Is intra-arterial hepatic chemotherapy painful?

BACKGROUND: Liver metastases are mainly supplied by the hepatic artery, allowing the administration of intra-arterial hepatic chemotherapy (IAHC) while preserving normal parenchyma. The progression-free survival and response rate are prolonged by IAHC which can improve the rate of secondary resectability. Severe abdominal pain requiring high-dose opioids can appear during HIAC administration. This pain is related to extrahepatic infusion and gastroduodenal ulceration. However, intense abdominal pain was observed under oxaliplatin IAHC specifically without any extrahepatic infusion. METHOD: We retrospectively reviewed the charts of 68 patients who received IAHC in our center between 2011 and 2015. Patient's demographics and disease characteristics were collected. Other variables such as the type, duration, and dosage of the chemotherapy administered, as well as the usage of painkillers before, during, or after intra-arterial administration, were also registered. RESULTS: The mean age of the patients was 59 years. 61.7% were male (n = 42). The mean dose of oxaliplatin administered was 162 mg per cure over 6.7-h course. Fifty percent were diagnosed with a left colon cancer, and 85.2% had synchronous liver metastasis. While 47% of patients received IAHC as a third-line therapy, the main chemotherapeutic drug was oxaliplatin (85.2% of cases; n = 58), then OPTILIV protocol (5FU, irinotecan, oxaliplatin) (13.3%; n = 9), and mitomycin C (1.5%; n = 1). A dose reduction of 23.6% had been noted in 58.8% (n = 40) cases due to adverse effects. Among patients who received opioids during IAHC (n = 40), 20% required opioids in intercure. Before, during, and after IAHC administration, patients complained of abdominal pain in 8.8%, 58.8%, and 19.1%, and opioids were used in 10.2%, 57.3%, and 19.1%, respectively. The main onset of pain occurs during the third cycle of chemotherapy. Among our patients, 11.7% and 22% had ulcer and extrahepatic perfusion, respectively, while 7.3% of them were asymptomatic. The mean occurrence of these signs was during the fourth cycle of IAHC. 33.8% and 52.9% of patients had abdominal pain while an extended and short infusion time, respectively. CONCLUSION: Lengthening of the infusion time did not prevent the occurrence of abdominal pain significantly but was nonetheless decreased compared with patients undergoing short infusion durations. Pain was more common in patients who did not have a dose reduction and who presented with ulcer and extrahepatic perfusion. Abdominal pain occurred on average one cycle before ulcer or extrahepatic perfusion diagnosis. In current practice, pain should be an alarming indicator in patients receiving IAHC, as it may be associated with ulcer or extrahepatic perfusion and thus requiring opioids.

Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis.

PURPOSE: To analyze the impact of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) performed 1 year after resection of the primary tumor in asymptomatic patients at high risk of developing peritoneal carcinomatosis (PC). PATIENTS AND METHODS: From 1999 to 2009, 41 patients without any sign of recurrence on imaging studies underwent second-look surgery aimed at treating limited PC earlier and more easily. They were selected based on 3 primary tumor-associated criteria: resected minimal synchronous macroscopic PC (n = 25), synchronous ovarian metastases (n = 8), and perforation (n = 8). RESULTS: PC was found and treated with complete surgery plus HIPEC in 23 of the 41 (56%) patients. The other patients underwent complete abdominal exploration plus systematic HIPEC. Median follow-up was 30 (9-109) months. One patient died postoperatively at day 69. Grade 3-4 morbidity was low (9.7%). The 5-year overall survival rate was 90% and the 5-year disease-free survival rate was 44%. Peritoneal recurrences occurred in 7 patients (17%), 6 of whom had macroscopic PC discovered during the second-look (26%), and one patient had no macroscopic PC (6%). In the univariate analysis, the presence of PC at second-look surgery was a significant risk factor for recurrence (P = 0.006). CONCLUSION: Selection criteria for high-risk patients appear to be accurate. In these patients, the second-look strategy treated peritoneal carcinomatosis preventively or at an early stage, yielding promising results. This study has allowed us to design a multicentric randomized trial (comparing the second-look + HIPEC approach versus standard follow-up alone), which is beginning.

Endoscopic ultrasonography is an independent predictive factor of prognosis in locally advanced esophageal cancer. Results from the randomized FFCD 9102 study from the Fédération Francophone de Cancérologie Digestive.

