PURPOSE: Performance of anatomical metrics of Response Evaluation Criteria in Solid Tumors (RECIST1.1) versus Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST1.0) for ...neoadjuvant chemoradiation (nCR) of pancreatic adenocarcinoma was evaluated based on the pathological treatment response (PTR) data. METHODS AND MATERIALS: The pre- and post-nCR CT and PET data for 14 patients with resectable or borderline resectable pancreatic head adenocarcinoma treated with nCR followed by surgery were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade 0, 1, 2 or 3 (G0, G1, G2 or G3) for complete, moderate, minimal and poor responses, respectively. Maximum standardized uptake value (SUVmax) was defined using body-weight (SUVbw). PERCIST1.0 was defined using lean-body mass normalized SUV (SUVlb or SUL). RECIST1.1 was defined by contouring the whole pancreas head on the CT image. Pre- and post-SUL-peak and SUVmax, RECIST1.1 and PETRECIST1.0 were correlated with PTR using Pearson’s correlation coefficient test. RESULTS: The average mean and SD in SUL-peak for all patients analyzed were lower in post-nCR (3.63±1.06) compared to those at pre-nCR (4.29±0.89). Using PERCIST1.0, 62% of patients showed stable metabolic disease (SMD), 23% partial metabolic response (PMR), and 15% progressive metabolic disease (PMD). Using RECIST1.1, 85% of patients showed stable disease (SD), 8% partial response (PR), and 7% progressive diseases (PD). A poor insignificant correlation was established between PRT and PERECIST1.0 (r=0.121), whereas no correlation was seen with RECIST1.1. CONCLUSIONS: PERCIST1.0 appears to increase the chance of detecting patients with progressive disease compared to the conventional anatomical-based assessment of RECIST1.1. The integration of these additional radiographic metrics in assessing treatment response to nCR for pancreatic adenocarcinoma may provide a promising strategy to better select patients that are most suitable for therapeutic intensification.
Many hepatologic pathologies mimic autoimmune hepatitis (AIH). Researchers developed the International Autoimmune Hepatitis Group (IAIHG) scoring system to compensate for the lack of specific ...diagnostic tests for AIH. The scoring system was not designed with pediatric patients in mind, so there are limits to its pediatric use. Additionally, there is limited information on the value of a liver biopsy in conjunction with its use.
In this retrospective study, we evaluated the effect of liver biopsy scores on the IAIHG scoring system in patients that were 0-18 years old with suspected AIH. We also analyzed demographic data and laboratory values associated with a final AIH diagnosis.
We found that interface hepatitis and predominant plasma cells found during the biopsy were significantly associated with a final AIH diagnosis. We also found that abnormal laboratory values were associated with an AIH diagnosis. We found that IAIHG scores calculated post-liver biopsy showed a greater area under the receiver operating characteristic curve (AUROC) of 0.95, which was compared to 0.88 for the scores calculated before a liver biopsy. Including biopsy metrics lowered the optimized cutoff score and test specificity.
Incorporating liver histopathological features improved the performance of the IAIHG scoring system. Further studies to identify other potential elements in liver histology may improve the performance metrics of the IAIHG test in the pediatric population.
A diet supplemented with freeze‐dried black raspberries (BRBs) has been demonstrated to modulate various biochemical and physiological pathways in both colorectal cancer (CRC) patients and ApcMin/+ ...mice, which are utilized to model CRC. These changes have been previously shown to exert beneficial chemopreventive effects against CRC, with outcomes such as reduction of adenoma development and inflammation. This study aimed to assess whether these effects manifest in a meaningful change in survival rates by comparing these rates between ApcMin/+ mice administered a 5% BRB‐supplemented diet or a control AIN‐76A diet. Percent survival over days elapsed was assessed in order to determine a median length of survival for each group of mice. Significant increases in survival rates with consumption of the BRB diet versus the control diet were demonstrated in both male and female mouse study groups. Male and female control groups were also compared in order to reduce confounding due to the sex of the mice; the difference in survival rates between male and female mice was not significant (p = 0.07, *p < 0.05), as male mice lived for a median of 143 days and females for 194 days. The results of this study suggest that administration of a BRB‐supplemented diet may potentially prolong the lifespan and increase survival rates of colorectal cancer patients.
An AIN 76‐A control diet supplemented with 5% BRBs significantly improved rates of survival and median lifespan in both male and female ApcMin/+ mice.
Background Treatment sequencing in older patients is difficult because of concomitant comorbidities and often decreasing performance status. The present study sought to examine the effect of ...neoadjuvant therapy and pancreatic surgery in older patients with resectable or borderline-resectable (BLR pancreatic cancer (PC). Methods Patients with resectable or BLR PC treated with neoadjuvant therapy were classified as older (≥75 years) or younger (<75 years). Results Neoadjuvant therapy was initiated in 246 patients; 210 (85%) younger than 75 years and 36 (15%) older. Older patients had a greater median Charlson comorbidity index (CCI): 6 vs 4 ( P < .01). Completion of all intended therapy (neoadjuvant therapy and surgery) occurred in 177 (72%) of the 246 patients; 153 (73%) of the 210 younger and 24 (67%) of the 36 older patients ( P = .43). Failure to complete all therapy was associated with BLR clinical stage (odds ratio OR 0.26, P = .001), increased posttreatment/preoperative serum levels of CA19–9 (OR 0.27, 95% confidence interval 0.14–0.53), and CCI ≥6 (OR 0.44, 95% confidence interval 0.22–0.86). Median overall survival for all study patients was 26.1 and 19.7 months ( P = .13) for younger and older patients, respectively. Of the 177 patients who completed all therapy, the difference in survival between younger and older patients was not statistically significant (36.5 months vs 27.2 months, P = .47). Conclusion Failure to complete neoadjuvant therapy and eventual pancreatic resection is associated with BLR stage, increased posttreatment/preoperative CA19–9, and CCI ≥6, but not older age. Older patients who completed neoadjuvant therapy and underwent resection experienced a survival benefit compared with those who did not complete all intended therapy. Balancing the toxicity of sequential therapies with their cumulative effect on tolerance and risk for pancreatic surgery will be the key to developing optimal treatment sequencing in older patients with PC.
