I patients with nonendocrine pancreas carcinoma

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1 LYMPH NODE INVOLVEMENT IN CARCINOMA OF THE HEAD OF THE PANCREAS AREA ANTONIO L. CUBILLA, MD,* JOSEPH FORTNER, MD,+~ AND PATRICK J. FITZGERALD, MD*~ A prospective study to determine the lymph node involvement in 33 pancreatectomy specimens (regional pancreatectomy 18, total pancreatectomy 7, Whipple partial pancreatectomy 8) was undertaken. There were 22 patients with pancreas duct adenocarcinoma, 6 with ampullary carcinoma, 3 with duodenal adenocarcinoma, 1 bile duct carcinoma and 1 of undetermined site of origin. Peripancreatic lymph nodes were divided into 5 main groups with subgroups. They are 1) Superior, Superior Head, Superior Body and Gastric; 2) Inferior: Inferior Head and Inferior Body, 3) Antenor: Anterior Pancreaticoduodenal, Pyloric and Mesenteric, 4) Posterior: Posterior Pancreaticoduodenal, Common Bile Duct, and 5) Splenzc: lymph nodes at hilum of spleen and at the tail of pancreas. The average number of lymph nodes found in different types of surgical specimens was: regional pancreatectomy 70, total pancreatectomy 4 1, and Whipple procedure 33. The average number of lymph nodes involved with metastatic tumor in these specimens was, respectively, 5, 3 and 1. The most common sites of metastasis were in the Superior Head and in the Posterior Pancreaticoduodenal groups. Pancreatic duct adenocarcinoma tended to metastasize to multiple lymph nodes of the Superior Head, Superior Body and Posterior Pancreaticoduodenal lymph nodes (88% of patients). Ampullary adenocarcinoma metastasized less often (33%), usually to fewer nodes and to one adjacent periampullary group. Since in 33% of patients nodal metastases of duct adenocarcinoma of the head of the pancreas were present in groups not usually removed in the Whipple procedure, it would appear that this operation is inadequate for surgical eradication of pancreas duct adenocarcinoma of the head of the pancreas. Cower 41: , N PRIOR RETROSPECTIVE STUDIES OF ABOUT 500 I patients with nonendocrine pancreas carcinoma it was apparent that most tumors were relatively large, averaging 5 cm in diameter, and had spread beyond the pancreas in about 85% of patients, at the time of diagn~sis. ~~~ This may have explained the poor 5-year survival figure of 1 %. 2,8 If survival after surgical extirpation were to be improved, it would be necessary to know the pathway of spread of the cancer. Although the Presented at the Society of Surgical Oncology, May 4-7, 1977, Hilton Head, South Carolina. From the Departments of Pathology* and Surgery (Gastric and Mixed Tumor Service, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York. Chief, Mixed Tumor Service. 5 Chairman, Department of Pathology. Supported, in part, by contracts N01-CP and N01-CB from the National Cancer Institute. Address for reprints: Antonio L. Cubilla, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY Accepted for publication July 25, X normal lymphatic drainage of the pancreas has been well delineated, 3l3 we have not found a detailed description of the lymph node involvement by pancreas cancer. This knowledge is necessary for clinical staging, since it is important for evaluating the resectability of tumors and necessary for proper evaluation of the efficacy of various types of therapy. A prospective program was established wherein peripancreatic lymph nodes, or nodules in the resected specimen of cancers of the head of the pancreas area were examined in considerable detail. MATERIALS AND METHODS Forty-four curative surgical resections for pancreas and periampullary neoplasms were performed at Memorial Hospital during the period August 1974 through December The first 11 resections were used for orientation purposes and from these a prospective study was designed. All following 33 operative specimens were subjected to the planned detailed gross American Cancer Society

2 No. 3 LYMPH NODES IN PANCREATIC CANCER Cubilla et al. 881 histological examination of the resected specimen. The types of operation performed in the 33 cases were: regional pancreatectomylo*" in 18 patients; total pancreatect~rny~*~j~ in 7 patients, and a Whipple pr~cedure'~ in 8 patients (Table 1). Surgical Procedures Regional pancreatectomy. Total pancreatectomy, partial gastrectomy, cholecystectomy, duodenectomy, splenectomy, resection of portal vein, with or without transverse colectomy, mesocolon, omentum, regional lymph nodes. Total pancreatectomy: Total pancreatectomy, partial gastrectomy, duodenectomy, splenectomy, peripancreatic lymph nodes. Whipple procedure: Partial pancrea t ec to my (head of