BACKGROUND: No multivariate study has assessed the independent prognostic role of endoscopic ultrasonography (EUS) in esophageal cancer, even when considering computed tomography (CT). OBJECTIVE: To evaluate the prognostic value of EUS in esophageal cancer before exclusive or preoperative radiochemotherapy. METHODS: From 1993 to 1999, the FFCD 9102 study enrolled 444 patients who had cancer of the thoracic esophagus, stages T3-4, N0-1 and M0 on CT. The patients received two sessions of chemotherapy in addition to radiotherapy. The 259 patients with objective response and no contraindications for further treatment were randomized to undergo surgery or to continue with radiochemotherapy. EUS was performed in 174 patients enrolled in the trial (mean age: 59 years). Tumor characteristics and lymph node status were prospectively recorded. A Cox statistical model was used to identify any predictive prognostic factors among the clinical, EUS and CT data. RESULTS: In the multivariate analysis, three factors were associated with a poor prognosis: inability to ingest solid food (OR: 1.98; P=0.0008); more than three neoplastic subdiaphragmatic lymph nodes (LN) on EUS (OR: 2.41; P<0.0045) and age>65 (OR: 1.53; P<0.056). Their prognostic value persisted after adjustment for type of treatment given. Two- and five- year survival rates were 21.5 and 10.5%, respectively, in the presence of three neoplastic subdiaphragmatic LN, and 43 and 30%, respectively, in all other cases. CONCLUSION: Degree of dysphagia, age and presence of neoplastic subdiaphragmatic LN on EUS were independently predictive of the prognosis for locally advanced esophageal cancer. EUS results should be taken into account in future trials.

The safety of endoscopic sphincterotomy in patients receiving antiplatelet agents: a case-control study.

OBJECTIVE: To determine whether antiplatelet agents are associated with endoscopic sphincterotomy-related haemorrhage as few well-controlled data exist on this controversial issue. METHODS: A case-control study in a tertiary care setting included cases with bleeding following endoscopic sphincterotomy, matched with 2-3 controls selected according to age +/- 15 years, sex, and procedural date+/- 2 years. Cases and controls were compared for possible risk factors of postendoscopic sphincterotomy bleeding (presence of a coagulopathy and cholangitis). The main outcome measurement was the association between the use of antiplatelet medications and postendoscopic sphincterotomy bleeding after adjustment for possible confounding. RESULTS: The 40 cases [mean age 68 +/- 17 (s.d.) years, 50% female] and 86 controls [68 +/- 16 years, 50% female] were comparable except for differences noted in International Normalized Ratio (INR) (>2 in four cases vs. two controls), and pre-endoscopic sphincterotomy cholangitis (45% vs. 20%). Amongst cases, 13% were on aspirin and 3% on clopidogrel; 17% of controls took aspirin, and 4% a non-steroidal anti-inflammatory drug. 53% of cases bled immediately; the remainder haemorrhaged at 2 +/- 3 days. After adjustment for an elevated INR and cholangitis, exposure to antiplatelet agents was not significantly associated with procedure-related bleeding (odds ratio = 0.41, 95% CI [ 0.13; 1.31]). CONCLUSION: This case-control study provides controlled data suggesting that antiplatelet agents do not significantly increase the risk of clinically-important bleeding related to endoscopic sphincterotomy. The low prevalences of non-steroidal anti-inflammatory drugs and clopidogrel use limit any definite conclusion on their elective use before endoscopic sphincterotomy.

[MR-endoscopic US correlation for loco-regional staging of rectal carcinoma]. / Corrélation IRM-échoendoscopie dans le bilan d'extension locorégional initial du cancer du rectum.

