA) and Duncan's test were used to compare the 4 groups. Significance was predetermined at p = 0.05. Significant inter-group differences were found (p < 0.0001). The mean SBS (and SD), in MPa were: Group 1: 15.9 (4.7); Group 2: 20.3 (2.5); Group 3: 16.7 (2.6); Group 4: 11.7 (2.5). Glass ionomer cement without etching and composite with Etch & Prime showed adhesive failures at the enamel and good enamel integrity after debonding. The other specimens showed mixed or adhesive fractures at the bracket failure sites. Glass ionomer used on wet tooth surfaces without etching shows a clinically acceptable bond strength with clean separation from the enamel after debonding.

[Motor blockade by retrobulbar anesthesia. Phenomenology and mechanism of action]. / Motorische Blockade durch Retrobulbäranästhesie. Phänomenologie und Mechanismen.

UNLABELLED: The aim of this study was to analyze quantitatively the phenomenology and mechanisms of motor blockade induced by retrobulbar anesthesia (RETRO). PATIENTS AND METHODS: Prior to cataract surgery, 34 patients received RETRO using the intraconal technique of Atkinson. Four milliliters of mepivacaine 2% (Scandicain), prilocaine 2% (Xylonest) or lidocaine 2% (Xylocain) were injected in randomized order. Prior to injection, as well as 5, 30, 90, 120, 180, 300 and 420 min after injection, the following variables were determined: deviation of the eye from the primary position (Krimsky test), horizontal and vertical ocular motility (Kestenbaum limbustest), and rotatory ocular motility (presence of in- or excycloductions). RESULTS: The directions in which the eye deviated after RETRO were abduction and depression. The maximum deviations amounted to 7-8 degrees abduction and 3-4.5 degrees depression and were observed 30 min after injection. Horizontal and vertical ocular motility was nearly completely and symmetrically reduced 30 min after RETRO. There were no significant differences between the three local anesthetics used. DISCUSSION: The present findings may be interpreted as temporary palsy of N.III and N.VI during RETRO (symmetrical blockade of horizontal and vertical recti eye muscles) with unaffected function of N.IV and superior oblique muscle (maintained incycloduction ability; hypotropia and exotropia). An additional possible mechanism to account for the observed downward deviation is that the eye assumes its physiological divergent resting position during RETRO.

Corneal lipidosis in rats treated with amphiphilic cationic drugs.

The purpose of this study was to investigate whether generalized lipidosis experimentally induced by cationic amphiphilic drugs in rats is regularly associated with lipidotic alterations in the cornea. After chronic oral treatment with chlorphentermine, iprindole, or tamoxifen all animals showed clear lipidosis-like alterations in corneal cells. After chronic oral treatment with chloroquine and quinacrine the results were variable and unpredictable; however, consistent lipidosis-like alterations were found when chloroquine was applied locally onto the cornea. The present results show that basically the cornea of rats is involved in drug-induced lipidosis. For toxicological studies it must be kept in mind, however, that the reactions of rat cornea may be unreliable and less marked than in the cornea of human beings.