Temozolomide and Pazopanib Combined with FOLFOX Regressed a Primary Colorectal Cancer in a Patient-derived Orthotopic Xenograft Mouse Model.

PurposeThe goal of the present study was to determine the efficacy of temozolomide (TEM) and pazopanib (PAZ) combined with FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil) on a colorectal cancer patient-derived orthotopic xenograft (PDOX) mouse model.Materials and methodsA colorectal cancer tumor from a patient previously established in non-transgenic nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Then labeled tumors were orthotopically implanted into the cecum of nude mice. Mice were randomized into four groups: Group 1, untreated control; group 2, TEM + PAZ; group 3, FOLFOX; group 4, TEM + PAZ plus FOLFOX. Tumor width, length, and mouse body weight were measured weekly. The Fluor Vivo imaging System was used to image the GFP-lableled tumor stromal cells in vivo. H&E staining and immunohistochemical staining were used for histological analysis.ResultsAll three treatments inhibited tumor growth as compared to the untreated control group. The combination of TEM + PAZ + FOLFOX regressed tumor growth significantly more effectively than TEM + PAZ or FOLFOX. Only the combination of TEM + PAZ + FOLFOX group caused a decrease in body weight. PAZ suppressed lymph vessels density in the colorectal cancer PDOX mouse model suggesting inhibition of lymphangiogenesis.ConclusionOur results suggest that the combination of TEM + PAZ + FOLFOX has clinical potential for colorectal cancer patient

High-efficacy targeting of colon-cancer liver metastasis with Salmonella typhimurium A1-R via intra-portal-vein injection in orthotopic nude-mouse models.

Liver metastasis is the main cause of colon cancer-related death and is a recalcitrant disease. We report here the efficacy and safety of intra-portal-vein (iPV) targeting of Salmonella typhimurium A1-R on colon cancer liver metastasis in a nude-mouse orthotopic model. Nude mice with HT29 human colon cancer cells, expressing red fluorescent protein (RFP) (HT29-RFP), growing in the liver were administered S. typhimurium A1-R by either iPV (1×104 colony forming units (CFU)/100 μl) or, for comparison, intra-venous injection (iv; 5×107 CFU/100 μl). Similar amounts of bacteria were delivered to the liver with the two doses, indicating that iPV delivery is 5×103 times more efficient than iv delivery. Treatment efficacy was evaluated by tumor fluorescent area (mm2) and total fluorescence intensity. Tumor fluorescent area and fluorescence intensity highly correlated (p<0.0001). iPV treatment was more effective compared to both untreated control and iv treatment (p<0.01 and p<0.05, respectively with iPV treatment with S. typhimurium arresting metastatic growth). There were no significant differences in body weight between all groups. The results of this study suggest that S. typhimurium A1-R administered iPV has potential for peri-operative adjuvant treatment of colon cancer liver metastasis

MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX).

A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy

Rak jelita grubego z potencjalnie resekcyjnymi przerzutami do wątroby: optymalizacja leczenia

