Successful continuance of CDK4/6 inhibitor treatment with palbociclib after abemaciclib-induced hepatotoxicity in breast cancer: a case report.

Abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, causes severe hepatotoxicity, a severe adverse event associated with the loss of treatment opportunities. We report a case of liver injury (grade 4) during treatment with abemaciclib, in which the patient was switched to palbociclib and successfully treated with this CDK4/6 inhibitor. A 73-year-old woman with bone metastatic breast cancer (hormone-positive, HER2-negative) was treated with abemaciclib, fulvestrant, denosumab, and precipitated calcium carbonate with cholecalciferol and magnesium carbonate (pCCCM). On day 17, the patient developed skin rashes on her trunk and arms. On day 22, abemaciclib and pCCCM were discontinued due to drug eruption. Grade 3 aspartate aminotransferase (AST) and grade 4 alanine aminotransferase (ALT) levels increased on day 29. Therefore, fulvestrant and denosumab were suspended as the causes of severe hepatotoxicity, in addition to the two drugs suspected of causing the skin eruption. On day 43, AST and ALT levels did not improve, and the patient was referred to a hepatologist. The hepatologist diagnosed hepatotoxicity as a drug-induced liver injury through additional tests and interviews. Fulvestrant treatment was resumed on day 78, and palbociclib on day 92, and denosumab and pCCCM on day 134. On day 287, treatment with the CDK4/6 inhibitor was continued without evidence of liver dysfunction. This case suggests that rechallenge with palbociclib after severe liver injury with abemaciclib may allow for continued treatment with CDK4/6 inhibitors.

The authors reply: Re: Yamamoto R, Sugiura T, Ashida R, Ohgi K, Yamada M, Otsuka S, and Uesaka K. Prognostic value of carbohydrate antigen 19-9 and the surgical margin in extrahepatic Cholangiocarcinoma. Ann Gastroenterol Surg. 2022;6:307-315.

The specific growth rate of the perioperative carbohydrate antigen 19-9 values was not related to the prognosis of extrahepatic cholangiocarcinoma.

Retroperitoneal and Mediastinal Emphysema after Sigmoid Colon Resection.

Retroperitoneal and mediastinal emphysema after colon resection is extremely rare, especially in the absence of anastomotic leakage. The feasibility and safety of conservative treatment for this complication are unknown. We report a patient who underwent open sigmoid colon resection for colon cancer and developed retroperitoneal and mediastinal emphysema that was not caused by anastomotic leakage. Retroperitoneal and mediastinal emphysema occurred as a result of diverticular perforation. We were able to treat this patient successfully with conservative management.

Vascular resection for distal cholangiocarcinoma.

PURPOSE: Vascular resection (VR) is extended surgery to attain a negative radial margin (RM) for distal cholangiocarcinoma (DCC). The present study explored the significance of VR for DCC, focusing on VR, RM, and findings suggestive of vascular invasion on multidetector-row computed tomography (MDCT). METHODS: Patients with DCC who underwent resection between 2002 and 2019 were reviewed. RESULTS: Among 230 patients, 25 received VR. The overall survival (OS) in the VR group was significantly worse than in the non-VR group (16.7% vs. 50.7% at 5 years, P < 0.001). Patients who underwent VR with a negative RM failed to show a better OS than those who did not undergo VR with a positive RM (19.7% vs. 35.7% at 5 years, P = 0.178). Of the 30 patients who were suspected of having vascular invasion on MDCT, 11 did not receive VR because the vessels were freed from the tumor; these patients had a significantly better OS (57.9% at 5 years) than those who underwent VR. CONCLUSIONS: VR for DCC was associated with a poor prognosis, even if a negative RM was obtained. VR is not necessary for DCC when the vessels are detachable from the tumor.

A calcitonin-producing pancreatic neuroendocrine neoplasm treated with distal pancreatectomy a lengthy time after a left trisectionectomy for liver metastases: a case report.

