Giant appendiceal mucocele: report of a case.

Mucoceles of the appendix are a group of mucus-filled lesions causing obstructive dilation of the ileocecal appendix. We report a rare case of giant appendiceal mucocele. A 48-year-old woman, with no discomfort, was admitted to our hospital after a mass was detected in the right lower quadrant of the abdomen. The patient underwent right hemicolectomy on the basis of the clinical diagnosis of a possible appendiceal tumor. The final pathologic diagnosis was mucocele of the appendix.

Hepatic pedicle clamping does not worsen survival after hepatic resection for colorectal liver metastasis: results from a systematic review and meta-analysis.

BACKGROUND: Hepatic pedicle clamping (HPC) has been demonstrated to be effective for short-term outcomes during hepatic resection. However, HPC-induced hepatic ischemia/reperfusion injury can accelerate the outgrowth of hepatic micrometastases in experimental studies. The conclusive evidence regarding effects of HPC on long-term patient outcomes after hepatic resection for colorectal liver metastasis (CRLM) has not been determined. METHODS: A comprehensive electronic literature search was performed to identify studies evaluating the oncological effects of HPC after hepatic resection for CRLM. The main outcome measures were intrahepatic recurrence (IHR), disease-free survival (DFS), and overall survival (OS). A meta-analysis was performed using the random-effects models to compute odds ratio (OR) along with 95% confidence intervals (CI). RESULTS: Four studies, with a total of 2,114 patients (73.7% HPC, 26.3% non-HPC), matched the inclusion criteria. Meta-analyses revealed that IHR (OR 0.88; 95% CI 0.69-1.11; P = 0.27), DFS (OR 0.88; 95% CI 0.70-1.10; P = 0.27) and OS (OR 0.99; 95% CI 0.79-1.24; P = 0.90) did not differ significantly between the HPC and non-HPC groups. CONCLUSIONS: This meta-analysis provides persuasive evidence that HPC during hepatic resection for CRLM has no significant adverse oncological outcomes. HPC should be considered an option during parenchymal liver resection from current available evidence.

Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis.

BACKGROUND: The negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM). METHODS: Studies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95 % CI). RESULTS: The outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95 % CI = 1.33-2.96; P = .0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95 % CI = 1.25-2.27; P = .0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses. CONCLUSIONS: This study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs.

A case of gastric cancer with perforation caused by chemotherapy with docetaxel and S-1.

We treated a patient who had gastrointestinal perforation during chemotherapy with docetaxel and S-1 which was successfully treated with percutaneous drainage. A 66-year-old man was admitted to our hospital with complaints of abdominal pain. Gastric cancer (T3N1M0) had been diagnosed 3 years earlier, and distal gastrectomy had been performed. Two years later, intrapelvic recurrence of the cancer was diagnosed. We administered docetaxel and S-1. After 3 courses of chemotherapy, he complained of abdominal pain of sudden onset. Computed tomography showed free air and limited ascites, and gastrointestinal perforation was diagnosed. We performed percutaneous drainage. The abdominal pain improved 3 days later, and he was able to eat meals 15 days after the onset of abdominal pain. He was discharged 27 days after admission. Because the patient's general condition was poor, we started providing best supportive care only. He died 10 months after the perforation was found.

The effect of intraoperative rectal washout on local recurrence after rectal cancer surgery: a meta-analysis.

