A 53-year-old male patient with no family history or personal history of bowel cancer presented for "intermittent abdominal distention for more than 1 month". The patient did not experience nausea or vomiting, blood or black stools, abdominal pain or diarrhea, and fever or jaundice during the onset of the disease. Eating, defecation, and body position were not associated with bloating symptoms; urine color deepening was greater than before; and stool was normal.
The routine physical examination: the patient had better mental status, with stable vital signs and no yellowish skin and sclera, no enlarged superficial lymph nodes, and no liver and spleen enlargement affected; both lungs breathing sounds were normal; and no abnormal breathing sounds could be detected. There was no pain, rebound pain, and muscle tension, and bowel sounds can be heard in the whole abdomen, with an average of three to five times/minute. Weight loss was approximately 4-5 kg, and no remaining abnormalities were noted.
After admission, abdominal MRI scan was performed, and the results showed space occupying lesions in the hook region of the pancreatic head region; possibility of malignancy was high; the clinical stage of cT3N1Mx was concomitant, accompanied by bile duct system expansion; and multiple liver metastases may be present. The value of the tumor marker CA19-9 was 94.9 U/ml above the normal reference range (0-37 U/ml), and the CEA and lactate dehydrogenase (LDH) levels were in the normal range. Two ultrasound-guided liver biopsies were performed to clarify the patient's diagnosis, but these were negative. Finally, a PET/CT examination was performed, and the results showed the following: ampullary space-occupying lesions, possibly ampullary carcinoma; low-density nodules at liver S4 and S8; the tumor possibly showing metastasis; and the paralesional lymph nodes showing radioactive concentration, with high possibility of tumor metastasis. The patient also had low biliary obstruction. Second, we recommend the patient for endoscopic pathology by ultrasound, hoping to undergo surgical treatment after a clear pathologic diagnosis. However, because the patient had undergone two biopsies of liver puncture but had not obtained the pathological tissue, the patient and family members refused to perform endoscopic ultrasonography and hoped to undergo exploratory laparotomy as soon as possible to establish a clear diagnosis. When the opinions of the patients and their families were integrated, the patient did not have obvious organic lesions in the heart, lung, kidney, and other organs, and both liver puncture tests did not show any positive findings in pathological tissue scan. In addition, the patient has developed low biliary obstruction with elevation of tumor landmarks. Consent was obtained after a multidisciplinary consultation to be transferred to surgical therapy.
Downward surgery under epidural composite general anesthesia occurred on 2 October 2020. The surgical name was "exploratory laparotomy + modified pancreaticoduodenectomy". Surgery was an R0 resection, starting with the resection of the pancreatic head, duodenum, proximal jejunum, distal stomach, common bile duct, and gallbladder, followed by the reconstruction of the three sites: the pancreas and transverse colon, common bile duct and jejunum, and stomach and jejunum. Surgical records showed the following: the surgical incision was located in the right upper quadrant, and the skin was cut about 24 cm through the rectus abdominis incision. Intraoperative exploration showed the following: no abdominal ascites, no implant nodules in the peritoneum, and the right liver surface adhered to the diaphragm, which was released. The imaging showed that the occupation of the liver and the surface of the whole liver were not touched, the volume of the gallbladder increased, and about 200 ml of dark-green bile was drained by decompression. The common bile duct was seen after dissection of the hepatic duodenal ligament, which had dilation, approximately 1.5 cm in diameter. A 1 cm * 1 cm mass was reached in the ampulla region of the inferior common bile duct with a hard texture. Enlargement of hilar lymph nodes, paraciliary choledochal lymph nodes, and common hepatic artery lymph nodes were found. The lesion was found to be resectable after free exploration, so the decision to perform pancreaticoduodenectomy was made. The gallbladder was removed, and a total of 12 parahepatic arteries and common bile duct lymph nodes were removed and submitted for examination. The common bile duct was cut above the gallbladder junction, draining all bile, cutting