Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Vascular Resections for Pancreatic Ductal Adenocarcinoma: Vascular Resections for PDAC.

BACKGROUND AND AIMS: It has become clear that vein resection and reconstruction for pancreatic ductal adenocarcinoma (PDAC) is the standard of care as supported by multiple guidelines. However, resection of large peri-pancreatic arteries remains debatable. MATERIALS AND METHODS: This review examines the current state of vascular resection with curative intent for PDAC in the last 5 years. Herein, we consider venous (superior mesenteric vein, portal vein), as well as arterial (superior mesenteric artery, celiac trunk, hepatic artery) resection or both with or without reconstruction. RESULTS: Improvement of multidrug chemotherapy has revolutionized care for PDAC that should shift traditional surgical thinking from an anatomical classification of resectability to a prognostic and biological classification. CONCLUSION: The present review gives an overview on the results of pancreatectomy associated with vascular resection, with consideration of new perspectives offered by the availability of better systemic therapies.

Thirty robotic adrenalectomies: a single institution's experience.

BACKGROUND: Robotic adrenalectomy is a minimally invasive alternative to traditional laparoscopic adrenalectomy. To date, only case reports and small series of robotic adrenalectomies have been reported. This study presents a single institution's series of 30 robotic adrenalectomies, and evaluates the procedure's safety, efficacy, and cost. METHODS: Thirty patients underwent robotic adrenalectomy at the Johns Hopkins Hospital between April 2001 and January 2004. Patient morbidity, hospital length of stay, operative time, and conversion rate to traditional laparoscopic or open surgery are presented. Improvement in operative time with surgeon experience is evaluated. Hospital charges are compared to charges for traditional laparoscopic and open adrenalectomies performed during the same time period. RESULTS: Median operative time was 185 min. Patient morbidity was 7%. There were no conversions to traditional laparoscopic or open surgery. The median hospital stay was 2 days. Operative time improved significantly by 3 min with each operation. Hospital charges for robotic adrenalectomy (12,977 dollars) were not significantly different than charges for traditional laparoscopic (11,599 dollars) or open adrenalectomy (14,600 dollars). CONCLUSIONS: Robotic adrenalectomy is a safe and effective alternative to traditional laparoscopic adrenalectomy.

Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors.

Chemically functionalized congeners of N6-phenyladenosine and 1,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglycerides, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosine binding to A1-adenosine receptors in rat cerebral cortex membranes. A xanthine-phosphatidylethanolamine conjugate bound with a Ki value of 19 nM. Various xanthine esters of low potency are potential prodrugs. Amides of an adenosine amine congener (ADAC) with 18-carbon fatty acids exhibited Ki values at A1-adenosine receptors of 70 pM, representing a 130-fold enhancement over the affinity of the corresponding acetyl amide. The very high affinity of adenosine-lipid conjugates may be due to stabilization of these adducts in the phospholipid microenvironment of the receptor protein.

Longitudinal study of in vitro CD4+ T helper cell function in recently transplanted renal allograft patients undergoing tapering of their immunosuppressive drugs.

Three distinct T helper activation pathways contribute to interleukin-2 production by human peripheral blood mononuclear cells following in vitro stimulation with HLA alloantigens in a mixed lymphocyte reaction. These pathways involve both CD4+ and CD8+ T helper cells, as well as self and allogeneic antigen-presenting cells. The pathways are differentially susceptible to cyclosporine in vitro, with the CD4+ T helper cell and selfAPC (CD4 approximately sAPC) pathway being the most sensitive. Furthermore, these pathways are differentially susceptible to immunosuppressive drugs in renal allograft patients, and by functional analysis of these pathways we have identified patients who are at increased risk for rejection of their kidney allografts. The present report provides a longitudinal study of the functional T helper cell status of recently transplanted renal allograft recipients undergoing tapering of their immunosuppressive drugs by testing the ability of recipient PBMC to generate IL-2 in response to pathway-specific stimuli. This study provides evidence that IL-2 generation by T helper pathways is dynamic, fluctuating independently of the commonly followed clinical parameters used to assess graft function and degree of immunosuppression. Significantly, the function of the CD4 approximately sAPC activation pathway correlates with risk of acute rejection. As such, we suggest that periodic assessment of pathway specific T helper function is a more sensitive index for the detection of subtherapeutic dosing of immunosuppressives--and, in particular, for assessing cyclosporine maintenance requirements. Monitoring of pathway specific activity with appropriate cyclosporine dosing adjustments might prevent the initiation of the rejection process and reduce a major source of late graft failure.

