Lesion Cavitation Research Articles

Influence of Tumor Cavitation on Assessing the Clinical Benefit of Anti-PD1 or PD-L1 Inhibitors in Advanced Lung Squamous Cell Carcinoma

PurposeA considerable portion of lung squamous cell cancer (LUSC) displays radiographic signs of cavitation. The cavitation of lesions is not accounted for in the prevailing Evaluation Criteria of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or iRECIST in lung cancer. We hypothesized that cavitation might alter response assessment in these patients. Patients and MethodsWe performed a retrospective radiologic review of 785 patients with stage IV LUSC treated with PD-1/PD-L1 antibody combined with platinum-based doublet chemotherapy. 131 patients exhibited cavitation lesions pre- or after-treatment. Response was assessed by RECIST v1.1 and a modified Evaluation Criteria in Solid Tumors (mRECIST) guidelines in which the longest diameter of any cavity was subtracted from the overall longest diameter of that lesion to measure target lesions. The response rate and PFS and OS between mRECIST and RECIST v1.1 were compared. Survival curves of different response categories in each criterion were prepared using the method of Kaplan-Meier and log-rank tests. Weighted κ statistics were used to assess interobserver reproducibilities and to compare response rates. The chi-square test confirmed the relationship between PD-L1 expression and post-treatment cavitation. ResultsNotable cavitation of pulmonary lesions was seen in 16.7% of 785 patients treated with immunotherapy combined with platinum-based chemotherapy. Using the mRECIST for response assessment resulted in a higher response rate than RECIST v1.1 (66% vs. 57%). mRECIST might better identify patients with PFS and OS benefits who have cavitation. The chi-square test revealed a marginally significant difference between PD-L1 expression and tumor cavitation. Interobserver reproducibility of mRECIST for tumor cavitation evaluation was acceptable (the weighted k coefficients for mRECIST criteria was 0.821). ConclusionCavitation lesions at baseline and after checkpoint treatment are common in LUSC patients. mRECIST records a significantly higher response rate than RECIST for these LUSC patients. Response assessment might be improved by incorporating cavitation into volume assessment for target lesions. These results may inform further modifications to RECIST V1.1 to better reflect efficacy with immunotherapy.

Modified response evaluation criteria in solid tumors: A better response evaluation criteria for patients with non-squamous non-small cell lung cancer after bevacizumab treatment.

Cavitation of lesions is common in non-squamous non-small cell lung cancer (non-squamous-NSCLC) patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRIs). However, traditional response evaluation criteria in solid tumors (RECIST) do not take cavitation into consideration and may no longer be accurate for potentially reflecting the real clinical efficacy of anti-vessel growth therapy. Here, we aimed to optimize the traditional RECIST version 1.1 by adding cavitation into the evaluation criteria. We performed a post-hoc radiologic review of 517 patients in a phase III clinical trial of bevacizumab biosimilar (SIBP04) combined with chemotherapy for the treatment of non-squamous NSCLC. Tumor responses were assessed by RECIST1.1 and mRECIST criteria (modified RECIST, a novel alternate method where the longest diameter of the cavity was subtracted from the overall longest diameter of that lesion to measure target lesions), respectively, and correlated with clinical outcomes. Cavitations of pulmonary lesions were seen in nine (2%) patients at baseline, and 97 (19%) during treatment. The use of mRECIST resulted in an alteration of the response category. For patients with post-therapy cavitation, the objective response rate was 56% using RECIST1.1 and 67% by mRECIST. In addition, the survival rates between partial response, stable disease, and progressive disease when the mRECIST was applied were significantly different (p<0.05), while RECIST1.1 failed to show survival differences (p=0.218). For patients with post-therapy cavitation, mRECIST exhibited higher predictability of survival than RECIST1.1. Response assessment might be improved by incorporating cavitation into assessment, potentially altering outcomes of key clinical efficacy parameters.

Association of total cerebral small vessel disease burden with the cavitation of recent small subcortical infarcts.