INTRODUCTION: To correlate findings at high-resolution MR and endoscopic US (EUS) for preoperative loco-regional staging of rectal carcinoma. PATIENTS AND METHODS: Fifty-two patients with rectal carcinoma underwent high-resolution MR imaging. Only 43 of these patients underwent EUS due to technical limitations and stenosing carcinomas. Morphological imaging features and TNM staging were evaluated for both imaging modalities. The degree of correlation and accuracy were calculated for both. RESULTS: The correlation between MR and EUS was good for tumor length and thickness (r=0.7 and 0.61) for for nodal (N) staging (k=0.53). Correlation was good for T1 and T2 stages (k=0.51) and T3 stage (k=0.43) and very poor for stage 4 (k= -0.09), because no T4 lesion was detected at EUS. 81.8% of patients where T stage was over-estimated on MRI and 100% of patients where T stage was over-estimated on EUS had received preoperative radiation therapy. Therefore, results should be interpreted with caution. The predictive evaluation of tumor resectability (absence of perirectal fascia invasion) with a circumferential margin on MR> or =5 mm was 93%. CONCLUSION: Correlation between MR and EUS was moderate for T staging, because of limitations of EUS for large tumors. Results confirm that high-resolution MRI is useful for loco-regional staging of rectal carcinoma, especially for large tumors. EUS should be limited to the valuation of superficial tumors of the rectum.

Receptor for plasmin on human carcinoma cells.

We have shown that cells from human tumor cell line SW 1116 have receptors for plasmin and plasminogen. These receptors are the same for the proenzyme and the enzyme, but they have a much higher affinity for plasmin (Kd = 6 X 10(-8) M) than for plasminogen (Kd = 5 X 10(-6) M). Plasminogen binding was strongly increased by preincubation of the tumor cells with urokinase and was inhibited by anti-urokinase serum. Because free plasmin is rapidly neutralized in vivo, it is likely that, under physiological conditions, plasminogen is bound by tumor cells and partially transformed into plasmin by urokinase already present at the surface of these cells. Bound plasmin retains its enzymatic activity, which demonstrates that its binding does not involve the enzyme's active site.

Determination of levels of carcinoembryonic antigen and nonspecific cross-reacting antigen in the sera of neonatal infants: brief communication.

Seventy-eight sera from neonatal infants, born at full term or prematurely, were studied for their carcinoembryonic antigen (CEA) and nonspecific cross-reacting antigen (NCA) concentrations, which were compared to the normal adult concentrations. The levels of CEA in the sera were significantly higher in newborns than in adults: 9.05 ng CEA/ml in newborns as compared to 2.5 ng CEA/ml in adults (P=0.001). The levels of NCA in the sera were also higher in newborns: 164 ng NCA/ml in newborns as compared to 130 ng NCA/ml in adults. This difference in NCA levels was not significant, although 80% of the newborns had increased values (greater than 130 ng/ml). Whether the infant was born at full term or prematurely and whether the infant was a boy or girl had no statistically significant influence on the concentration of the CEA and the NCA in the infant.

Immunohistology of the antigenic pattern of a continuous cell line from a human colon tumor.

The antigenic surface pattern of a continuous cell line (HT29) derived from a human primary carcinoma of the colon was studied by the immunofluorescence technique. Monovalent and polyvalent immune sera were used. The cells of this long-term culture kept the ability to synthesize the three principal colon tumor antigens: carcinoembryonic and nonspecific cross-reacting antigens, and the membrane-associated tissular autoantigen. On the HT29 cells, which still carry the original blood group of the tumor donor, no receptors for human Ig's were detected.

Demonstration of nonspecific suppressor cells in the peripheral lymphocytes of cancer patients.

The response to phytohemagglutinin of peripheral blood lymphocytes was studied in 169 cancer patients. There was a significant decrease compared with control groups (normal persons and those with benign disease). By selecting cancer leukocyte samples with reactivity to phytohemagglutinin that was increased by carrageenan, a macrophage-toxic agent, and by mixing them with normal lymphocytes, we have demonstrated that the depressed phytohemagglutinin of six cancer patients' lymphoyctes was due to the presence of suppressor cells that possibly were monocytes.

Fetal gastric and small intestine pattern of intestinal mucus antigens in human gastric carcinomas.