8-Substituted xanthines as antagonists at A1- and A2-adenosine receptors.

Two classes of 8-substituted analogs of theophylline (1,3-dialkylxanthines), having 8-cycloalkyl, 8-cycloalkenyl or 8-(para-substituted aryl) groups, were shown to be potent and, in some cases, receptor subtype selective antagonists at A1- and A2-adenosine receptors. New analogs based on a functionalized cogener approach and on classical medicinal chemical approaches were prepared. Affinity at A1-adenosine receptors was evaluated by inhibition of binding of [3H]N6-phenylisopropyladenosine to rat brain membranes. Activity at A2-adenosine receptors was measured by the reversal of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated production of cyclic AMP in membranes from rat pheochromocytoma PC12 cells. Cycloalkenyl analogs containing rigid olefinic bonds differed greatly in potency from the saturated analogs. The selectivity of phenylsulfonamide analogs depended on distal structural features. Novel xanthine analogs include diamino-, thiol-, aldehyde, and halogen-substituted derivatives, peptide conjugates of 8-[4-[2-aminoethylaminocarbonylmethyloxy]phenyl]1,3-dipropylxan thi ne (XAC), and a hydroxyethylamide analog of XAC.

Hypereosinophilic sclerosing cholangitis: findings using half-Fourier magnetic resonance imaging.

Hypereosinophilic sclerosing cholangitis is a rare disease caused by eosinophilic infiltration of the gallbladder and biliary tract seen in the idiopathic hypereosinophilic syndrome. We report a 42-year-old woman who presented with symptoms of cholecystitis and obstructive cholangitis. Imaging with magnetic resonance cholangiography using a half-Fourier spinecho sequence, we were able to visualize rapidly and non-invasively a severely abnormal gallbladder, evidence of liver parenchymal inflammation, and biliary duct dilatation.

Criteria of unresectability and the decision-making process.

Determination of the exact criteria for resectability in patients with cholangiocarcinoma and how they are most efficiently evaluated has many limitations. Among many factors taken into account in this decision-making process are: the condition of the patient, the biology of the disease, and the technical expertise of the surgeon and hospital. An attempt is made here to organize recommendations for the work-up of patients and the main criteria for resectability as best possible, keeping in mind that there will always be some limited room for exceptions, especially if the biology is favorable. Work-up and determination of resectability for patients with distal cholangiocarcinoma are more straightforward than at the other two sites of the disease (perihilar and peripheral). In general, these follow the same principles as those for other periampullary carcinomas (pancreas, ampullary, and duodenal). The work-up and determination of resectability for patients with peripheral cholangiocarcinoma can be relatively straightforward if the lesion is away from the hilus of the liver and does not involve a significant proportion of parenchyma, but can be problematic if it is more central or very large. Patients with perihilar cholangiocarcinomas are perhaps the most challenging, as factors such as patient condition, biology of the disease, local involvement of the major vessels and bile ducts at the hilum, and the future liver remnant all have a bearing in the decision-making process.

Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma.

BACKGROUND: One of the key issues in the treatment of adrenocortical carcinoma is the efficacy of repeat resection of local recurrence and metastatic disease in affected patients. Options in the treatment of locally recurrent or metastatic disease are limited because chemotherapy and radiotherapy generally do not provide any significant prolongation in survival in treated patients. METHODS: A series of 113 patients who presented to Memorial Sloan-Kettering Cancer Center for treatment of adrenocortical carcinoma are presented. RESULTS: The median overall survival for all 113 patients was 38 months (5-year survival, 37%). Patients presenting with early stage I or II disease (n = 57) had a median survival of 101 months (5-year survival, 60%), whereas those with late stage III or IV disease (n = 56) had a median survival of 15 months (5-year survival, 10%). Patients who had complete primary resection (n = 68) had a median survival of 74 months (5-year survival, 55%), whereas those with incomplete primary resection (n = 45) had a median survival of 12 months (5-year survival, 5%). Resection of locally recurrent or distant metastatic disease was performed in 47 of these patients. Patients who had a complete second resection had a median survival of 74 months (5-year survival, 57%), whereas those with incomplete second resection had a median survival of 16 months (5-year survival, 0%). CONCLUSIONS: Improved survival is seen in patients who present with early stage and have complete primary resection. Patients who undergo complete repeat resection of local recurrence or distant metastasis also have improved survival. Complete repeat resection was more readily accomplished in discrete distant metastatic lesions compared with bulky local recurrences.