BACKGROUND: Implantation of exfoliated cancer cells has been suggested as a possible mechanism of local recurrence at the site of colorectal anastomosis. Intraoperative rectal washout has been suggested to eliminate free cancer cells; however, there is no conclusive evidence of a beneficial effect of intraoperative rectal washout on local recurrence after anterior resection of rectal cancer. METHODS: Studies published through February 2012 evaluating the impact of intraoperative rectal washout for local recurrence or positive cytology from donuts wash were identified by an electronic literature search. A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute risk ratio (RR) along with 95% confidence intervals (CI). RESULTS: Nine studies met the inclusion criteria, yielding a total of 5,395 patients. Eight studies evaluated overall local recurrence, including anastomotic recurrence, and five of the eight studies evaluated anastomotic recurrence separately. Two studies evaluated positive cytology from donuts wash. Local recurrence rate was 5.79% in the washout group and 10.05% in the no washout group-a difference that was statistically significant (RR = 0.57; 95% CI = 0.46-0.71; P < 0.00001). Rectal washout significantly reduced the risk of anastomotic recurrence (RR = 0.3; 95% CI = 0.12-0.71; P = 0.007). No influence of rectal washout was observed on positive cytology from donuts wash. CONCLUSIONS: From the results of this meta-analysis, it may be justified to recommend intraoperative rectal washout to prevent local recurrence in rectal cancer surgery.

[Reduction in oxaliplatin-related neurotoxicity by the administration of Keishikajutsubuto(TJ-18)and powdered processed aconite root].

Oxaliplatin (L-OHP)is an important chemotherapeutic drug for the treatment of colorectal cancer. Peripheral neuropathy was observed in 90% of patients who received L-OHP.Neuropathy often results in the discontinuation of treatment or a decrease the quality of life(QOL). The most effective method for reducing neuropathy is the discontinuation of L-OHP. To reduce neuropathy, we administered Keishikajutsubutou(TJ-18)with powdered processed aconite root(TJ-3023), and we report the effect of these compounds. The subjects comprised 11 patients with metastatic colorectal cancer. L-OHP(85mg/m2)was administered as part of the FOLFOX6(10 patients)or FOLFOX7(1 patient)regimen. All patients had experienced neuropathy. We administered TJ-18(7.5 g)and T-3023(1 g). After 2 weeks, the TJ-3023 dose was increased to 2 g for nonresponders. The response was evaluated according to the Neurotoxicity Criteria of DEBIOPHARM. Reduction in neuropathy was observed in 5 cases(45.5% ). Among 6 patients whose feet and hands felt warm, reduction in neuropathy was observed in 5(83.3% ).

[Prevention of nausea and vomiting in pain medication for digestive cancer].

Nausea and vomiting are common side effects due to opioid therapy, and may greatly impede the quality of life of cancer patients. A preventive method for nausea and vomiting has not yet been established. We developed a clinical pathway(CP) for cancer pain management in which prochlorperazine is used for the prevention of nausea and vomiting caused by opioids. We have shown that this CP is effective for relieving cancer pain. In this study, we investigated the efficacy prochlorperazine has for preventing nausea and vomiting caused by opioids in patients treated with the CP. The incidence of nausea and vomiting of those patients was 15. 8% which was lower than the results of other previous clinical trials. However, we could not show the effectiveness of prochlorperazine. Prochlorperazine, which is a dopamine D2 receptor antagonist, may show limited utility for the prevention of nausea and vomiting; however, in opioid therapy, histamine receptor(H1)prevention is also important.

Success rate of collagen gel droplet-embedded culture drug sensitivity test in colorectal cancer: are antibiotics a prerequisite for specimen irrigation?

The collagen gel droplet-embedded culture drug sensitivity test (CD-DST) is one of the best chemosensitivity tests owing to its high success rate. However, CD-DST is often a culture method, and contamination is a serious problem, especially in the case of colorectal cancer, which is contaminated by enteric bacteria. It has been reported that the success rate of CD-DST is 64.0% in the case of colorectal cancer. Therefore, the sampling and washing of specimens before culture are extremely important. By washing specimens carefully with normal saline containing antibiotics, we achieved a success rate of 85.3% in the case of colorectal cancer. To improve the success rate, we started specimen irrigation with a large amount of normal saline in January 2007. As a result, a success rate exceeding 90% was acquired. For the success of CD-DST for colorectal cancer, it is important to irrigate specimens many times with a large amount of normal saline.

[Evaluation of S-1 for stage IV gastric cancer].