The present immunohistological study was performed to investigate the expression of intestinal mucus-associated antigens in the different histological types of gastric carcinoma according to the classification of Laurèn and the WHO classification. We used the following antigenic markers: M3, present in all the goblet cells of the whole small and large intestine; M3SI, expressed in all the goblet cells of the small intestine, but only in some of them of the large intestine; M3D, mainly produced in the upper small intestine; and M3C, specific for colonic mucus cells. All these antigens were found to be similarly expressed in both Laurèn's intestinal and diffuse types. Nevertheless, M3 and M3C appeared to be more largely produced in carcinomas showing well-differentiated cells (tubulopapillary, mucinous, and signet ring cells according to the WHO classification). Our results evidenced the occurrence of two main fetal antigenic patterns in gastric carcinomas, one of the gastric type (M3SI produced to a larger extent than M3 and M3C) and the other one of the small intestinal type (M3 and M3SI more largely expressed than M3C). On the basis of their similar antigenic pattern, the histogenesis of carcinomas showing the fetal small intestinal antigenic profile may be associated with intestinal metaplasia. On the other hand, carcinomas with the fetal gastric pattern may originate from undifferentiated stem cells of the gastric mucosa. Thus, such immunohistological studies could lead to a better understanding of the histogenesis of gastric carcinomas.

Abnormal pattern of mucus-associated M1 antigens in histologically normal mucosa adjacent to colonic adenocarcinomas.

Apparently normal mucosae adjacent to colon adenocarcinomas were studied by cutting strips of mucosa from the entire length of 120 surgical specimens (94 located on the distal colon and 26 on the proximal colon). These mucosae were coiled into "Swiss rolls." Their mucus alterations were mapped by immunoperoxidase using antibodies against M1 antigens, oncofetal markers associated with precancerous colonic mucosa. We demonstrated mucus modifications in patches of mucosa at a distance from frank tumors. The extent of these alterations was not related to invasion by the adjacent carcinoma according to Dukes' classification. However, these mucus modifications were more frequently observed on the distal than on the proximal side, were more often found adjacent to mucinous hyperplasia or adenoma, and were observed in 8 of 10 mucosae bearing metachronous or synchronous distal colonic adenocarcinomas. Our results suggest that the M1 modifications characterizing an early stage of carcinogenesis could have a putative prognostic value in estimating the risk for metachronous distal colonic adenocarcinomas.

Alterations in expression and synthesis of glycolipid antigens in human colonic tumor cell lines.

Incubation of human intestinal SW1116 tumor cells in serum-free medium containing butyric acid reduced their capacity to synthesize gastrointestinal carcinoma-associated (GICA) glycolipid antigen 4- to 8-fold as determined by a radioimmunobinding assay using anti-GICA monoclonal antibody:high-performance thin-layer chromatography; autoradiography; and densitometry. The structure of GICA has been described as a sialylated Lea glycolipid (J. L. Magnani, B. Nilsson, M. Brockhaus, D. Zopf, Z. Steplewski, A. Koprowski, and V. Ginsburg. J. Biol. Chem., 257: 14365-14369, 1982). Tritiated fucose incorporation into GICA was reduced per cell (7-fold), per mg protein (5-fold), and per mg lipid (4-fold). A purified organically soluble glycolipid fraction from control SW1116 cells contained more Lewis antigen than did butyrate-treated cells as determined by the high-performance thin-layer chromatography radioimmunobinding assay. Incorporation of radioactivity from [3H]fucose and guanosine diphosphate [14C]fucose into Lewis antigens in butyrate-treated cells was 2- to 3-fold lower than in control cells. HT29 cells carry the blood type of the original donor, Blood Group A. Isotope incorporation into A glycolipid antigen was reduced 2- to 8-fold upon exposure to butyrate. Commensurate with these results was a dramatic reduction in cell population-doubling rate. We propose that synthesis of these fucolipid antigens is associated more with dividing, undifferentiated tumor cell populations. The diminution in antigen levels may derive from diminished cells' capacity for fucosylation in the presence of butyrate.

Early oncofetal antigenic modifications during rat colonic carcinogenesis.

M1 antigens, associated with adult rat surface gastric epithelium and which are present in fetal but not adult distal colon, were investigated in this colonic mucosa during carcinogenesis. Fifty Wistar rats were given s.c. injections of 1,2-dimethylhydrazine for 28 weeks. Using an immunohistochemical method, M1 antigens associated with goblet cells were shown to be present after 2 weeks of 1,2-dimethylhydrazine treatment in histologically normal mucosa and then in 78% of mucinous hyperplasia and polypoid-like glands, in 54% of hyposecreting glands, in 58% of dysplasias, Grades 1 and 2, in two of 12 dysplasias, Grade 3, and in five of five transitional mucosas adjacent to carcinoma. The production of sialomucins associated with M1 antigens was often seen in the same histological lesion, although not always associated in the same goblet cells. The number of these histological lesions as well as the production of M1 antigens increased with the number of injections. Thus, these antigenic changes of an oncofetal nature can be regarded as early transformations of goblet cell differentiation in colonic mucosa subjected to chemical carcinogen.