BACKGROUND: Calcitonin-producing pancreatic neuroendocrine neoplasms (PanNENs) are extremely rare. There have been no reports of a patient in whom liver metastases were the presenting finding, and a calcitonin-producing PanNEN was subsequently detected after a lengthy period. CASE PRESENTATION: A 53-year-old man had diarrhea for several years. Computed tomography (CT) revealed multiple liver tumors. We performed a left trisectionectomy with a bile duct resection. The histologic examination showed neuroendocrine tumors G1. Immunohistochemistry was positive for calcitonin and the serum calcitonin level was elevated. Neuroendocrine neoplasms of hepatic origin are extremely rare, so a systemic exploration was performed, but no tumor was detected. CT showed a 4-mm calcification in the pancreatic body, but no contrast-enhanced mass was noted. Although the liver tumors were resected, the diarrhea and high serum calcitonin level persisted. Serial examinations were performed for 6 years, but no tumor was identified; however, 6.5 years after the hepatectomy the serum calcitonin level increased. CT showed a 10-mm contrast-enhanced mass in the calcified area of the pancreatic body. A distal pancreatectomy was performed. The histologic examination showed a neuroendocrine tumor G1, which mimicked the liver tumors. Immunohistochemistry was positive for calcitonin. After the distal pancreatectomy, the serum calcitonin level decreased and diarrhea resolved. The calcitonin-producing neuroendocrine neoplasm was considered the pancreatic primary and the hepatic tumors were metastases. CONCLUSIONS: Calcitonin-producing PanNENs may be initially recognized as liver tumors and may become evident after a lengthy period, thus long-term observation is recommended. Aggressive surgeries may contribute to long-term survival.

Preoperative risk factors for early recurrence after resection of perihilar cholangiocarcinoma.

BACKGROUND: Early recurrence after curative resection of perihilar cholangiocarcinoma (PHCC) often occurs within a year of surgery. Preoperative predictors of early recurrence remain unclear. The aim of this study was to define reliable preoperative predictors of early recurrence. METHODS: Medical records and preoperative multidetector-row CT of patients with PHCC who underwent resection between 2002 and 2018 were reviewed. Clinical findings, tumour markers, and radiological appearances including a 'periductal enation sign' (PES) where there was evidence of soft tissue enhancement appearing to arise from the extrahepatic bile duct, were analysed. RESULTS: Among 261 patients who underwent resection for PHCC, 67 (25.7 per cent) developed early recurrence. Multivariable analysis identified four preoperative risk factors for early recurrence, namely carbohydrate antigen 19-9 (CA19-9) 37 U/ml or higher (OR 2.19, 95 per cent confidence interval (c.i.) 1.08 to 4.46), positive PES (OR 7.37, 95 per cent c.i. 2.46 to 22.10), mass-forming tumour (OR 4.46, 95 per cent c.i. 1.83 to 10.90), and luminal-occlusion tumour (OR 4.52, 95 per cent c.i. 2.11 to 9.68). The OR of preoperative risk factors were used to define four risk subgroups for early recurrence. The early recurrence rates in the low, moderate, high, and very-high risk groups were 0, 9.4 , 39.7, and 65.0 per cent respectively. CONCLUSION: CA19-9, PES, mass-forming tumour, and luminal-occlusion tumour identify patients at higher risk for early recurrence after resection of PHCC.

Converted-hepatopancreatoduodenectomy for an intraoperative positive ductal margin after pancreatoduodenectomy in distal cholangiocarcinoma.

PURPOSE: Pancreatoduodenectomy (PD) is the standard treatment for distal cholangiocarcinoma, and a negative ductal margin (DM0) is indispensable for the long-term survival. When intraoperative frozen sections of ductal margin after PD are positive, converted-hepatopancreatoduodenectomy (C-HPD) is the final option available to gain an additional ductal margin. However, the efficacy of C-HPD remains unclear. METHODS: Patients who underwent PD or C-HPD for distal cholangiocarcinoma between 2002 and 2019 were analyzed. The type of hepatectomy in C-HPD was restricted to left hepatectomy to prevent posthepatectomy liver failure. RESULTS: Of 203 patients who underwent PD for distal cholangiocarcinoma, 49 patients exhibited intraoperative positive ductal margin (DM1) after PD. Eleven patients underwent C-HPD for intraoperative DM1 after PD, in which intraoperative DM1 with invasive carcinoma (DM1inv) was observed in 3 patients, and intraoperative DM1 with carcinoma in situ (DM1cis) was observed in 8 patients. The median additional ductal margin yielded by C-HPD was 9 mm (interquartile range 7-13 mm). C-HPD eradicated intraoperative DM1inv in 3 patients, with 2 patients showing DM0 and 1 patient showing DM1cis. Regarding 8 patients who underwent C-HPD for intraoperative DM1cis, 4 patients had DM0, but the others had DM1cis. C-HPD was associated with a high complication rate, but no mortality was observed. The median survival time of patients who underwent C-HPD was 48.8 months. CONCLUSION: C-HPD was able to safely eradicate intraoperative DM1inv after PD. However, the length of the resected bile duct according to C-HPD may not be sufficient to remove intraoperative DM1cis after PD.