the common bile duct about 1.5 cm in diameter, and the distal bile duct was ligated. The broken end of the common bile duct was sent to the frozen pathological examination, and no tumor cells were found. The gastric tissue was severed between the gastric body and the antrum, and the pancreas was then exposed. The transverse mesentery was dissected until the inferior margin of the pancreas, revealing the pancreatic head and superior mesenteric arteries, cutting the jejunum at the 10-cm jejunum, distal suture, and proximal suture from the transverse colon mesoic pore pulled back to the right. The pancreatic tissue was cut open after ligating the severed blood vessels of the pancreas, and the posterior pancreatic hook process appeared and the posterior resection mesangium was ligated. Since then, the tissues of the pancreatic head, duodenum, proximal jejunum, distal stomach, and the common bile duct and gallbladder have been completely removed. Reconstruction was then performed. In pancreatic and jejunal anastomosis, after leaving free the distal jejunum, the transverse colon was mentioned above from the transverse colon posterior mesangial fissure, and the anastomosis was made at 5 cm from the jejunal fracture end and the pancreas. In common bile duct and jejunal anastomosis, a longitudinal incision equal to the aperture of the common bile duct was made in the lateral edge of the jejunum from the pancreas and jejunostomy, followed by common bile duct jejunoanastomosis. In gastric jejunum anastomosis, a transverse colonic anterior gastrojejunostomy was performed about 50 cm below the common hepatic jejunal anastomosis. An ampullary carcinoma was intraoperatively diagnosed. However, the postoperative pathology showed a poorly differentiated DA, tumor tissue invaded the base layer of the duodenal intestinal wall involving parenteral adipose tissue, and there is also nerve invasion, pancreatic resection (-), bile duct resection (-), gastric resection (-), duodenal resection (-), and lymph nodes 0/7 in each group. Therefore, this patient was eventually diagnosed with poorly differentiated DA.
After the operation, the patient failed to perform adjuvant chemotherapy on time due to the COVID-19 outbreak. Review at 6 months thereafter revealed an elevation of the tumor marker CA19-9 to 515.5 U/ml; the abdominal MRI found multiple nodules in the liver, low signal on the T1WI sequence, a slightly higher signal in T2WI, some lesions with T2WI, larger nodules located in S6, about 10 mm * 8 mm in size, and a high possibility of metastasis. Combined with the elevation of the patient's tumor markers, considering the patient's disease progression, admission to chemotherapy is recommended. The chemotherapy regimen for cycle 1 was the SOX regimen (oxaliplatin+S-1:oxaliplatin: 220 mg per dose, intravenous administration, administered once during a treatment cycle, 21 days is used for one treatment cycle, S-1: each time 60 mg, oral medication, twice daily for 14 consecutive days per treatment cycle). The SOX treatment regimen is guidelines for gastric cancer. Hematological indicators were checked before medication in cycle 2, and it was found that tumor markers continued to rise (CEA: 5.03 ng/ml, CA19-9: 747.30 U/ml). After 1 cycle of chemotherapy, the tumor markers still show a significant upward trend, perhaps indicating that chemotherapy alone cannot effectively control the progression of the disease; after a multidisciplinary consultation, it was agreed that targeted drugs might be added to try them out.
The patient's primary tumor was located in the duodenum, and postoperative immunohistochemistry was performed: HER-2(1+), VEGF(+), Topo-IIalpha(+2%), PDGER-alpha (-), Ki67 (+30%), KRAS (-), NRAS (-), BRAF (+), MLH1 (+50%), PMS2 (+40%), MSH2 (+60%), MSH6 (+40%). The patient developed capecitabine-related adverse drug reactions after 1 cycle of oral capecitabine. The main manifestation is hand-foot syndrome, reaching grade 4. Due to the above reasons, coupled with the patient being not too old and in good physical condition, after consulting with the family members and obtaining their informed consent, capecitabine was replaced with S-1 during cycle 2 of chemotherapy. In addition, we added bevacizumab to conventional chemotherapeutic agents (the dose was 5 mg/kg, administered intravenously, administered once during a treatment cycle, and 21 days was used for one treatment cycle). Then, the patient regularly completed the following 7 cycles of treatment, and the patient tolerated the drug well throughout the treatment period and showed no serious drug-related adverse reactions again.