Colorectal cancer is a common malignancy and often presents with synchronous or metachronous distant spread. For patients with hepatic metastases, resection is the principal curative option. Liberalization of the indications for hepatic resection has introduced a number of challenges related to the size, distribution, and number of metastases as well as the condition of the future liver remnant. Advances in systemic therapy have solidified its role as both an important adjunct to surgery and also for many patients as a mechanism to facilitate resection. In patients whose disease is marginally resectable as a consequence of the distribution of hepatic lesions that precludes complete resection or out of concern for the future liver remnant, a number of strategies have been advocated, including prehepatectomy systemic therapy, staged surgical approaches, ablative technologies, and preoperative portal vein embolization. It is the purpose of this review to discuss ways in which to optimize the treatment of patients with potentially resectable disease, specifically those who are judged to have “borderline” resectable situations.Rak jelita grubego jest często występującym nowotworem, w którego przebiegu mogą występować synchronicznie lub metachronicznie przerzuty odległe. Podstawową metodę leczenia w przypadku przerzutów do wątroby stanowi chirurgiczna resekcja. Rozszerzenie wskazań do leczenia operacyjnego przerzutów do wątroby przyniosło szereg wyzwań dotyczących wielkości przerzutów, ich lokalizacji i liczby, a także wydolności pozostawionego miąższu narządu. Postęp w leczeniu systemowym ugruntował rolę tej metody zarówno w postępowaniu uzupełniającym po leczeniu chirurgicznym, jak i indukcyjnym ułatwiającym resekcję przerzutów. U chorych z przerzutami o wątpliwej resekcyjności z powodu rozmieszczenia zmian w wątrobie wykluczającego doszczętne wycięcie przy zachowaniu akceptowalnej funkcji pozostawionego miąższu, podejmuje się próby stosowania różnych metod, w tym neoadiuwantowego leczenia systemowego, kilkuetapowych resekcji, a także ablacji i przedoperacyjnej embolizacji żyły wrotnej. W niniejszym opracowaniu przedstawiono strategie optymalizacji leczenia chorych z potencjalnie lub w szczególności z granicznie resekcyjnymi zmianami przerzutowymi w wątrobie

Fluorescent humanized anti-CEA antibody specifically labels metastatic pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model.

Pancreatic cancer is a highly lethal disease in part due to incomplete tumor resection. Targeting by tumor-specific antibodies conjugated with a fluorescent label can result in selective labeling of cancer in vivo for surgical navigation. In the present study, we describe a patient-derived orthotopic xenograft model of pancreatic cancer that recapitulated the disease on a gross and microscopic level, along with physiologic clinical manifestations. We additionally show that the use of an anti-CEA antibody conjugated to the near-infrared (NIR) fluorescent dye, IRDye800CW, can selectively highlight the pancreatic cancer and its metastases in this model with a tumor-to-background ratio of 3.5 (SEM 0.9). The present results demonstrate the clinical potential of this labeling technique for fluorescence-guided surgery of pancreatic cancer

A Scoping Review to Assess Risk of Fracture Associated with Anxiolytic Medications

Introduction. Recent research has focused on evaluating the impact of pharmalogical sources on fracture risk. The purpose of this study was to review the literature on anxiolytic medications that may be associated with an increased risk of fracture. Methods. A search was conducted in MEDLINE and Embase databases to identify primary clinical studies of patients who sustained a fracture while prescribed anxiolytic medications and were published prior to July 2021. Anxiolytics defined by ATC Class N05B, beta blockers, and zolpidem were included. The search terms consisted of variations of the following: (“Psychotropic Drugs” or MeSH terms) AND (“Fracture” or MeSH terms).  Results. Of 3,213 studies, 13 (0.4%) met inclusion criteria and were evaluated. Fractures associated with benzodiazepine were reported in 12 of 13 studies; the highest risk occurred in patients aged 60 years and older, RR=2.29, 95% CI (1.48-4.40). The ATC Class N05B showed an increased fracture risk for those < 55 years of age that differed by sex: for men RR=5.42, 95% CI(4.86-6.05) and for women it was RR=3.33, 95% CI (3.03-3.66). Zolpidem also showed an increase fracture risk, RR=2.29, 95% CI(1.48-3.56), but only during the first 4 weeks of treatment. A relative risk of 0.77, 95% CI(.72-.83) was observed for beta blockers. Conclusions.  Fractures are a mainstay of traumatic injuries and are accompanied by economical, physiological, and psychological hardship. Fortunately, with proper assessment and prophylactic measures, fracture risk can be reduced dramatically. Anxiolytic medications have been described widely to increase fracture risk, such as benzodiazepines  in 60+ year old patients, and ATC Class N05B Anxiolytics increased fracture risk of RR=5.42, 95% CI (4.86-6.05) in 55+ year old men and  in 55+ year old women. Yet, some studies showed that at low doses, nitrazepam lowered fracture risk. Other anxiolytic medications, such as zolpidem and beta blockers, also showed a decrease in fracture risk; however, only one study has been published on each of these medications. Ultimately, this scoping review helped to illuminate the inconsistency of anxiolytic fracture risk assessment while simultaneously illustrating the necessary steps to guide future research