Prognostic Value of Carbohydrate Antigen 19-9 and the Surgical Margin in Extrahepatic Cholangiocarcinoma.

Aim: The prognostic value of the perioperative carbohydrate antigen 19-9 (CA19-9) value and the prognostic relationship between the CA19-9 value and the surgical margin in extrahepatic cholangiocarcinoma (EHCC) have not been fully discussed. Methods: A total of 390 patients who underwent curative resection for EHCC between 2002 and 2018 were retrospectively analyzed. According to the perioperative CA19-9 value, patients were divided into three groups: preoperative normal (Normal, n = 178), preoperative high and postoperative normal (Normalization, n = 155), and preoperative high and postoperative high (Nonnormalization, n = 57). Survival was analyzed according to the perioperative CA19-9 value and surgical margin. Results: The optimal cutoff value of CA19-9 was 37 U/mL. Overall survival (OS) was significantly stratified according to the perioperative CA19-9 value. The 5-y OS rates in the Normal, Normalization, and Nonnormalization groups were 53%, 38%, and 23%, respectively (P < .001). Although the locoregional recurrence rate was comparable among the groups, the Normal group exhibited distant recurrence less frequently in comparison to the other groups. In the Normal group, the margin status had a significant impact on the OS (surgical resection with a negative margin [R0], 59% vs a microscopically positive margin [R1], 7% at 5-y, P < .001). In contrast, in the Normalization and Nonnormalization groups, the OS rate of the R0 and R1 resection groups did not differ to a statistically significant extent. Conclusion: The perioperative CA19-9 value was related to the prognosis of resectable EHCC. A preoperative CA19-9 value of ≥37 U/mL reflected systemic disease. R0 resection did not affect the survival in this patient group.

A novel method for predicting perineural invasion of distal cholangiocarcinoma on multidetector-row computed tomography.

PURPOSE: Excessive perineural invasion (PNI) is associated with a high risk of radial margin (RM) positivity and a poor prognosis for patients with distal cholangiocarcinoma (DCC). This study evaluates a new method of predicting the extent of PNI preoperatively. METHODS: The subjects of this retrospective study were 201 patients who underwent resection for DCC between 2002 and 2018. This study identified the 'periductal enation sign' (PES), defined as the surrounding soft tissue enhancement that appears as an enation from the circumference of the enhanced extrahepatic bile duct on multidetector-row computed tomography (MDCT) scans, as a predictor of PNI. We analyzed the outcomes of the patients in relation to the presence or absence of the PES on MDCT scans. RESULTS: The PES in the PNI-positive group was significantly longer than that in the PNI-negative group. As the length of the PES extended, the grade of PNI increased. A positive PES was defined as a PES length of ≥ 2.0 mm. Patients with a positive PES were more frequently positive for RM (23.7% vs. 2.1%) and locoregional recurrence (23.7% vs. 6.3%) and exhibited significantly poorer overall survival than those with a negative PES (30.2% vs. 54.6% at 5 years). CONCLUSIONS: The presence and extent of PNI can be predicted easily and effectively by the PES length. A positive PES was associated with poor local controllability and a poor prognosis.

Absolute configuration of tetrandrine and isotetrandrine influences their anti-proliferation effects in human T cells via different regulation of NF-κB.