pancreas), partial gastrectomy, duodenec t o my. The histologic diagnoses were duct adenocarcinoma of the pancreas, 22 (21 head and 1 body of pancreas); ampullary carcinoma, 6; duodenal carcinoma, 3; bile duct carcinoma, 1; and 1 was a large adenocarcinoma involving the head of pancreas and periampullary-duodenal regions whose site of origin was undetermined (Table 2). A careful gross description of the primary tumor was made after the identification and opening of both common bile and main pancreatic ducts. The separation of pancreatic duct cancer from bile duct, ampullary or duodenal cancer in terms of site of origin was usually done at the time of gross examination, but histologic patterns were helpful ancillary evidence in a few difficult cases.' Histologic sections were stained with hematoxyline and eosin. Tissues for electron microscopy processing were taken in 30 cases. Tissues were embedded in paraffin, and usually 3 or 4 intact lymph nodes were embedded per block. When the size of the lymph nodes was more than 1 cm, as often was true for the hyperplastic nodes in patients with previous surgery, or in the common bile duct lymph nodes (often enlarged because of the presence of lipogranulomas), the node was bisected and both halves embedded. When the number of lymph nodes described grossly did not correspond with the number present in the histologic slides, deeper cuts of blocks were performed. When lymph nodes were not identified in the anatomical site where they were usually found tissue from that area was submitted for histologic study. TABLE 1. Average Number of Peripancreatic Lymph Nodes and Presence of Metastasis in 33 Pancreas Resections No. of No. of lymph positive Operation No. cases nodes nodes Regional pancreatectomy Total pancreatectomy Whipple pancreatectomy The gross examination and lymph node dissection in all cases was done by one of us (AC), or under his direct ~upervision.~ All specimens were studied in the fresh state as soon as possible after surgical resection. The number of lymph nodes observed grossly did not necessarily correspond with the final number after microscopic examination because 1) in about 10 to 15% of the specimens, small lymph nodes of the Superior and Inferior groups and, especially the pancreaticoduodenal subgroup, were only recognized microscopically and they often were within the substance of the pancreas; 2) often what, macroscopically, appeared to be a lymph node, was shown, microscopically, to represent peripancreatic, neural, ganglionic, paraganglionic or accessory splenic tissue; 3) previous surgical procedures done at other hospitals often resulted in the presence of numerous nodules of suture granulomas and these were confused grossly with lymph nodes. On the contrary, in some of the patients, many nodes were enlarged because of reactive hyperplastic changes secondary to previous operations and this made recognition easier. NORMAL LYMPHATICS AND LYMPH NODES The lymphatic vessels of the pancreas arise in a rich perilobular interastomosing network TABLE 2. Nonendocrine Carcinoma of the Head of the Pancreas Region Type of operation Site of origin No. Regional Total Whipple Pancreas Duct Adenocarcinoma Arnpullary Adenocarcinoma Duodenal Adenocarcinorna Bile Duct Adenocarcinorna Undetermined TOTAL

3 882 CANCER March 1978 Vol. 41 FIG. 1. Distribution of lymph nodes in 18 regional pancreatectomy resection specimens. Numerator of fraction of each group indicates number of patients with metastasis in that lymph node group; denominator indicates number of patients in which group nodes were examined. Thirteen cases were pancreas duct cancer, 5 were other cancers in the head of the pancreas area (Table 2). SH = superior head; SB = superior body; IH = inferior head; IB = inferior body; APD = anterior pancreaticoduodenal; PPD = posterior pancreaticoduodenal; CBD = common bile duct; Py = pyloric; LC = lesser curvature; GC = greater curvature; S = tail of pancreas and splenic; Je = Jejunal; Col = mid colic. which is followed by channels running along the surface of the gland and in the interlobular spaces with the blood vessel^.^^'^ These lymphatics drain into 5 main collecting trunks and lymph node groups (Figs. 1-3). I. Superior These collecting trunks arise from the anterior and posterior upper half of the pancreas and most of them end in the suprapancreatic lymph nodes located along the superior border of the pancreas; these are designated SH (Superior head) and SB (Superior body) for nodes in the respective areas (Fig. 1). Occasionally, some lymphatics terminate in the nodes of the gastropancreatic fold or in the lymph nodes of the hepatic chain (also called SH). 