Recent small subcortical infarcts (RSSIs) could evolve into cavitation (lacunes) or non-cavitation (white matter hyperintensities or disappearance) during the chronic period, but the factors involved remain unclear. To explore the association between total cerebral small vessel disease (CSVD) burden and lesion cavitation. We retrospectively selected 202 inpatients with an isolated RSSI who underwent baseline and follow-up magnetic resonance imaging (median interval = 16.6 months; interquartile range [IQR]=8.2-30.1). Inpatients were divided into cavitation and non-cavitation groups depending on whether a fluid-filled cavity formed. Data including demographic, clinical, and radiological features were collected and analyzed. To determine total CSVD burden, four imaging markers, including lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, were rated and summed as a final practical score between 0 and 4. Overall, 137 (67.8%) patients progressed to cavitation and 65 (32.2%) to non-cavitation. Binary multivariable regression analysis showed that the baseline total CSVD burden (P = 0.005) and infarct diameter (P = 0.002) were independent risk factors for cavitation. A severe total burden (scores of 3-4) at baseline was independently related to cavitation (P = 0.001). Moreover, the total CSVD burden score varied from 2 (IQR=1-3) at baseline to 3 (IQR=2-4) at follow-up. The extent of the increase in total burden was correlated with cavitation (r = 0.201; P = 0.004). Total CSVD burden, both the baseline value and extent of increase, was positively associated with cavitation. RSSIs with severe total CSVD burden at baseline have a greater potential to become cavitated.

Predictors of Lesion Cavitation After Recent Small Subcortical Stroke

Morphologic evolution of recent small subcortical infarcts (RSSI) ranges from lesion disappearance to lacune formation and the reasons for this variability are still poorly understood. We hypothesized that diffusion tensor imaging (DTI) and blood-brain-barrier (BBB) abnormalities early on can predict tissue damage 1 year after an RSSI. We studied prospectively recruited patients with a symptomatic MRI-defined RSSI who underwent baseline and two pre-specified MRI examinations at 1–3-month and 1-year post-stroke. We defined the extent of long-term tissue destruction, termed cavitation index, as the ratio of the 1-year T1-weighted cavity volume to the baseline RSSI volume on FLAIR. We calculated fractional anisotropy and mean diffusivity (MD) of the RSSI and normal-appearing white matter, and BBB leakage in different tissues on dynamic contrast-enhanced MRI. Amongst 60 patients, at 1-year post-stroke, 44 patients showed some degree of RSSI cavitation on FLAIR, increasing to 50 on T2- and 56 on T1-weighted high-resolution scans, with a median cavitation index of 7% (range, 1–36%). Demographic, clinical, and cerebral small vessel disease features were not associated with the cavitation index. While lower baseline MD of the RSSI (rs = − 0.371; p = 0.004) and more contrast leakage into CSF (rs = 0.347; p = 0.007) were associated with the cavitation index in univariable analysis, only BBB leakage in CSF remained independently associated with cavitation (beta = 0.315, p = 0.046). Increased BBB leakage into CSF may indicate worse endothelial dysfunction and increased risk of tissue destruction post RSSI. Although cavitation was common, it only affected a small proportion of the original RSSI.

Detection of Approximal Caries Lesions in Adults: A Cross-sectional Study.

Detection and management of posterior approximal caries lesions are still problematic. Inspection of approximal surfaces is challenging, and bitewing radiographs are used when direct vision is not possible. Unfortunately, there is no definite radiographic appearance to identify lesion cavitation with absolute certainty. Many lesions detected radiographically within the outer half of dentin are not cavitated, often resulting in unnecessary restorative treatment. Our study compared radiographic depth of approximal caries lesions with presence of cavitation in adults using visual inspection following temporary tooth separation (TTS). We conducted this observational descriptive cross-sectional study at two dental schools in two cities in Chile. Clinicians were unaware of radiographic depths of lesions and examined 147 participants (57.3% female and 42.7% male) following TTS. Using the common classification system that consists of E0 (no lesion), E1 (lesion within the outer half of enamel), E2 (lesion within the inner half of enamel), D1 (lesion within the outer third of dentin), D2 (lesion within the middle third of dentin), and D3 (lesion within the inner third of dentin), a trained dentist evaluated all the processed films. Cavitation was detected in only three sites (0.22%) within the E0 category, seven sites (3.41%) in E1, five sites (14.8%) in E2, four sites (14.8%) in D1, six sites (50%) in D2, and eight sites (61.5%) in D3. Considering that restorative treatment should be indicated strictly for cavitated lesions, our findings support indication for restorative treatment for D3 lesions and the rationale for TTS for D1-D2 caries lesions to allow direct visual inspection to determine whether there is surface cavitation.

Assessment of cavitation in artificial approximal dental lesions with near-IR imaging.

