Preoperative radiation therapy and chemotherapy for adenocarcinoma of the pancreas.

Since preoperative radiation therapy combined with chemotherapy (CTRT) was first performed in 1986 for patients with pancreatic adenocarcinoma, there have been several reported experiences with varying drugs and radiotherapy regimens. We describe those experiences and contrast them to a series of patients treated at our institution with resectional surgery before CTRT. Finally, the current role of preoperative CTRT in the therapy of pancreatic adenocarcinoma is proposed.

Preoperative versus postoperative chemoradiation for patients with resected pancreatic adenocarcinoma.

Two groups of patients with adenocarcinoma of the pancreas treated with either preoperative chemoradiation (preop CTRT) or postoperative chemoradiation (postop CTRT) were retrospectively analyzed for various treatment-related parameters. Between November 1986 and October 1996, a total of 70 patients with pancreatic adenocarcinoma were enrolled into preop CTRT protocols at our institution. Twenty-five patients with adenocarcinoma of the head of the pancreas underwent pancreaticoduodenectomy with curative intent. After the closure of the preop CTRT protocols, we had the opportunity to perform 23 pancreatic resections without preop CTRT. After surgery, these patients were advised to undergo CTRT. These two groups of patients were therefore selected consecutively, dependent only on the time of referral and no other bias. These two cohorts of patients are compared for various intraoperative parameters, length of hospital stay, pathologic findings, time to recurrence, and survival. Mean age was 65 and 66 years in the preop and postop CTRT groups, respectively. Sex distribution was almost equal. Treatment breaks resulting in greater than 1 week delay in the radiotherapy occurred in 2 (8%) of 25 patients in the preop CTRT group (myelotoxicity in 1 case and biliary sepsis in 1 case), whereas no treatment breaks >1 week occurred in those receiving postop CTRT. Eleven patients in preop CTRT had grade 3 or 4 toxicity, whereas none was noted in those with postop CTRT. There was one postoperative death in the preop CTRT group and none in the postop CTRT group. Mean time to the start of CTRT was 45 days (range, 20-66 days) after pancreaticoduodenectomy. Delay of >60 days to the onset of CTRT occurred in 2 (22%) patients and was attributable to patient delays in time to recover from surgery or patient noncompliance. Furthermore, 5 of 23 patients (22%) in the postop CTRT group did not receive treatment for various reasons. Average estimated operative blood loss was 1933 mL (median 1550) and 1060 mL (median 1000) for preop and postop CTRT groups, respectively. Mean length of operation was 488 minutes (median 480) and 486 minutes (median 480). Median length of postoperative stay was 22 and 20 days (ranges, 9-144 and 10-38). Pathological findings in the resected specimens showed significantly fewer involved nodes in the preop CTRT group (28 vs 87%; P = 0.0006), whereas similar numbers of nodes/patient were counted in each group (14 vs 22, P = 0.11). More negative resection margins were observed in the preop CTRT group (28 vs 56%; P = not significant). A significantly greater amount of fibrosis replacing the tumor was observed in the preop CTRT group (70 vs 40%; P = 0.0001). There were no significant survival differences observed (median 20 months vs 25 months; P = 0.48), in follow-up that ranged from 4 to 76 months (median 44 months for surviving patients) for the preop group and 4 to 40 months (median 16 months for surviving patients) for those with postop CTRT. Local failure either alone or as a component of distant failure occurred in 16 per cent (4 of 25 patients) with preop CTRT and 16.6 per cent (3 of 18) with postop CTRT. Analysis of differences between those treated with preoperative and postoperative CTRT demonstrates similarity in toxicity and effects. However, 22 per cent of patients intended for postoperative therapy did not receive treatment.

Preoperative chemotherapy of chemoradiotherapy for the treatment of adenocarcinoma of the pancreas and ampulla of Vater.

Much has been written about preoperative strategies in the treatment of pancreatic adenocarcinoma, yet there has been very little comment concerning other periampullary malignancies. This review discusses current issues relevant to the further development of preoperative adjuvant treatment of pancreatic adenocarcinoma. A small series of patients with ampullary adenocarcinomas treated with preoperative adjuvant chemoradiotherapy is also described.

Implications of fine-needle aspiration in patients with resectable pancreatic cancer.