To evaluate the efficacy of S-1 for Stage IV gastric cancer, we retrospectively examined 124 patients with Stage IV gastric cancer. We classified patients into two groups based on the presence or absence of S-1 administration: the S-1 therapy group (n= 56) and the non-S-1 therapy group (n=68). Basically, patients received S-1 orally at 40 mg per square meter of body surface area twice daily for 4 weeks, followed by 2 weeks without chemotherapy. When side effects appeared, we tried dose reduction or cut short the administering period according to the dose modification criteria. Major patient characteristics were as follows: gender (male/female: 76/48), and age (median[range]: 63[24-83]). The median S-1 dosage was about 5 courses, and the median of the S-1 total dosage was 10. 08 g, based on the amount of tegafur. The relative dose intensity (RDI) was well maintained (average: 74. 9%). The survival rate in the S-1 therapy group was significantly higher than in the non-S-1 therapy group. The median survival time (MST) was 308 days in the S-1 group and 157 days in the non-S-1 group. In the S-1 therapy group, the MST was 629 days for those receiving 10 g or more, while that of those receiving less than 10 g was 209 days. The MST of patients administered 10 g or more was significantly longer than that of those receiving less than 10 g (p<0. 0001). Therefore, we consider that S-1 therapy improves survival in patients with Stage IV gastric cancer.

Pyogenic liver abscess caused by direct invasion of esophageal squamous cell carcinoma to the liver: report of a case.

We report a case of esophageal squamous cell carcinoma (ESCC) directly invading the liver and causing a pyogenic liver abscess. The patient was a 66-year-old man who presented with dysphagia. Esophagography, endoscopic study, and computed tomography (CT) showed a mass lesion in the lower third of the esophagus. A high fever developed on hospital day 17 and another CT scan revealed a liver abscess, 50 × 45 mm, in the left lateral lobe of the liver. Although imaging demonstrated a liver abscess continuous with the tumor, we performed percutaneous transhepatic drainage, followed thereafter by distal esophagectomy and total gastrectomy with a left lateral segmental resection of the liver. The pathological findings confirmed a diagnosis of ESCC with direct invasion (T4N1M0, stage IVa in the TNM classification). The patient had an uneventful postoperative recovery. Microscopic examination of the resected specimen revealed the expansive growth of tumor cells into the hepatocellular tissues. To our knowledge, this is the first report of the direct invasion of esophageal cancer to the liver causing a pyogenic liver abscess; however, it should be borne in mind when a patient with esophageal cancer becomes febrile.

[Effects of irinotecan and 5-FU combination therapy in gastric cancer--is combination therapy synergic?].

UNLABELLED: The response rate of Irinotecan for gastric cancer is reported to be 18. 4%. The rate is improved by combination with 5-FU. However, it remains unclear whether or not the effect of the two drugs is synergy or antagonistic. The purpose of this study is to clarify whether the effect of Irinotecan and 5-FU in gastric cancer is synergy or antagonistic. We performed study using 13 specimens removed surgically and 2 specimen collected from ascites. We performed the Collagen Gel Droplet Embedded Culture Drug Sensitivity Test (CD-DST) with 3 assumptions. In the first assumption, we let 5-FU come in contact with a tumor at a level of 1 mg/mL for 24 hours. The second assumption was SN-38 at a level of 30 mg/mL for 24 hours and the 3rd assumption was SN-38 at a level of 30 mg/mL and 5-FU at a level of 1 mg/mL for 24 hours. If the combination index was more than 1, the combination therapy was judged as synergic; if less than 1, it was considered antagonistic. RESULTS: The inhibition rate of combination therapy was significantly higher than that of monotherapy. The inhibition rate of combination therapy was significantly correlate with that of monotherapy (Irinotecan; r=0.704, p=0.003, 5-FU; r=0.746, p=0.001). The combination index was antagonistic in only 6 of 15 cases. However, it was synergic in all well-differentiated adenocarcinomas (4/4). DISCUSSION: We conclude that combination therapy is antagonistic in most cases of gastric cancer in vitro. However, it may be synergic in well-differentiated adenocarcinomas.

A case of extrahepatic bile duct wall recurrence of gastric carcinoma that was treated with pancreaticoduodenectomy.