Bitewing radiography is still considered state-of-the-art diagnostic technology for assessing cavitation within approximal carious dental lesions, even though radiographs cannot resolve cavitated surfaces but instead are used to measure lesion depth in order to predict cavitation. Clinicians need new technologies capable of determining whether approximal carious lesions have become cavitated because not all lesions progress to cavitation. Assessing lesion cavitation from near-infrared (NIR) imaging methods holds great potential due to the high transparency of enamel in the NIR region from λ=1300-1700-nm, which allows direct visualization and quantified measurements of enamel demineralization. The objective of this study was to measure the change in lesion appearance between non-cavitated and cavitated lesions in artificially generated lesions using NIR imaging modalities (two-dimensional) at λ =1300-nm and λ=1450-nm and cross-polarization optical coherence tomography (CP-OCT) (thee-dimensional) λ =1300-nm. Extracted human posterior teeth with sound proximal surfaces were chosen for this study and imaged before and after artificial lesions were made. A high speed dental hand piece was used to create artificial cavitated proximal lesions in sound samples and imaged. The cavitated artificial lesions were then filled with hydroxyapatite powder to simulate non-cavitated proximal lesions.

A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury.

Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.

Incidence and clinical implication of tumor cavitation in patients with advanced non-small cell lung cancer induced by Endostar, an angiogenesis inhibitor.

Antiangiogenesis plays a key role in the treatment of non-small lung cancer (NSCLC). We observed the cavitation of lesions in patients with stage IIIB/IV NSCLC treated with Endostar and vinorelbine-cisplatin (NP) chemotherapy, and evaluated the imaging characteristics and clinical outcome of patients who developed tumor cavitation. Our study included 105 untreated NSCLC patients who received Endostar in combination with NP chemotherapy at the Tianjin Lung Cancer Center. Chest computed tomography (CT) was performed to evaluate the efficacy every two cycles. The number of activated circulating endothelial cells (aCECs) was measured by flow cytometry. Rates of tumor cavitation were documented and their clinical CT imaging data were analyzed. Tumor cavitation occurred in 11 of the 105 (10.5%) patients treated with Endostar and NP. The response rates were 37.2% (35/94) in patients without cavitation, 27.3% (3/11) evaluated by Response Evaluation Criteria in Solid Tumors, and 100.0% (11/11) if evaluated by an alternate method in patients who developed cavitation. Three of the 11 cases with cavitation had a centrally located tumor. No patients had hemoptysis or any other severe side effects. Compared with patients not developing cavitation, cavity formation resulted in a longer median survival time (13.6 vs. 11.8 months, P = 0.011) and an increase in the number of aCECs (244.4/10(5) vs. 23.3/10(5), P = 0.000). Intratumoral cavitation induced by Endostar is common in NSCLC patients, and is not correlated with squamous histology, tumor location or pulmonary hemorrhage. Cavitation might have a significant effect on the number of aCECs and overall prognosis.

Two-Year Caries Clinical Study of the Efficacy of Novel Dentifrices Containing 1.5% Arginine, an Insoluble Calcium Compound and 1,450 ppm Fluoride

A 2-year double-blind randomized three-treatment controlled parallel-group clinical study compared the anti-caries efficacy of two dentifrices containing 1.5% arginine, an insoluble calcium compound (di-calcium phosphate or calcium carbonate) and 1,450 ppm fluoride (F), as sodium monofluorophosphate, to a control dentifrice containing 1,450 ppm F, as sodium fluoride, in a silica base. The 6,000 participants were from Bangkok, Thailand and aged 6-12 years initially. They were instructed to brush twice daily, in the morning and evening, with their randomly assigned dentifrice. Three trained and calibrated dentists examined the children at baseline and after 1 and 2 years using the National Institute of Dental Research Diagnostic Procedures and Criteria. The number of decayed, missing and filled teeth (DMFT) and surfaces (DMFS) for the three study groups were very similar at baseline, with no statistically significant differences among groups. After 1 year, there were no statistically significant differences in caries increments among the three groups. After 2 years, the two groups using the dentifrices containing 1.5% arginine, an insoluble calcium compound and 1,450 ppm F had statistically significantly (p < 0.02) lower DMFT increments (21.0 and 17.7% reductions, respectively) and DMFS increments (16.5 and 16.5%) compared to the control dentifrice. The differences between the two groups using the new dentifrices were not statistically significant. The results of this pivotal clinical study support the conclusion that dentifrices containing 1.5% arginine, an insoluble calcium compound and 1,450 ppm F provide significantly greater protection against caries lesion cavitation, in a low to moderate caries risk population, than dentifrices containing 1,450 ppm F alone.