Adjuvant Radiotherapy in the Treatment of Invasive Intraductal Papillary Mucinous Neoplasm of the Pancreas: an Analysis of the Surveillance, Epidemiology, and End Results Registry

Background: Management and outcomes of patients with invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas are not well established. We investigated whether adjuvant radiotherapy (RT) improved cancer-specific survival (CSS) and overall survival (OS) among patients undergoing surgical resection for invasive IPMN. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was used in this retrospective cohort study. All adult patients with resection of invasive IPMN from 1988 to 2007 were included. CSS and OS were analyzed using Kaplan-Meier curves. Unadjusted and propensity-score-adjusted Cox proportional-hazards modeling were used for subgroup analyses. Results: 972 patients were included. Adjuvant RT was administered to 31.8% (n=309) of patients. There was no difference in overall median CSS or OS in patients who received adjuvant RT (5-year CSS: 26.5months; 5-year OS: 23.5months) versus those who did not (CSS: 28.5months, P=0.17; OS: 23.5months, P=0.23). Univariate predictors of survival were lymph node (LN) involvement, T4-classified tumors, and poorly differentiated tumor grade (all P<0.05). In the propensity-score-adjusted analysis, adjuvant RT was associated with improved 5-year CSS [hazard ratio (HR): 0.67, P=0.004] and 5-year OS (HR: 0.73, P=0.014) among all patients with LN involvement, though further analysis by T-classification demonstrated no survival differences among patients with T1/T2 disease; patients with T3/T4-classified tumors had improved CSS (HR: 0.71, P=0.022) but no difference in OS (HR: 0.76, P=0.06). Conclusion: On propensity-score-adjusted analysis, adjuvant RT was associated with improved survival in selected subsets of patients with invasive IPMN, particularly those with T3/T4 tumors and LN involvemen

Positive Surgical Margins in the 10 Most Common Solid Cancers.

A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes

Trends in Racial Disparities in Pancreatic Cancer Surgery

Objectives: We tested three hypotheses: (1) blacks with pancreatic cancer are recommended surgical resection less often than whites; (2) when recommended surgical resection, blacks refuse surgery more often than whites; and lastly, (3) racial differences in refusal of surgical resection have decreased over time. Methods: A retrospective cohort study was conducted on patients with potentially resectable, nonmetastatic pancreatic adenocarcinoma of the Surveillance, Epidemiology, and End Results registry from 1988 to 2009. Univariate and multivariable logistic regression analyses were performed to assess whether differences in the proportion of whites versus blacks refusing surgery among patients recommended for resection changed over time. Results: A total of 35,944 patients were included; most were white (87.6%). After adjusting for covariates including tumor stage, pancreatic cancer resection was less often recommended to and performed in blacks compared with whites (adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.82-0.95; aOR 0.83, 95% CI 0.76-0.91, respectively). Blacks also underwent surgical resection less often when surgery was recommended (aOR 0.73, 95% CI 0.64-0.85). Racial disparities in surgery recommendation and its performance did not decrease from 1988 to 2009. In multivariable adjusted analyses, blacks refused surgery more often when it was recommended (aOR in 1988 4.75, 95% CI 2.51-9.01); this disparity decreased over time (aOR 0.93 per year, 95% CI 0.89-0.97). Conclusions: Although racial disparities in pancreatic cancer surgery refusal have diminished over the past two decades, significant disparities in the recommendation and performance of surgery persist. It is likely that both provider- and patient-level factors have a substantial impact on surgery recommendation and its acceptance. The identification of such factors is critical to design a framework for eliminating disparities in cancer-directed surgery for pancreatic cance