11. Inferior The collecting trunks of this group of nodes drain the anterior and posterior lower halves of the head and body of the pancreas and lead into the inferior pancreatic group of lymph nodes, most of them located along the inferior border of head (IH) and body (IB) of pancreas. They may also extend into the superior mesenteric and left lateroaortic lymph nodes. There is a very rare situation in which a collecting trunk terminates in a lumbar trunk directly (this might explain the unusual cases of lung or systemic metastasis from pancreas cancer without involvement of liver) Anterior Two collecting trunks run along the anterior surface of both superior and inferior portions of the head of the pancreas, extend to the infrapyloric (Py) and the anterior pancreaticoduodenal lymph nodes (APP) and-to some of the mesenteric lymph nodes at the root of the mesentery (Mesenteric-Jejunal) IV. Posterior These lymphatics run along the posterior surface of the superior and inferior portions of the head of the pancreas. They empty into the posterior pancreaticoduodenal lymph nodes (PPD) as well as into the common bile duct lymph nodes (CBD), right lateroaortic lymph nodes and to some nodes at the origin of the superior mesenteric artery. Most of the lymphatics of the common bile duct and ampulla of Vater terminate in the PPD group of lymph nodes. V. Splenic These lymphatics lead from the tail of the pancreas and drain into the following lymph nodes; those at the hilum of the spleen, phrenolienal ligament, and at the inferior and superior lymph nodes of the tail of the pancreas. They were labeled the S group. There are a few lymphatic channels, however, which terminate in the lymph nodes superior and inferior to the body of the pancreas.

4 No. 3 LYMPH NODES IN PANCREATIC CANCER Cubilla et al. 883 LIMITATIONS OF THE STUDY The surgical specimens available for study of lymph nodes were of 3 different types (regional, total and Whipple pancreatectomies) each containing different groups, subgroups and numbers of lymph nodes (Table 3). Because particular subgroups of lymph nodes normally present in the human body were not identified specifically at surgery by a metalic tag or label we sometimes arbitrarily had to label various subgroups in the en bloc specimen without the benefit of contiguous organs being in place. We could not, for example, always separate the suprapancreatic lymph nodes around the head of pancreas from the nodes of the hepatic and pyloric chain. The lymph nodes from the infrapancreatic head of pancreas region were also lumped with the inferior mesenteric, and left lateroaortic nodes. The lymph nodes superior and inferior to the tail of the pancreas were grouped together with the splenic (S) lymph nodes. In 5 of the nonpancreatic cancers only a Whipple resection was performed and there is the possibility that a total, or a regional, resection might have demonstrated more nodes and possibly more positive nodes (Fig. 3). In 3 of 21 patients with duct cancer in the head of the pancreas a Whipple resection was performed so that we probably did not obtain the maximum possible number of peripancreatic lymph nodes. We do not believe, however, that this will appreciably alter our major conclusions. In about 15-20% of cases with carcinoma in lymph nodes, a direct invasion of lymph node, rather than embolic spread, was apparent in the histologic sections. We realize that clearing, or other, techniques, would probably identify more lymph nodes than discovered by our detailed gross and histologic examinations, so that our figures are minimal ones for the number of nodes present. Whether the percentage of lymph nodes involved by metastatic cancer found by the former techniques would change is less certain. RESULTS A total of 1812 peripancreatic lymph nodes (average of 55 nodes per specimen) was studied in the 33 specimens and their distribution is listed in Table 3. The lymph node groups and subgroups commonly involved with metastatic carcinoma were the Superior group, 18 patients (12 SH and 6 SB subgroups); the Posterior group; 14 patients (PPD); the Inferior group, 10 patients (IH 8, IB 1 and midcolic, 1) (Table 4). The superior group contained the largest number of lymph nodes in all three types of specimens studied. The larger number of nodes in the Superior Head (SH) and Superior Body (SB) subgroups FIG. 2. Lymph node group involvement in 21 patients with duct cancer in the head of the pancreas. Nomenclature, numerator and denominator same as in Fig. 1. Thirteen regional pancreatectomies, 5 total pancreatectomies and 3 Whipple procedures were performed (Table 7).