A reassessment of a classic neuroprotective combination therapy for spinal cord injured rats: LPS/pregnenolone/indomethacin

These experiments were completed as part of an NIH-NINDS contract entitled “Facilities of Research Excellence-Spinal Cord Injury (FORE-SCI)—Replication”. Our goal was to replicate data from a paper published by Dr. Lloyd Guth and colleagues in which combined injections of lipopolysaccharide, indomethacin and pregnenolone (referred to herein as LIP therapy) conferred marked neuroprotection in a pre-clinical model of spinal cord injury (SCI). Specifically, post-injury injection of the combination LIP therapy was found to significantly reduce tissue damage at/nearby the site of injury and significantly improve recovery of locomotor function. In this report, we confirm the primary observations made by Guth et al., however, the effects of LIP treatment were modest. Specifically, LIP treatment improved myelin and axon sparing, axonal sprouting while reducing lesion cavitation. However, spontaneous recovery of locomotion, as assessed using historical (Tarlov scoring) and more current rating scales (i.e., BBB scoring), was not affected by LIP treatment. Instead, more refined parameters of functional recovery (paw placement accuracy during grid walk) revealed a significant effect of treatment. Possible explanations for the neuroprotective effects of LIP therapy are described along with reasons why the magnitude of neuroprotection may have differed between this study and that of Guth and colleagues.

Techniques for assessing tooth surfaces in school-based sealant programs

The authors reviewed the evidence supporting current guidelines for the detection of cavitated carious lesions. Currently, cavitation is the point at which sealants are not placed in school-based programs. The authors did not perform a formal systematic review. However, they examined existing systematic reviews of caries detection and diagnosis, including those presented at the 2001 National Institutes of Health Consensus Conference on Management of Caries, published evidence related to the International Caries Detection and Assessment System criteria and other peer-reviewed publications. Where the authors found ambiguity or uncertainty in the evidence, they consulted with fellow members of an expert work group. Visual examination is appropriate and adequate for caries assessment before placing sealants. The clinician should not use an explorer under force. Radiographs are not indicated solely for the placement of sealants, and the use of magnification and caries detection devices is not necessary to determine cavitation. This report focuses on tooth assessment, in particular the detection of carious lesion cavitation in school-based sealant programs. These recommendations must be balanced with the dentist's expertise, available treatment options, the patient's preferences and access to care.

Tumor Cavitation: Impact on Objective Response Evaluation in Trials of Angiogenesis Inhibitors in Non–Small-Cell Lung Cancer

We have observed cavitation of lesions in clinical trials of an angiogenesis inhibitor combined with chemotherapy for non-small-cell lung cancer (NSCLC). We hypothesized that cavitation might alter response assessment in such clinical trials. We performed a retrospective radiologic review of patients with NSCLC enrolled onto three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trials of platinum-based chemotherapy with or without a small-molecule angiogenesis inhibitor (vascular endothelial growth factor receptor inhibitor [VEGFRI]). Response was assessed both by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and a novel alternate method in which the longest diameter of any cavity was subtracted from the overall longest diameter of that lesion to measure target lesions. Rates of cavitation were documented. Marked cavitation of pulmonary lesions was seen in 24% of 33 patients treated with VEGFRI combined with platinum-based chemotherapy but in none of 18 patients treated with platinum-based chemotherapy alone. Use of the alternate method for response assessment resulted in an alteration of response assessment, time to best response, duration of response, and time of disease progression in a minority of patients compared with RECIST. Cavitation of target and nontarget lesions is common in NSCLC patients treated with VEGFRIs and platinum-based chemotherapy. Impact on response and time to event outcomes occurred but seems to be less common. Response assessment might be improved by incorporating cavitation into volume assessment for target lesions, potentially altering outcomes of key efficacy parameters in clinical trials. This should be prospectively assessed in clinical trials of angiogenesis inhibitors.