A 9-year experience with fine-needle aspiration (FNA) in patients with resectable pancreatic adenocarcinoma was reviewed to determine whether this procedure is associated with positive peritoneal cytology, peritoneal recurrences, or decreased survival in patients who had pancreatic resection with curative intent. Forty-one patients underwent pancreatic resection for primary pancreatic adenocarcinoma from July 1987 to February 1996. Nine patients had open biopsies prior to definitive resection and were excluded from this study. Of the remaining 32 patients, 21 (66%) had preoperative computed tomography-guided or fluoroscopically guided FNA biopsy of the pancreas for diagnosis. FNA confirmed the diagnosis of adenocarcinoma in 17 of 21 patients (80%). Fifteen of 21 FNA biopsies were performed in patients who went on to receive neoadjuvant chemoradiation. Twenty-eight of 32 patients (87%) had peritoneal washings at the time of laparotomy. Five patients had suspicious or positive washings (18%), and 23 patients had negative washings (82%). Three of 18 patients (16.7%) who had both FNA and peritoneal washings and 2 of 10 patients (20%) who had no FNA but had peritoneal washings had positive or suspicious peritoneal cytology. Eight of 32 patients ultimately failed in the peritoneum. Six of 21 patients (28%) who had prior FNA and 2 of 11 (18%) who had no prior FNA failed in the peritoneum. Although the number of patients is small, none of these differences proved to be statistically significant. No difference in median survival was observed between the FNA and no FNA groups. We conclude that FNA is a safe and useful tool to confirm the diagnosis of pancreatic cancer when patients are to be treated with neoadjuvant chemoradiation.

Surgical management of pancreatic cancer.

The treatment of patients with pancreatic cancer requires the expertise of medical oncologists, radiation oncologists, radiologists, and surgical oncologists. The surgeon's role in the management of patients with pancreatic cancer extends beyond the performance of surgical resection and bypass procedures to include diagnosis, staging (including determination of resectability), and therapy (both curative and palliative). If a lesion is deemed resectable, the surgeon's goal is to achieve clear pathologic margins in order to optimize the patient's chances for cure. The surgeon also plays a key role in the palliation of disease in patients with unresectable lesions. Biliary and duodenal bypass, endoscopic stenting, laparoscopy, and celiac ganglion injection may be needed to maximize a patient's remaining quality of life. In addition, the surgical oncologist should be involved in clinical trials testing neoadjuvant or adjuvant chemoradiotherapies that may lead to the development of more effective therapies for pancreatic cancer.

Laparoscopic bilateral inguinal hernia repair under local anesthesia.

A case report of the laparoscopic repair of bilateral inguinal hernias performed under local anesthesia with intravenous sedation is presented. The combination of nitrous oxide for peritoneal insufflation and an ultrasonically activated scalpel for dissection made the procedure feasible. It is hoped that this technique can extend laparoscopic surgery to patients who are poor candidates for general anesthesia.

Human lymphokine-activated killer cells augment immunotherapy of human colon carcinoma xenografts with monoclonal antibody D612.

The tumoricidal properties of an anti-human colon carcinoma monoclonal antibody (MAb), designated D612 (IgG2a), alone and in combination with IL-2-activated human lymphocytes were investigated in athymic mice bearing LS-174T colon tumor xenografts. Treatment of mice bearing LS-174T tumors (1 day, s.c.) with a single i.v. dose of 400 micrograms of D612 alone resulted in a significant inhibition of tumor growth. Lower doses of D612 had an intermediate effect on tumor growth. Similar inhibition of tumor growth was obtained when D612 was administered in three doses of 400 or 800 micrograms each during the first week after tumor implantation. Mouse macrophages but not splenocytes mediated antibody-dependent cellular cytotoxicity with D612, suggesting that tumor inhibition was due to the participation of host macrophages with D612. Human lymphokine-activated killer (LAK) cells were generated by incubating human peripheral blood mononuclear cells (PBLs) from normal donors with 100 U/ml of IL-2 for 24 h. An administration of human LAK cells did not significantly inhibit the growth of the human xenograft tumor. Adoptive transfer of a single dose of human LAK cells (2 x 10(7), i.v.) into mice treated with a suboptimal dose of D612 (200 micrograms) significantly inhibited tumor growth compared to that obtained with either D612 or LAK cells alone. Similar results were obtained with three doses of D612 plus human LAK cells although there was a tendency for multiple doses of LAK cells alone to show some antitumor effects. LAK cells or PBLs had similar antitumor activities when used in conjunction with D612. When larger established tumors were treated, single or multiple doses of D612 or LAK cells alone were without effect; however, LAK cells plus D612 elicited significant growth inhibition. These results demonstrate that the tumoricidal properties of LAK cells and the D612 MAb can be augmented when used together in the immunotherapy of human colon cancer xenografts.

Lymphokine-activated killer cell cytotoxicity against human colon carcinomas enhanced by monoclonal antibody D612.