Adrenocortical carcinoma.

Adrenocortical carcinoma is rare, tends to occur in the first decade as well as the fourth and fifth decades of life, and is slightly more common in women. The tumors are classified as functional or nonfunctional, depending on tumor production of corticosteroid, androgen, estrogen, or mineralocorticoid. Most patients present with large masses and with stage IV disease. Abdominal computerized tomography and magnetic resonance imaging are used in the evaluation of intra-abdominal disease. The most effective treatment for adrenocortical carcinoma is complete resection. Surgical resection remains the only potentially curative treatment for this disease. Early stage and curative resection are the two clinical factors that are of prognostic significance for long-term survival. Mitotane is the chemotherapeutic agent most often used to treat adrenocortical carcinoma. Its efficacy in prolonging survival is limited but may be enhanced by monitoring of serum levels and their maintenance at elevated values. Even for patients who undergo complete resection, recurrent and metastatic disease are extremely common. The only effective treatment for recurrent disease is reoperation.

Reductive-oxygenation mechanism of metabolism of carbon tetrachloride to phosgene by cytochrome P-450.

The mechanism of metabolism of carbon tetrachloride (CCl4) to phosgene (COCl2) in rat liver microsomes was investigated. When the oxygen dependency of the reaction was studied, it was found that the rate of the reaction increased as the oxygen concentration in the reaction atmosphere was decreased from 100% to 5%. Decreasing the oxygen concentration below 5% caused a decrease in the rate of the reaction. The reaction was not inhibited by superoxide dismutase or catalase nor was it supported by cumene hydroperoxide. A reconstituted form of cytochrome P-450 from phenobarbital-pretreated rats metabolized CCl4 to COCl2. These results are consistent with a mechanism we call reductive oxygenation. The first step of the reaction is the cytochrome P-450-dependent reductive dechlorination of CCl4 to trichloromethyl radical (CCl3.). This intermediate is trapped by oxygen to form trichloromethylperoxyl radical (CCl3OO.), which decomposes to COCl2 and possibly an electrophilic form of chlorine.

Immunochemical evidence of trifluoroacetylated cytochrome P-450 in the liver of halothane-treated rats.

Four hours after the administration of halothane to phenobarbital-pretreated rats, subcellular fractions of liver were isolated and the proteins in the fractions were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to nitrocellulose sheets, and immunochemically stained with anti-trifluoroacetylated antibodies. The microsomal fraction contained the highest level of trifluoroacetylated adducts. Its major trifluoroacetylated component was immunochemically identified as a phenobarbital-inducible form of cytochrome P-450 (54 kDa), whereas the other observed trifluoroacetylated protein fraction (59 kDa) was not identified. The plasma membrane fraction also contained a 54-kDa trifluoroacetylated adduct, which was immunochemically related to the 54-kDa cytochrome P-450. Microsomes from untreated rats that were administered halothane contained only the 59-kDa trifluoroacetylated protein fraction. The specificity of the immunochemical staining for the bound oxidative metabolite of halothane was confirmed by the finding that rats treated with deuterated halothane had considerably less stained liver proteins than did those treated with halothane. These results suggest that the CF3COX oxidative metabolite of halothane is so reactive that it binds predominantly to the cytochrome P-450 that produced it.

Comparison of the effects of methyl-N-butyl ketone and phenobarbital on rat liver cytochromes P-450 and the metabolism of chloroform to phosgene.