Natural compound tetrandrine was reported to inhibit the proliferation of T cells by inhibiting activation of NF-κB. Chemically, isotetrandrine differs from tetrandrine only in the stereochemistry at the chiral centers. The present study aimed to compare their anti-proliferation effects on human T cells with a focus on NF-κB. The IC50 values of tetrandrine against MOLT-4 cells, MOLT-4/DNR cells, and concanavalin A-activated peripheral blood mononuclear cells of healthy subjects and dialysis patients were 4.43 ± 0.22, 3.62 ± 0.22, 1.91 ± 0.22 and 3.03 ± 0.28 µM, respectively. Whereas, the IC50 values of isotetrandrine against the above immune cells were 2.19 ± 0.27, 2.28 ± 0.33, 1.29 ± 0.14 and 1.55 ± 0.26 µM, respectively. The inhibitory effect of isotetrandrine against the proliferation of T cells was stronger than that of tetrandrine significantly (p < 0.05). Molecular mechanism investigation showed that 10 µM of isotetrandrine largely decreased the expression of p-NF-κB and NF-κB in both MOLT-4 and MOLT-4/DNR T cells (p < 0.05), whereas 10 µM of tetrandrine slightly inhibited the phosphorylation of p-NF-κB with little influence on the expression of NF-κB. Taken together, absolute configurations of tetrandrine and isotetrandrine are suggested to influence on their anti-proliferation effects in human T cells via different regulation of NF-κB.

[A Case of Adult T-Cell Leukemia/Lymphoma with Severe Hand-Foot Syndrome during Administration of Modified LSG15 Regimen].

The patient was a 56-year-old woman. A modified LSG15(VCAP-AMP-VECP)regimen was initiated as the first-line treatment for acute adult T-cell leukemia/lymphoma. On day 13 from the initiation of the second course of chemotherapy, the onset of hand-foot syndrome(HFS)(hands: Grade 2; feet: Grade 1)occurred. Therefore, the administration of a heparin analog cream and betamethasone butyrate propionate ointment was initiated. On day 20 from the start of the second course of chemotherapy, the foot symptoms improved; however, hand symptoms deteriorated to Grade 3. Frequent use of alcohol-based hand hygiene products is associated with infection prevention during neutropenia, but was likely an exacerbating factor. The symptoms gradually improved after this was taken into consideration, and the usage was discontinued. At the start of the third course, the symptoms had improved to Grade 1, and chemotherapy was continued. On day 11, symptoms worsened(Grade 2). HFS management was performed similar to that in the second course, and symptoms improved again.

Multidisciplinary treatment of left hepatic artery pseudoaneurysm after hepatobiliary resection for gallbladder cancer: a case report.

BACKGROUND: When a postoperative hepatic artery pseudoaneurysm develops after massive hepatectomy, both an intervention for the pseudoaneurysm and patency of hepatic artery should be considered because occlusion of the residual hepatic artery results in critical liver failure. However, the treatment strategy for a pseudoaneurysm of the hepatic artery after hepatobiliary resection is not well established. CASE PRESENTATION: A 65-year-old woman underwent right hepatectomy, extrahepatic duct resection, and portal vein resection, for gallbladder cancer. Although the patient had an uneventful postoperative course, computed tomography on postoperative day 6 showed a 6-mm pseudoaneurysm of the hepatic artery. Angiography revealed the pseudoaneurysm located on the bifurcation of the left hepatic artery to the segment 2 artery plus the segment 3 artery and 4 artery. Stent placement in the left hepatic artery was not feasible because the artery was too narrow, and coiling of the pseudoaneurysm was associated with a risk of occluding the left hepatic artery and inducing critical liver failure. Therefore, portal vein arterialization constructed by anastomosing the ileocecal artery and vein was performed prior to embolization of the pseudoaneurysm to maintain the oxygen level of the remnant liver, even if the left hepatic artery was accidentally occluded. The pseudoaneurysm was selectively embolized without occlusion of the left hepatic artery, and the postoperative laboratory data were within normal limits. Although uncontrollable ascites due to portal hypertension occurred, embolization of the ileocolic shunt rapidly resolved it. The patient was discharged on postoperative day 45. CONCLUSION: Portal vein arterialization prior to embolization of the aneurysm may be a feasible therapeutic strategy for a pseudoaneurysm that develops after hepatectomy for hepatobiliary malignancy to guarantee arterial inflow to the remnant liver. Early embolization of arterioportal shunting after confirmation of arterial inflow to the liver should be performed to prevent morbidity induced by portal hypertension.

Chylothorax after hepatectomy: a case report.