Immunohistochemical and biochemical study of a cathepsin B-like proteinase in human colonic cancers.

An immunohistological study was carried out on 51 human colorectal adenocarcinomas and eight samples of histologically normal colonic mucosa removed far from tumors, using anti-rabbit cathepsin B and anti-human cathepsin B immunoglobulins. Positive reactions were obtained on tumor cells and macrophage-like cells. However, as these immunoglobulins could not discriminate between cathepsin B and cathepsin B-like proteinases, and as they cross-reacted with cathepsins H and L, a partial characterization of the proteinase activities was performed in order to identify the type of enzyme present in the positive cells. The levels of cathepsins H and L were very low in extracts of colorectal tumors and normal colonic mucosa. A peculiar cathepsin B-like proteinase activity with pH optimum at 6.8 was found in tumor extracts together with the lysosomal cathepsin B, whereas normal colonic mucosa showed only cathepsin B activity (pH optimum, 6.0). These results indicate that lysosomal cathepsin B is responsible for staining of macrophage-like cells found in the lamina propria of colonic mucosa and in the peritumoral stroma. Immunohistochemical staining of colonic tumor cells observed in 29/51 cases seems on the other hand to be primarily due to a cathepsin B-like proteinase. Three colonic tumor cell lines, Colo-205, HT-29, and SW-1116, were also studied using the same methods. These cells produced a latent cathepsin B-like proteinase which, after activation, was similar to that found in tumor extracts. This latent proteinase was detected mainly in the culture media. The cultured colonic tumor cells, after staining by anti-cathepsin B antibodies, showed strongly positive granules. In conclusion, this work demonstrates that malignant colonic cells are the source of a cathepsin B-like proteinase, with optimal activity near neutrality. Its secretion into the extracellular space indicates furthermore, that it may be an important component of the "proteinase cascade" associated with tumor invasion and metastasis.

Fetal pancreatic antigens in the Syrian golden hamster and their relationship to development and carcinogenesis.

A rabbit antiserum raised against pancreatic extracts of newborn Syrian hamsters was used in a histological study of pancreas development. This antiserum, after being rendered specific by appropriate absorption, stained the cytoplasm of acinar cells in neonatal pancreas. The reaction was observed from the 13th day of gestation (3 days before delivery) until the 10th day after birth. This period was characterized by a progressive maturation of the endocrine pancreas. The disappearance of fetal pancreatic antigens coincided with the appearance of Langerhans islets. Adult pancreas was not stained with the antiserum, but a good reaction was observed in chemically induced pancreas adenocarcinomas. All reactions were confirmed by immunochemical studies. Polyacrylamide gel electrophoresis followed by immunodetection on nitrocellulose blots demonstrated the presence of two major fetal antigens. Thus, this study demonstrates the existence of fetal pancreatic antigens associated with development which are reexpressed in pancreatic tumors.

Distribution of oncofetal fibronectin in human mammary tumors: immunofluorescence study on histological sections.

Two types of human fibronectin have been detected by the reactivity of specific monoclonal antibody FDC-6: (a) those present in normal plasma and adult tissues, which do not react with FDC-6 (normal fibronectin or norFN); and (b) those present in fetal tissues and in tumoral cell lines, which do react with FDC-6 (oncofetal fibronectin or onfFN) (H. Matsuura and S. I. Hakomori, Proc. Natl. Acad. Sci. USA, 82: 6517-6521, 1985). We compared the distribution of norFN and onfFN in normal breast tissue (15 samples), breast fibroadenoma (ten samples), and breast adenocarcinoma (80 samples), using an immunofluorescence technique with monoclonal antibody FDC-6. A polyclonal antiserum against human normal fibronectin was used as a control. While norFN was diffusely present in normal gland and in benign and malignant tumors, onfFN was absent in normal gland and in benign tumors. In carcinomas, however, its presence was frequent, as we found it in 60% of cases. Among classical prognosis factors in breast carcinomas, onfFN distribution was significantly correlated with histological grade. Indeed, the presence of FDC-6 labeling was significantly linked with intermediary and high malignancy grades, while its absence was significantly linked with low malignancy grade. onfFN could be considered a marker of the neoplastic state; its immunohistological detection may represent a new prognosis factor in breast carcinomas.