The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically ...important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine CWHM‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.
In the present study, by targeting RGD‐binding integrins in a mouse model of NASH that closely resembles a human liver fibrosis phenotype in NASH, we identified a key role for these integrins in promoting NASH fibrosis and demonstrated the possibility of decreasing and even reversing already established fibrosis.
The gut microbiota—the community of microorganisms in the gut—has been implicated in many physical and mental disorders in addition to intestinal diseases. Diets are the most studied and promising ...factors for altering it. Indeed, certain dietary interventions that increase fiber intake rapidly change levels of certain nutrients that can modify the composition of the microbiota, promoting richness and diversity. Recent intriguing evidence from several human clinical trials suggested that the composition and diversity of patients’ gut microbiotas at baseline can influence their responses to cancer immunotherapy. If the factors that influence the gut microbiota were fully understood, it is conceivable that manipulating them could boost therapeutic responses in cancer patients. In this review, we investigate the possibility of using fruits, vegetables, or whole grains to enhance response to cancer therapies in humans, as current evidence suggests that these dietary components can manipulate and enhance diversity of the gut microbiota. Accordingly, dietary interventions with locally available fruits, vegetables, and whole grains might be an affordable and safe approach to enhancing the diversity of the gut microbiota before immunotherapy, in turn improving patients’ responses to their treatments.
Graphical Abstract
AbstractIlntroduction and aims. We aimed to investigate the clinical and pathological differences between low-AFP-secreting (AFP < 20 ng/mL) and high-AFP-secreting (AFP ≥ 20 ng/mL) hepatocellular ...carcinomas in patients who undergo liver transplant (LT). Material and methods. We evaluated 145 patients who underwent deceased donor LT for HCC from January 1, 2005 until August 1, 2015 at the Johns Hopkins Hospital. Results. Median pre-LT AFP in the entire cohort was 13 ng/mL (IQR 6-59). Using serum AFP cutoff of 20 ng/mL, 61 (42%) patients had high-AFP-secreting tumors and 84 (58%) had low-AFP-secreting tumors. Patients with high-AFP-secreting tumors had larger lesions (3 cm vs. 2.4 cm, p = 0.024), and were more likely to have microvascular-invasion (36.1% vs. 20.2%, p = 0.02) and poor-differentiation (18% vs. 4.8%, p = 0.01), and tumor recurrence following LT (28% vs. 6%, p < 0.001). The 1-year, 3-year, and 5-year recurrence-free survival for patients in the low-AFP-secreting group compared to the high-AFP-secreting group were 100%, 92%, 92% vs. 81.3%, 71.3%, 68.5% respectively (p = 0.0003). Conclusion. AFP is a suboptimal predictor of tumor recurrence following liver transplant in HCC patients. However, it can have some value in distinguishing more aggressive forms of HCC (high-AFP-secreting) that are associated with higher tumor recurrence. Novel tumor biomarkers are needed that can enhance predicting tumor recurrence following LT based on tumor biology.
Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American ...Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.
As novel therapeutic regimens continue to lead to increased survival of patients with lung cancer, it is imperative to remain mindful of the accompanying increase in the incidence of new primary ...malignancies. Although the most common secondary malignancies in patients with lung cancer have historically included colon, rectal, esophageal, and thyroid cancers, we report here two rare cases of new primary hepatocellular carcinomas in patients receiving immune checkpoint inhibitor therapy for NSCLC. In both cases, the diagnosis of hepatocellular carcinoma, rather than assuming a hepatic metastasis, was crucial for determining the appropriate approach for treatment. These cases thus underscore the importance of appropriate diagnostics to ensure that the proper therapeutics are chosen and present important considerations for the lung cancer community going forward.
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, with a steadily rising prevalence in Western and newly industrialized countries. UC patients have a cancer incidence as high as ...10% after 20 years of the disease. Although the importance of fruits and vegetables in defense against UC is beginning to be appreciated, the mechanisms remain largely unclear. In the current study, we reported that dietary black raspberries (BRBs) decreased colonic inflammation in the mucosa and submucosa of interleukin (IL)-10 knockout (KO) mice. We then used colon, spleen, and plasma from those mice to investigate whether BRBs exert their anti-inflammatory effects by correcting dysregulated toll-like receptor (TLR)-4 signaling to downregulate prostaglandin E2 (PGE2). Other studies reported that spleen is the reservoir of macrophages and depletion of macrophages in IL-10 KO mice prevents the development of colitis. Our results showed that BRBs decreased the percentages of macrophages in spleens of IL-10 KO mice. Moreover, mechanistically, the BRB diet corrected dysregulated TLR-4 signaling in cells from the colon and spleen, decreased PGE2 and prostaglandin I2, and increased 15-lipoxygenase and its product, 13-S-hydroxyoctadecadienoic acid, in plasma of IL-10 KO mice. Therefore, we have elucidated one of the anti-inflammatory mechanisms of BRBs, and have identified biomarkers that could be indicators of response in UC patients treated with them. Our findings with BRBs could well apply to many other commonly consumed fruits and vegetables.
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