BACKGROUND: Chylothorax is the accumulation of chyle within the pleural space. Chylothorax can occur as a complication after multiple different types of surgery, most frequently after thoracic surgery, albeit with an incidence rate of less than 1%. Chylothorax after abdominal surgery is extremely rare, and there are only a few case reports. CASE PRESENTATION: A 74-year-old Japanese woman presented with jaundice. She was diagnosed as having hilar cholangiocarcinoma and underwent right hepatectomy, caudate lobectomy, extrahepatic bile duct resection, and lymph node dissection after preoperative percutaneous transhepatic portal vein embolization. Postoperative liver function was normal. She developed chylous ascites on postoperative day 5, for which conservative treatment was initially effective. Dyspnea developed suddenly on postoperative day 42, and she had a massive right pleural effusion and a small amount of ascites. Management with pleural drainage, total parenteral nutrition, and octreotide injections decreased the chylothorax. However, the chylous effusion reaccumulated on postoperative day 57. As conservative treatments ultimately failed, lymphangiography was performed on postoperative day 62. Lymphangiography with Lipiodol (ethiodized oil) revealed extravasation into the pleural space, but the location of the leak was not identified. There was neither obstruction nor dilation of the thoracic duct. A lymphatic leak in her abdominal cavity was not demonstrated. A chest tube was placed after lymphangiography, and the chylothorax was diminished by postoperative day 71. She was discharged on postoperative day 72. Two and a half years after surgery, she is doing well with no evidence of recurrence of either chylothorax or cancer. CONCLUSIONS: Chylothorax can occur after hepatectomy and pleural effusion should raise suspicion for chylothorax. Lymphangiography may be effective for both diagnosis and treatment in the case of chylothorax after hepatectomy.

Multiple mesenteric desmoid tumors after gastrectomy for gastric cancer: A case report and literature review.

INTRODUCTION: Many patients with desmoids have an antecedent trauma, particularly surgical intervention for familial adenomatous polyposis. However, cases of mesenteric desmoid after gastrectomy are extremely rare. We present a case of multiple mesenteric desmoids after total gastrectomy for gastric cancer. PRESENTATION OF CASE: A 70-year-old man had undergone a total gastrectomy for early stage gastric cancer. He had no other relevant medical history or family history. A year after gastrectomy, a computed tomography showed three mesenteric masses, and we performed careful observation. The 2-year postoperative examination indicated slowly growing masses. There were no other lesions except for the three masses. We decided to perform diagnostic surgery to evaluate the tumors. There were three mesenteric masses (1.5 cm, 4 cm and 1.5 cm in diameter). We performed partial small intestinal resections for each mass. Histological examination showed that the tumors were desmoids. A year after surgery, he was doing well with no evidence of recurrence of the desmoids or the gastric cancer. DISCUSSION: Diagnosing intra-abdominal desmoid tumors is often difficult. Especially if a patient has a history of malignancy, it may be extremely difficult to differentiate multiple mesenteric desmoids from a cancer recurrence. In the current case, surgical resection was a useful treatment option as diagnostic therapy. CONCLUSIONS: Multiple mesenteric desmoids could emerge after gastrectomy for gastric cancer, and surgical resection of the tumors is a useful option as a diagnostic therapy.

Laparoscopic low anterior resection for rectal cancer with rectal prolapse: a case report.

BACKGROUND: Rectal cancer with rectal prolapse is rare, described by only a few case reports. Recently, laparoscopic surgery has become standard procedure for either rectal cancer or rectal prolapse. However, the use of laparoscopic low anterior resection for rectal cancer with rectal prolapse has not been reported. CASE PRESENTATION: A 63-year-old Japanese woman suffered from rectal prolapse, with a mass and rectal bleeding for 2 years. An examination revealed complete rectal prolapse and the presence of a soft tumor, 7 cm in diameter; the distance from the anal verge to the tumor was 5 cm. Colonoscopy demonstrated a large villous tumor in the lower rectum, which was diagnosed as adenocarcinoma on biopsy. We performed laparoscopic low anterior resection using the prolapsing technique without rectopexy. The distal surgical margin was more than 1.5 cm from the tumor. There were no major perioperative complications. Twelve months after surgery, our patient is doing well with no evidence of recurrence of either the rectal prolapse or the cancer, and she has not suffered from either fecal incontinence or constipation. CONCLUSIONS: Laparoscopic low anterior resection without rectopexy can be an appropriate surgical procedure for rectal cancer with rectal prolapse. The prolapsing technique is useful in selected patients.