A new mucin-associated oncofetal antigen, a marker of early carcinogenesis in rat colon.

We report the characterization of an IgG2a monoclonal antibody, (MAb) 660, prepared against rat gastric high molecular weight glycoproteins. By immunoperoxidase staining, MAb 660 reacted only with the mucous cells of surface gastric epithelium and with a few duodenal goblet cells close to the pylorus in normal adult rats. In fetuses, it reacted with intestinal and colonic goblet cells. The adult colon was always negative. The MAb 660 stained 100% (30 of 30) of chemically induced colonic carcinomas and 100% (7 of 7) of duodenal carcinomas. Several weeks before the appearance of tumors, histologically normal glands, then hyperplasia and dysplasia were precociously stained with MAb 660. The tissue distribution was different from that of blood group related antigens and M1 fucomucins. The recognized antigen was not sensitive to neuraminidase treatment. After electrophoresis in polyacrylamide gel, staining with periodic acid-Schiff reagent and Western blotting showed that the MAb 660 recognized an epitope associated with high molecular weight glycoproteins. This epitope was unaffected by beta-mercaptoethanol reduction-periodate treatment and neuraminidase and trypsin digestion. However, trypsin digestion performed after beta-mercaptoethanol reduction destroyed the 660 epitope. These data suggest that the antibody could recognize the peptide moiety of the mucin rather than its carbohydrate moiety. Thus, the new antigen identified by MAb 660 is a mucin-type glycoprotein with an oncofetal behavior in the rat colon and is precociously expressed by precancerous colonic mucosa.

Immunohistological study of precancerous mucus modification in human distal colonic polyps.

The M1 antigens associated with gastric fucomucins, oncofetal markers of the distal colonic mucosa, were demonstrated to be more closely associated with adenomas [92 of 139 (66%)] than with invasive adenocarcinomas [27 of 218 (12%)]. They were always expressed in tumors containing the M3 antigen normally associated with the intestinal mucus. The M1 antigens, present in 100% of hyperplastic polyps (30 of 30), were not specific for a particular histological type of adenoma but were found to be more closely associated with those showing a villous differentiation [41 of 47 (87%)] than with those having a tubular pattern [51 of 92 (55%)]. The presence of these M1 antigens depended neither on the size nor on the degree of cytological atypia of the nodular adenomas. However, M1 antigens were found in 94% of the adenomas (35 of 37) concomitant with adenocarcinomas; in contrast, only 56% of adenomas (55 of 102) observed on noncancerous mucosa contained these M1 antigens. As already demonstrated during rat colonic carcinogenesis, mucus modification characterized by the presence of M1 antigens could represent early molecular changes occurring before malignant transformation related to a chemical carcinogen. These M1 antigens might be regarded as early precancerous markers of an oncofetal type, associated with human distal colonic mucosa.

Antigenic sites in carcinoembryonic antigen.

The epitope reactivities of 52 well-characterized monoclonal antibodies (Mabs) against carcinoembryonic antigen from 11 different research groups were studied using competitive solid-phase immunoassays. About 60% of all possible combinations of Mabs as inhibitors and as the primary binding antibody were investigated. The inhibition data were analyzed by a specially developed computer program "EPITOPES" which measures concordance and discordance in inhibition patterns between Mabs. The analysis showed that 43 of the 52 Mabs (83%) could be classified into one of five essentially noninteracting epitope groups (GOLD 1-5) containing between four and 15 Mabs each. The epitopes recognized by the Mabs belonging to groups 1 to 5 were peptide in nature. With one or two possible exceptions non-classifiable Mabs were either directed against carbohydrate epitopes (4 Mabs) or were inactive in the tests used. Within epitope groups GOLD 1, 4, and 5 two partially overlapping subgroups were distinguished. Mabs with a high degree of carcinoembryonic antigen specificity generally belonged to epitope groups GOLD 1 and 3.