We report on a patient with obstructive jaundice caused by recurrence of gastric carcinoma in the wall of an extrahepatic bile duct more than 5 years after gastrectomy who was treated with pancreaticoduodenectomy. Histopathologic examination of the surgically resected specimen revealed a poorly differentiated adenocarcinoma with focal signet ring cells in the wall of the common bile duct which was histologically similar to the primary gastric carcinoma. To confirm the diagnosis, immunohistochemical staining was performed with antibodies against cytokeratins (CK7, CK20) and mucin peptide core antigens (MUC5AC, MUC6, MUC2). Based on the expression patterns of this monoclonal antibody panel, the final diagnosis of the common bile duct tumor was an isolated local recurrence of the gastric carcinoma. The patient has survived for more than 26 months after pancreaticoduodenectomy without recurrence.

Left paraduodenal hernia incidentally diagnosed during operation for transverse colon cancer.

We report the case of a patient with paraduodenal hernia diagnosed incidentally during an operation for transverse colon cancer. The patient was a 77-year-old woman who complained of dizziness. Laboratory data revealed no abnormal findings except slight anemia. Barium enema and colonoscopic examination revealed an irregular surfaced mass, about 5.0 cm in size, located near the flexure of the spleen of the transverse colon. A biopsy of the mass was performed, and a moderately differentiated adenocarcinoma was diagnosed. In April 2009, following the diagnosis of transverse colon cancer, laparotomy was performed, which revealed that a few loops of the jejunum were herniated through the orifice into the space posterior to the transverse mesocolon. Moreover, the jejunal loops were located right between a shifted left branch of the middle colic artery and ascending left colic artery. There were no ischemic changes in the jejunum. These findings were consistent with a left paraduodenal hernia associated with transverse colon cancer. The scheduled left hemicolectomy was performed in addition to a radical operation of the left paraduodenal hernia. The abdominal computed tomography (CT) images were reviewed postoperatively. The scan projection radiogram obtained by CT revealed a packing of jejunal loops in the middle of the abdomen. Abdominal CT revealed ascending left colic artery at the left edge of a packing of jejunal loops. The patient was discharged from our hospital 14 days after the surgery without any complications. Left paraduodenal hernias are rare and constitute less than 0.4% of all intestinal obstructions. Retrospectively reviewed, the preoperative CT is suggestive. In addition to the packing of jejunal loops in the middle of the abdomen, ascending left colic artery was clearly observed at the left edge of the packing of jejunal loops, which indicates left paraduodenal hernia.

Liver cyst with biliary communication successfully treated with laparoscopic deroofing: a case report.

A 56-year-old woman visited our hospital because of high fever and right hypochondralgia. Abdominal computed tomography showed a liver cyst 10 cm in diameter and dilatation of the intrahepatic bile duct. Percutaneous transhepatic drainage of the cyst guided by ultrasonography disclosed that the cyst contained a brown milky fluid, and cystography showed biliary communication. Thus, the cyst was diagnosed as an infectious hepatic cyst with biliary communication. Treatments for liver cysts include aspiration therapy, alcoholic sclerotherapy, laparoscopic fenestration, fenestration by laparotomy, cystojejunostomy, cystectomy, and hepatectomy. Because a simple liver cyst is benign, treatments should be low-risk and minimally invasive; thus, we performed laparoscopic fenestration. Fenestration should not be performed if the case is complicated by infection or biliary communication. Although cystography showed biliary communication, the cyst was not visualized with endoscopic retrograde cholangiography, and we concluded that the biliary communication was small. Operation time was 95 minutes, and blood loss was 10 g. Pathological findings of the liver cyst were consistent with a simple cyst. The postoperative course was good, and the patient left the hospital 10 days after the operation. Eighteen months have passed since the operation, and no recurrent cysts have been detected with computed tomography. This is the second report of liver cyst with biliary communication successfully treated with laparoscopic deroofing. Laparoscopic fenestration is a useful method for treating simple benign liver cysts because of its minimal invasiveness and may be useful in cases with small biliary communication.