The antibody-dependent cellular cytotoxicity (ADCC) properties of a murine monoclonal antibody (MAb), designated D612 (IgG2a), which reacts with human colon carcinomas, was studied using normal human peripheral blood lymphocytes (PBMNC). Although the level of ADCC of PBMNC with D612 varied among different donors, it was 20 to 30 times higher than the lytic activity of control cultures containing isotype-matched control MAb. Incubation of PBMNC with recombinant interleukin-2 (IL-2) resulted in a 2- to 5-fold augmentation in the cytotoxicity of effector cells exposed to MAb. This augmentation was apparent after subtracting nonspecific cellular cytotoxicity from the total cytotoxicity mediated by activated effector cells in the presence of D612. Optimal stimulation of specific ADCC with IL-2 appeared after 24 hr of culture in 500 U/ml of IL-2, resulting in a 3.8 +/- 1.7 fold increase in lytic units. However, stimulation of ADCC was also evident at 10 U/ml of IL-2. Furthermore, antibody dose titrations with untreated and IL-2 activated effectors showed that the threshold dose of MAb needed for efficient ADCC was reduced by 200-fold with IL-2. Depletion of FcR gamma III-positive lymphoid cells markedly reduced D612 ADCC, demonstrating the participation of NK/LAK cells in D612-mediated ADCC. Low levels of ADCC activity were found associated with adherent cells, either untreated or following their activation with gamma-interferon, while D612 was most active with non-adherent effectors. The specificity and ADCC properties of the D612 MAb suggest that it should be considered as a candidate for immunotherapy of colon cancer, particularly when used in combination with IL-2 plus LAK cell treatment.

Chimeric B72.3 mouse/human (IgG1) antibody directs the lysis of tumor cells by lymphokine-activated killer cells.

Chimeric mouse/human B72.3 (cB72.3) antibodies having a human IgG1 (gamma 1) or IgG4 (gamma 4) constant region were compared to the native murine IgG1 B72.3 (nB72.3) monoclonal antibody (mAb) for their ability to participate with human effector cells in antibody-dependent cellular cytotoxicity (ADCC). Because the TAG-72 antigen recognized by B72.3 is poorly expressed on tissue-cultured tumor cell lines, the xenografted OVCAR-3 human ovarian carcinoma ascites was used as a cytotoxicity target. The lytic activity of the cB72.3(gamma 1) mAb with peripheral blood lymphocytes was 1.5- to 50-fold greater than that of the nB72.3 mAb and usually the cB72.3(gamma 4) mAb. However, lymphocytes from some donors had similar ADCC activity with either the cB72.3(gamma 1) or cB72.3(gamma 4) mAb. The cB72.3(gamma 1) and the murine anti-colon carcinoma CO17-1A mAb had comparable activity in mediating ADCC against the OVCAR-3 tumor. Exposure of lymphoid cells to interleukin-2 (IL-2) (100-500 U/ml) for 24 h to generate lymphokine-activated killer (LAK) cells augmented ADCC mediated by the cB72.3(gamma 1) mAb 2- to 22-fold. By contrast, LAK cells from most donors expressed weak non-specific cytotoxicity against OVCAR-3 ascites tumor cells. The cB72.3(gamma 1), and to a lesser extent, the cB72.3(gamma 4) chimera also participated with monocytes in mediating ADCC, but the antibody-dependent lytic potency of monocytic effectors was much weaker than that of IL-2-activated lymphoid cells. These studies show that the cB72.3(gamma 1) mAb has appreciable ADCC-mediating properties, suggesting a potential role for its incorporation into treatment strategies utilizing adoptive killer cell and/or lymphokine therapy.

Immunocytochemical localization and immunological characterization of vitamin D-dependent calcium-binding protein in the bullfrog cerebellum.

Antiserum prepared against rat renal calcium-binding protein (CaBP) was used with the unlabeled antibody peroxidase-antiperoxidase (PAP) technique to localize the 28,000 molecular weight CaBP in the cerebellum of the bullfrog, Rana catesbeiana. Whole brains of premetamorphic tadpoles and adults were fixed in Bouin's solution for 2 or 24 h and embedded in paraffin. 8-microns parasagittal sections were prepared and treated by the PAP method. Purkinje cells of the cerebellum in tadpoles and adults were specifically stained for CaBP. In the premetamorphic corpus cerebelli, the stained Purkinje cells corresponded to the precociously developed Purkinje cells described previously. In the auricular lobe region of the cerebellum mature Purkinje cells were stained. In addition, smaller stained cells were seen. The latter were presumed to be immature Purkinje cells that would mature at the time of metamorphosis. Immunoblot procedure demonstrated cross-reactivity for the ranid brains in the 28,000 molecular weight region. This immunoreactive band comigrated with the immunoreactive band observed with purified rat renal CaBP. Although the exact functional significance of CaBP is unknown at this time, our immunocytochemical and immunological findings indicate that CaBP is an excellent marker for studies of Purkinje cell maturation.