5 884 CANCER March 1978 Val FIG. 3. Lymph node group involvement in 11 patients with nonpancreatic cancer in the head of the pancreas area. Nomenclature, numerator and denominator same as in Fig. 1. Five regional pancreatectomies, 1 total pancreatectomy, and 5 Whipple resections were performed. found in the regional pancreatectomy (Fig. 1) specimens may be explained by the extensiveness of this operation which includes a dissection of porta hepatis nodes of the SH group and the celiac axis nodes of the SB group of lymph nodes. In the classical Whipple procedure, superior body (SB) lymph nodes are usually not removed. Regional pancreatectomy specimens showed more Inferior group lymph nodes because of the inclusion of the mesenteric lymph nodes located along the mesenteric vessels and the mid-colic lymph nodes. Of interest was the observation that duct adenocarcinomas of the head of the pancreas usually metastasized to Superior and Posterior TABLE 3. Anatomic Distribution of Peripancreatic Lymph Nodes in Resected Specimens 4v. No. of lymph nodes present Lymph node Group Subgroup Regional Total Whipple Superior Inferior Anterior Posterior Splenic Gastric Superior head Superior body Inferior head Inferior body Mid colic Pyloric 'Pancreatiocoduodenal Mesenteric (jejunal) Pancreatiocoduodenal Common bile duct Tail of pancreas-spleen groups of lymph nodes (Fig. 2 and Table 7). Nonpancreatic cancer tended to involve Posterior Pancreaticoduodenal (PPD) and Inferior Head (IH) lymph nodes (Table 5 and Fig. 3). Pancreatic duct neoplasms often metastasized to multiple lymph nodes and to more than one anatomic group. Ampullary adenocarcinomas tended to metastasize to fewer lymph nodes and usually involved only one or two subgroups of lymph nodes. Duodenal adenocarcinoma was intermediate and involved several lymph nodes and more than one subgroup, mainly those around the head of the pancreas region (Fig. 3). Duct adenocarcinoma of pancreas, in contrast to ampullary and duodenal cancers, often me- TABLE 4. Lymph Node Groups Commonly Involved by Metastatic Carcinoma of the Head of the Pancreas Region (33 Patients)* No. of patients with Lymph node positive nodes group S ubgroup Total Superior Inferior Anterior Posterior Splenic Superior head Superior body Inferior head Inferior body Mid colic Pancreaticoduodenal Pyloric Mesenteric (jejunal) Pancreaticoduodenal Tail of pancreas spleen * In 12 cases more than 1 group was involved l

6 ~~ ~~ No. 3 LYMPH NODES IN PANCREATIC CANCER Cubilla et a1 885 TABLE 5. Metastatic Involvement of Peripancreatic Lymph Nodes by Site of Origin* Duct adenocarcinoma Arnpullary Duodenal of pancreas carcinoma carcinoma Others' (22 cases) (6 cases) (3 cases) (2 cases) No. of No. of No. of Lymph node Group Subgroup pts. (%) pts. (%) pts. (%) No. of pts. (%) Gastric Superior Superior head 10 (45) 0 1 (33) Superior body 6 (27) 0 0 Inferior head 5 (23) 1 (17) 2 (67) Inferior Inferior body 1 (5) 0 0 Mid colic 1 (5) 0 0 Pyloric 1 (5) 0 0 Anterior Pancreaticoduodenal 2 (9) 0 1 (33) Mesenteric 1 (5) 0 0 Pancreaticoduodenal 10 (45) 2 (33) 2 (67) Posterior Common bile duct Splenic Tail of pancreas-spleen * In 12 patients more than one group was involved. t One bile duct adenocrcinoma and a large carcinoma involving pancreas and duodenum whose site of origin was undetermined tastasized to groups distant from the head of the pancreas, (SB, IB, pyloric, mesenteric and midcolic areas) (Table 5 and Fig. 2). The lymph nodes situated along the lesser and greater curvature of the stomach (Gastrfc), the common bile duct, and the spleen and tail of pancreas did not reveal evidence of metastasis in any case. The average number of positive lymph nodes containing cancer was regional pancreatectomy specimen 5, total pancreatectomy, 3; and Whipple resection, 1 (Table 1). Multiple Lymph Node Group Involvement In 8 patients (4 ampullary, 3 pancreas duct and 1 duodenal carcinoma) there was no evidence of metastasis in peripancreatic lymph nodes (Table 6). In 13 patients only 1 group of lymph nodes was involved: the Superior group in 7 patients (SB 3, SH 3 and both SH-SB l), six