Life-threatening bleeding from gastrointestinal stromal tumor of the stomach.

Here, we report on two patients with hemorrhagic shock due to hematemesis from a gastrointestinal stromal tumor (GIST) of the stomach. Patient 1 was a 64-year-old woman who was admitted to our hospital because of syncope due to hemorrhagic shock resulting from massive hematemesis. Emergent upper gastrointestinal (GI) endoscopy revealed a 5-cm-diameter submucosal tumor on the lesser curvature of the lower gastric body. In addition to the central ulceration of the tumor, a Dieulafoy-like lesion was present. Neither lesions showed active bleeding at the time of observation. Because the patient collapsed twice with fluminant hematemesis after admission, she underwent distal gastrectomy with Billroth-I reconstruction. Histological examination revealed a gastric GIST with no nodal metastasis and the mitotic count was less than 5 per 50 HPFs. Dilated vessels were prominent in the peritumoral submucosa, and a thrombus was seen in these vessels, which seemed to be a bleeding point. The patient had an uneventful postoperative course and has been alive without recurrence for 5 and a half years. Patient 2 was a 60-year-old man who presented with syncope due to hemorrhagic shock resulting from massive hematemesis. Because the source of the bleeding was not elucidated with an initial upper GI endoscopy, he was treated for a gastric ulcer. One week after admission, he suffered from hemorrhagic shock again, and a submucosal tumor 6 cm in size was revealed on the greater curvature of the upper stomach with upper GI endoscopy. The patient subsequently underwent wedge resection of the tumor. Histopathological findings were consistent with a GIST and the mitotic count was less than 5 per 50 high-power fields. The tumor showed no necrosis or intratumoral hemorrhage. A peritumoral submucosal artery, which was responsible for the massive hematemesis, was located at some distance away from the central ulceration. Postoperative recovery was without complications. After 4 years, the patient remains healthy and disease-free. Although hematemesis associated with gastric GIST has been said to originated from the central ulceration of the GIST, life-threatening, massive hematemesis is rare. The exact bleeding points of the gastric GISTs in these cases were submucosal vessels adjacent to the GIST, not the central ulceration. There have been no reports of peritumoral, submucosal vessels causing massive hematemesis from gastric GISTs. Because the origins and manner of bleeding varies in gastric GISTs, we must decide the methods of hemostasis immediately including the tumor excision.

Case of meningeal carcinomatosis with gastric cancer which manifested meningeal signs as the initial symptom; the palliative benefit of radiotherapy.

A 53-year-old male presenting with anorexia, intermittent diplopia, general fatigue, headache and vertigo was admitted to our hospital. He was diagnosed as having gastric cancer by endoscopy of his upper gastrointestinal tract. Brain computed tomography (CT) showed no abnormalities, but magnetic resonance imaging (MRI) showed slight enhancement in the cerebellar sulcus. Cytological examination of cerebrospinal fluid revealed malignant cells. He became blind one week after hospitalization. We diagnosed his condition as meningeal carcinomatosis (MC) and started radiotherapy. His vision improved after four weeks of treatment, and then he became totally blind again. Since his general condition remained poor, we did not perform chemotherapy. He died on the 127th day of hospitalization. MC is a rare pathosis of gastric cancer in comparison with leukemia and malignant lymphoma. This disease does not often show characteristic pictorial images, and early diagnosis is difficult. Moreover, it usually manifests itself in its late stages after several months or more of treatment, and it is rare for MC to be present at the time of initial diagnosis. We present a case of gastric cancer with meningeal signs present when the primary tumors were diagnosed. Radiotherapy alleviated some of the symptoms, and the patient survived for as long as patients undergoing enforced chemotherapy.

Case of adenosquamous carcinoma of the ascending colon.