Fatores de risco para a recidiva da tuberculose

To identify risk factors for recurrence of tuberculosis. We studied a cohort of 610 patients with active pulmonary tuberculosis who were enrolled for treatment between 1989 and 1994 and cured using a three-drug treatment regimen of rifampin, isoniazid and pyrazinamide (RHZ). The risk factors studied were age, gender, race, duration of symptoms, lesion cavitation, extent of disease, diabetes mellitus, alcoholism, HIV infection, delayed negative sputum conversion, treatment compliance, and medication doses. In order to detect recurrence, the patients were monitored through the Rio Grande do Sul State Healt Department Information System for 7.7 +/- 2.0 years after cure. Data were analyzed using the Student's t-test, the chi-square test or Fisher's exact test, and Cox regression models. There were 26 cases of recurrence (4.3%), which corresponds to 0.55/100 patients-year. The recurrence rate was 5.95 and 0.48/100 patients-year in HIV-positive and HIV-negative patients, respectively (p < 0.0001). In the multivariate analysis, HIV infection [RR = 8.04 (95% CI: 2.35-27.50); p = 0.001] and noncompliance [RR = 6.43 (95% CI: 2.02-20.44); p = 0.002] proved to be independently associated with recurrence of tuberculosis. Recurrence of tuberculosis was more common in HIV-positive patients and in patients who did not comply with the self-administered treatment (RHZ regimen). Patients presenting at least one of these risk factors can benefit from the implementation of a post-treatment surveillance system for early detection of recurrence. An alternative to prevent noncompliance with tuberculosis treatment would be the use of supervised treatment.

Hematogenous macrophages express CD8 and distribute to regions of lesion cavitation after spinal cord injury

Historically, CD4 and CD8 antigens have been used to designate functionally distinct T-lymphocyte subsets. However, these antigens also have been described on macrophages in the normal and pathologic central nervous system (CNS). Signaling through CD4 or CD8 may impart unique functions in macrophage subsets that express these antigens. In the current study, the distribution and temporal patterns of expression of CD4 and CD8 were evaluated on various cell types within the traumatically injured spinal cord. The data reveal divergent patterns of CD4 and CD8 expression on unique macrophage populations. Specifically, we show sustained elevations of CD4 expression on microglia and macrophages throughout the lesion site and spared white matter. In contrast, CD8 is predominantly associated with hematogenous macrophages that are recruited from the blood during the first week postinjury. The distribution of CD8-positive cells is restricted to areas of necrotic cavitation. Differential signaling of resident and recruited macrophages through CD4 or CD8 may explain the apparent dichotomy of CNS-macrophage-mediated injury and repair.

RATIONALE AND TREATMENT APPROACH IN MINIMALLY INVASIVE DENTISTRY

Current methods of detecting caries, especially fissure caries, are inaccurate, causing some caries to go undetected until it has reached more advanced stages. Minimally invasive dentistry is a philosophy in which the goal of intervention to conserve healthy tooth structure. The authors review the rationale and role of air abrasion in successful practice in the 21st century that includes the philosophy of minimal intervention. This objective encompasses a range of clinical procedures that includes assessment of caries risk to reinforce patient self-help, early detection of the disease before lesion cavitation to fortify the oral environment, restoration of fissure caries with maximum retention of sound tooth structure and sealant placement in unaffected areas. This conservative approach minimizes the restoration/re-restoration cycle, thus benefiting the patient over a lifetime.

The detection of cavitation in carious approximal surfaces in vivo by tooth separation, impression and scanning electron microscopy

Bitewings are the most effective method of detecting approximal lesions but correlation with surface integrity is poor. In this study teeth were separated using orthodontic elastic separators allowing impressions, taken in a vinyl polysiloxane impression material, to be viewed by scanning electron microscopy. Case reports demonstrate the effectiveness of this technique in assessing in vivo, and in detail, the extent of cavitation of lesions usually assessed by their radiographic image alone.

Legionnaires’ Disease Following Cardiac Transplantation

The first two cases of Legionnaires' disease in heart transplant patients are reported. Of interest in these cases were culture of the organism from sputum, diagnosis by percutaneous lung aspiration, bronchopleural fistula formation in the first case, which was then successfully treated with multiple-tube thoracostomies, early cavitation of lesions in both cases after the start of antibiotic therapy, positive direct fluorescent antibody staining from transtracheal aspirate 42 days after starting appropriate antibiotic therapy in the first case, apparent superiority of intravenous erythromycin therapy in the first case, and survival of both patients. Our laboratory isolated and identified the organism in both cases.