It was previously shown that treatment of rats with methyl-n-butyl ketone (MBK) produced an increase in the total level of liver microsomal cytochromes P-450 and an increase in the rate of metabolism of chloroform (CHCl3) to phosgene (COCl2). In the present study it was found that MBK also produced qualitative changes in the composition of microsomal cytochromes P-450 in rat liver as determined by anion-exchange chromatography. The degree of the chromatographic changes paralleled the effect of MBK on the rate of metabolism of CHCl3 to COCl2 and CHCl3-induced hepatotoxicity, suggesting that MBK potentiated the hepatotoxicity of CHCl3, at least in part, by inducing the formation of cytochromes P-450 that metabolized CHCl3 to the hepatotoxin COCl2. In this regard, reconstitution studies with a form of cytochrome P-450 isolated from rat liver microsomes from rats treated with MBK or phenobarbital (Pb) showed unequivocally that cytochrome P-450 can metabolize CHCl3 to COCl2. Although analysis of rat liver microsomes by SDS-polyacrylamide electrophoresis and anion-exchange chromatography suggested that MBK and Pb had similar effects on the composition of cytochromes P-450, metabolism studies indicated that differences did exist.

Limiting dilution analysis of interleukin-2-producing T cells responsive to recall and alloantigens in human immunodeficiency virus-infected and uninfected individuals.

Peripheral blood mononuclear cells (PBMC) from individuals who were seropositive for the human immunodeficiency virus type 1 (HIV), and most without symptoms (HIV+) were compared with PBMC from healthy HIV-seronegative (HIV-) individuals for in vitro generated T helper cell (Th) responses. Th function in bulk culture and limiting dilution analysis was assessed by IL-2 production following stimulation with influenza A virus (FLU) or irradiated allogeneic PBMC (ALLO). We observed that the frequencies of FLU- and ALLO-stimulated Th cells were not appreciably different in the PBMC of HIV- individuals, and that they were also not different in the PBMC of those HIV+ individuals who responded to both FLU and ALLO in bulk culture. However, there was a severe drop in the Th frequency to FLU in HIV+ individuals who were unresponsive to FLU but responsive to ALLO by bulk culture. The PBMC of HIV+ individuals who were unresponsive by bulk culture to both FLU and ALLO exhibited a drastic reduction in the Th frequencies for both stimuli. These results demonstrate a concordance between Th functional analysis performed by limiting dilution and bulk culture. The results also indicate that the early selective loss in Th function to recall antigens is not likely to be due simply to a difference in frequencies of FLU- and ALLO-stimulated Th cells present prior to the onset of Th dysfunction.

Unexpectedly low immunocompetence in transplant patients on ketoconazole.

The P450 inhibitor ketoconazole may be used to decrease the dose, and therefore cost, of cyclosporine (CYA) by greatly decreasing the dose necessary to obtain therapeutic levels. However, the degree of immunosuppression produced using this drug regimen is not certain. We studied the immunocompetence of patients that had been started on ketoconazole to reduce the dose of CYA compared with patients treated conventionally. 95 assays were done in 64 patients including 6 assays in patients receiving low dose CYA plus ketoconazole. Immunocompetence was tested by measuring the mixed lymphocyte response using stimulators either non-depleted (ND) or depleted (D) of antigen presenting cells, based on the finding that CYA inhibits the response against D at a lower dose than against ND. Responses to ND/D ranged from +/+ through +/- to -/-. Normal individuals were always +/+. In conventionally treated patients with CYA the incidence of immunocompetence < or = +/- was 48%, whereas all patients on CYA + ketoconazole had an immunocompetence score < or = +/- (p = 0.03, chi 2). This degree of immunosuppression contrasted strikingly with the chemical levels, which for those on ketoconazole were in the low acceptable area (182.3 +/- 77.1 ng/ml range from 67 to 230 ng/ml). Therefore, patients using low-dose CYA plus ketoconazole to inhibit metabolism were more immunosuppressed than those receiving conventional CYA treatment, in spite of comparable CYA blood levels. If confirmed, this unexpectedly depressed immunocompetence in these patients would warrant caution in general regarding interpretation of trough blood levels in patients receiving CYA that are also being treated with agents that alter P450 activity.