Adenocarcinoma accounts for most of the malignant tumors originating from the colon, whereas adenosquamous carcinoma is rare, accounting for about 0.1% of all colon cancers. We present herein a case of adenosquamous carcinoma of the ascending colon. The patient was a 94-year-old woman who presented with a chief complaint of lower abdominal pain. A barium enema examination and lower gastrointestinal endoscopy showed a type 3 tumor in the ascending colon, and a biopsy confirmed the diagnosis of adenosquamous carcinoma. Right hemicolectomy was performed, and the tumor was diagnosed as a stage III advanced colon cancer. The patient had postoperative aspiration pneumonia and died 35 days after surgery. A search of Japanese literature over the past 25 years yielded 70 patients with adenosquamous carcinoma of the colon, and the clinicopathological features are discussed herein.

Male choriocarcinoma with metastasis to the jejunum: a case report and review of the literature.

We report on a patient with male choriocarcinoma. The patient was a 31-year-old male patient with jejunal choriocarcinoma that metastasized from the mediastinum. He was admitted complaining of melena and severe anemia. Upper and lower gastrointestinal endosocopy was performed, but no source of bleeding was seen. Chest X-ray and CT revealed a mediastinal tumor 7 cm in size anterior to the arotic arch. Superior mesenteric arteriography showed irregularities and macular opacity in the jejunal artery. An emergency laparatomy was performed because of massive gastrointestinal bleeding. A jejunal tumor approximately 4 cm in size was resected and numerous metastases were observed in the liver and mesentery. Histopathological examination showed metastatic jejunal choriocarcinoma. Gynecomastia was not present and the testes were normal. Serum beta-human chorionic gonadotropin (HCG) was at an abnormally high level of 4,396 ng/mL. Because of metastases to the brain and invasion to the trachea, he died on postoperative day 20. We report this rare case of a male patient with metastases of choriocarcinoma to the gastrointestinal tract from the mediastinum, together with a review of the literature.

Correlation between clinical pathologic factors and activity of 5-FU-metabolizing enzymes in colorectal cancer.

INTRODUCTION: Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthase (TS) are initial key enzymes in the 5-fluorouracil (5-FU) metabolic pathway. The expression levels and activities of these three enzymes play important roles in the response of cancer patients to 5-FU-based chemotherapy. PURPOSE: The purpose of this study was to investigate the relationship between the activities of 5-FU metabolic enzymes and clinicopathologic factors in colorectal cancer. METHODS: We measured the activities of OPRT, DPD, and TS in colorectal cancer tissues. We also investigated the correlations between the activities of these three enzymes and clinicopathologic factors (histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, and vascular invasion). We examined 100 patients with surgically resected colorectal cancer. RESULTS: Poorly differentiated adenocarcinoma showed significantly higher DPD activities than did moderately differentiated or well-differentiated adenocarcinoma. In patients with lymph-node metastasis, OPRT activity was significantly lower than in patients without lymph-node metastasis. No significant relation was found between TS activity and histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, or vascular invasion. CONCLUSION: The response to 5-FU may be poor in patients with lymph-node metastasis, because of low OPRT activity, and in patients with poorly differentiated adenocarcinoma, because of high DPD activity.

[Antitumor effect of paclitaxel for gastric cancer is AUC dependent].

Paclitaxel (PTX), which is used for ovarian cancer, lung cancer, breast cancer and gastric cancer, is administered at a dose of 210 mg/m(2) once every three weeks. However, WHO grade 3-4 hematological and non-hematological toxicity occurred frequently in this manner. In recent studies about ovarian cancer and lung cancer, a schedule in which PTX was given weekly could have the same or better efficacy, with fewer side effects. The response rate of PTX administered every three weeks for gastric cancer, was 23.3 to approximately 28.0%, while that of PTX administered weekly was 24.0 to approximately 25.8%. Because of fewer adverse events, weekly PTX is widely used for gastric cancer in Japan. To prove the validity of PTX weekly administration, we performed a study using six specimens removed surgically and one specimen collected from ascites. A chemosensitivity test was performed on the basis of two assumptions: a high concentration for a short time, and a low concentration for a long time. A similar PTX effect was obtained when the AUC was equal. In this study, we demonstrated that the effect of low-dose PTX was equal to the effect of high-dose PTX in gastric cancer.