diagnosed as duct adenocarcinoma of pancreas, and one case was a bile duct carcinoma. The Posterior group (PPD) alone showed metastatic carcinoma in lymph nodes in 4 patients, 3 of them were duct adenocarcinomas of pancreas and 1 was an ampullary carcinoma. Of the remaining 2 patients, 1 had a duct adenocarcinoma of head and neck of pancreas, with metastasis to 1 IB lymph node and 1 had an ampullary carcinoma with metastasis to 1 IH lymph node. In 12 patients multiple lymph node groups in various combinations were involved by metastatic carcinoma (Table 6). The most common groups simultaneously showing evidence of metastatic tumor were the Superior/Inferior/Posterior combination, as seen in 4 patients with duct adenocarcinoma of pancreas. DISCUSSION Although our number of cases is small, this study appears to indicate that there are certain groups of peripancreatic lymph nodes which are more commohly involved by metastatic carcinoma from the head of the pancreas area; i.e., the SH and PPL) subgroups. Both are more commonly affected in duct adenocarcinoma of pancreas and the PPD group is usually involved in periampullary and duodenal cancer (Fig. 3). TABLE 6. Lymph Node Involvement by Site of Origin No. groups involved No. patients Pancreas duct CA Ampullary CA Duodenal CA Other No metastasis One group More than one group TOTAL

7 886 CANCER March 1978 Val. 41 TABLE 7. Number of Patients with Lymph Node Metastasis in 22 Cases of Duct Adenocarcinoma of Pancreas* Regional Total Whipple (13 Pts.) (6 Pts.) (3 Pts.) Gastric Superior Superior head Superior body Inferior head Inferior Inferior body Mid colic Pyloric Anterior Pancreaticoduodenal Mesenteric Posterior Pancreaticoduodenal Common bile duct Splenic Tail of pancreas-splenic * Some patients showed metastasis in more than 1 group of lymph nodes. The lymphatics of the ampulla and duodenum are said by Rouviere13 to drain into the PPD lymph nodes. A special effort was made to separate tumors arising in the pancreaticoduodenal biliary region in relation to their site of origin5 for it has been repeatedly reported that lesions arising in the ampulla of Vater, or periampullary cancers have a better prognosis than pancreas duct cancers.' It was apparent from this study that pancreas duct adenocarcinomas tended to metastasize to multiple lymph nodes more commonly to more than one group of nodes. Nonpancreatic duct adenocarcinoma, especially ampullary tumors, tended to involve only one lymph node and usually this was confined to one subgroup of lymph nodes. Overall, 86% of 22 duct adenocarcinomas metastasized to lymph nodes whereas 4 of 9 patients (44%) with ampullary or duodenal cancer showed metastasis. This difference in nodal involvement may partially explain the difference in prognosis for the two groups. The three pancreas duct carcinoma specimens without evidence of metastasis were relatively small tumors measuring 2, 2 and 4 cm in diameter, whereas in a larger number of cases with lymph node involvement (all Stage I1 or 111) the average diameter was 5 cm.e No differences in average size were present in the small number of non-pancreatic cancers associated with metastasis and those without metastasis. Since in 33% of specimens of duct adenocarcinomas of the head of pancreas, metastases were present in the lymph nodes along the superior and inferior borders of body of pancreas (SB and IB, or in the jejunal and mid-colic subgroups), it would appear that the Whipple procedure, in which these lymph nodes are not removed, is not an adequate operation for head of the pancreas duct cancer.'0*"~'2 In addition, some nodes of the SH group, such as nodes in the porta hepatis, or pyloric subgroups, may be involved with metastasis and these are not removed in the standard Whipple operation. Ampullary and duodenal adenocarcinomas tended to spread more locally to the adjacent lymph node groups around the duodenum and the head of the pancreas and it would appear that a Whipple pancreatectomy would be sufficient in the majority of these cases. The marked difference in the number of lymph nodes in the different types of specimens studied indicates the extent of the lymphatic network and even with the regional resection all lymphatics or lymph nodes draining the involved areas of pancreas were not resected.'