The patient was reviewed and evaluated on time throughout the treatment period. Evaluation criteria were according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1). The patient was rated as SD at cycle 3 (liver metastatic lesions decreased by 5% compared with before). At cycle 5, liver metastasis decreased by 30% and reached partial response (PR). The metastasis was visually invisible at cycle 7 and was assessed as complete remission (CR). During the entire treatment period from cycle 2 to the end of treatment, the liver metastases continued to decrease (ranging from 5% to 30%), and the tumor markers also decreased (CA19-9 decreased to normal levels from 949.0 U/ml and remained stable). When 8 cycles of treatment were completed, the patient's liver lesions were visually invisible from the initial 10 mm * 8 mm to the end of treatment.
After the end of chemotherapy, some lymph nodes in the hilar region and peritoneal cavity metastasis could not be significantly reduced compared with those before chemotherapy, which may be related to the tumor heterogeneity and drug tolerance. After a consultation in the radiotherapy department, they recommended abdominal radiotherapy. The original radiotherapy plan was 1.8 Gy each time, a total of 28 times, and a total radiation dose of 50.4 Gy. However, considering that the patient had experienced myelosuppression during chemotherapy and had a platelet decline after the second radiotherapy session (PLT: 70 * 109/l), combined with the patient's current physical state and disease condition, the radiotherapy schedule was changed to 20 times with a total radiation dose of 36 Gy. After radiotherapy, the abdominal metastatic lymph nodes showed a shrinkage trend, but the patient developed severe myelosuppression (PLT: 30 * 109/l) and jaundice after the 10th radiotherapy and finally failed to complete the radiotherapy plan. Bone marrow suppression seen during the radiotherapy process mainly showed decreased PLT, white blood cell (WBC), and neutrophil (NEU) count. The PLT value decreased to 30 * 109/l ((125-350 * 109/l), and the WBC value had a minimum drop to 1.5 * 109/l (3.5-9.5 * 109/l). The NEU value decreased to 0.8 * 109/l (1.8-6.3 * 109/l).
Up to the third degree according to the myelosuppression scores, the WBC levels were 1.29-1.0 * 109/l, NEU: 0.9-0.5 * 109/l, and PLT: 49-25 * 109/l. During radiotherapy, the patient's biochemical index was increased. Total bilirubin was 324.3 micromol/l (3.4-21 micromol/l), direct bilirubin was 180.80 micromol/l (0-3.4 micromol/l), indirect bilirubin was 143.50 micromol/l, and total bile acid was 13,000 U/l (5,300-11,300 U/l). The abnormalities of the above test indicators significantly fit with the jaundice symptoms of the patient. Subsequently, the patient underwent interventional therapy with "biliary drainage + biliary stenting", and the patient's jaundice symptoms significantly improved 3 days after surgery. However, the patient failed to continue the subsequent radiotherapy for factors such as myelosuppression and secondary infection. At present, the patient has been treated with bevacizumab plus S-1 for half a year, and no disease progression has occurred until June 2022 (  Table 1  ). 
Besides myelosuppression, drug-related adverse effects exist throughout patient treatment. For example, after the first cycle of capecitabine, the patient developed refractory hand-foot syndrome, mainly showing significant swelling and pain in the palm and foot with severe desquamation and ulcers, as well as local blisters and erythema. Such severe capecitabine-related adverse effects after 1 cycle are rare, as the drug-related adverse effects are usually proportional to the dose. Fortunately, capecitabine was replaced with S-1 in cycle 2, after which the patient gradually resolved. Furthermore, the patient also inevitably developed oxaliplatin-related peripheral sensory neuropathy after 8 cycles of oxaliplatin treatment until the last cycle severity had reached stage 3. This is inevitable, but at this time the patient has successfully completed the treatment and the effect was good (  Figures 1 - 8  ).