*13 Whether further experience will reveal metastasis to other nodes cannot be predicted from the small number of cases examined. The widespread distribution of metastasis found in peripancreatic lymph nodes would indicate the major procedures-regional or total pancreatectomies-as being more adequate to remove potential sites of nodal involvement by pancreas cancer. None of the cases showed metastasis to gastric or to splenic lymph nodes consistent with the implication that there are no lymphatic communications between the pancreas and the lymph nodes of the greater and lesser curvatures of the stomach.@*13 In a recent patient not included in this study, we found a metastasis in a CBD lymph node from a duct carcinoma of the head of the pancreas. The lymphatics of the head and body of pancreas do not drain into the tail of pancreas or splenic nodes, although rare lymph vessels from the tail of pancreas can terminate in the SB and IB subgroup^.'^ We did not have the opportunity to study cases of carcinoma of the tail of pancreas. The only duct carcinoma located in the body of the pancreas in this study was a relatively small tumor 1.0 cm in diameter, mostly in situ carcinoma but with small foci of invasion, which metastasized to 3 (SB) lymph nodes. This depressing finding of metastasis associated with a relatively very small cancer correlates with the very poor prognosis of the rare cancer of the body of the pancreas.'

8 No. 3 LYMPH NODES IN PANCREATIC CANCER Cubilla et al. 887 Whether the better 5 year survival with periampullary or ampulla cancers than with pancreas duct cancer' is related per se to the greater involvement of lymph nodes in the former is a matter of conjecture. The degree of involvement of lymph nodes may merely reflect the innate aggressiveness of the cancer and this may be a decisive factor in prognosis. Nevertheless the extent and degree of lymph node involvement is a practical matter in terms of the surgical extirpation of the primary tumor and the tissues involved. REFERENCES 1. Aston, S. J., and Longmire, W. P.: Pancreaticoduodenal resection: Twenty years' experience. Arch. Surg. 106: , Bowden, L., McNeer, G., and Pack, G. T.: Carcinoma of the head of the pancreas. Five year survival in four patients. Am. J. Surg. 109: , Cattell, R. B., and Pyrtek, L. J.: An appraisal of pancreatoduodenal resection: Follow-up study of 61 cases. Ann. Surg. 129: , Cattell, R. B., and Warren, K. W.: Pancreatic surgery. N. Engl. 3. Med. 244: , Cubilla, A. L.: Anatomical classification of carcinoma of the pancreaticoduodenal region. Carcinogenesis. Program of the Fourth Annual Collaborative Conference, Orlando, Florida, February 22-26, 1976, Division of Cancer Cause and Prevention. National Cancer Institute, National Institutes of Health. 6. Cubilla, A. L., and Fitzgerald, P. J.: Duct adenocarcinoma of pancreas. A clinicopathological study of 380 cases. Puthol. Ann. (In press). 7. Cubilla, A. L., and Fitzgerald, P. J.: Metastasis in pancreatic duct adenocarcinoma. Cancer Invasion and Me- tastasis. New York, Raven Press, Cubilla, A. L., and Fitzgerald, P. J.: Morphological lesions associated with human primary invasion nonendocrine pancreas cancer. Cancer Res. 36 : , Evans, B. P., and Ochsner, A.: The gross anatomy of the lymphatics of the human pancreas. Surgery 36: , Fortner, J. G.: Regional resection of cancer of the pancreas. A new surgical approach. Surgery 73: , Fortner, J. G., Kim, D. K., Cubilla, A. L., Turnbull, A,, Pahnke, L. D., and Shils, M. E.: Regional pancreatectomy. en bloc pancreatic, portal vein and lymph node resection. Ann. Surg. 186:42-50, ReMine, W. H., Priestly, J. T., Judd, E. S., and King, J. N.: Total pancreatectomy. Ann. Surg. 172: , Rouviere, H.: The lymphatics of the pancreas. In Anatomy of the Human Lymphatic System. M. J. Tobias, Ed. 1938; pp Whipple, A. O., Parsons, W. B., and Mullins, C. R.: Treatment of carcinoma of ampulla of vater. Ann. Surg. 102: , 1935.