Carcinoembryonic antigen testing after curative liver resection for synchronous liver metastasis of colorectal cancer: a Japanese multicenter analysis.

PURPOSE: To identify the possible roles of carcinoembryonic antigen (CEA) testing after liver resection for synchronous colorectal liver metastasis (CLM). METHODS: The subjects of this retrospective study were patients who underwent complete resection of primary tumors and synchronous CLM between 1997 and 2007 at 20 institutions in Japan. We studied the associations between perioperative CEA levels and the characteristics of recurrence. RESULTS: Recurrence was detected during the median follow-up time of 52 months in 445 (73.7%) of the total 604 patients analyzed. A postoperative CEA level >5 ng/ml was an independent predictor, with the highest hazard ratio (2.25, 95% confidence interval 1.29-3.91, P = 0.004). A postoperative CEA level >5 ng/ml had a specificity of 86.2% and a positive predictive value of 84.2% for recurrence. Patients with a high postoperative CEA level had a significantly higher recurrence rate, with a shorter time until recurrence and a higher frequency of multiple metastatic sites than those with a low postoperative CEA level. Among the patients with recurrence, 173 (52.7%) had an elevated CEA level (>5 ng/ml) when recurrence was detected. CONCLUSIONS: A postoperative CEA level >5 ng/ml was an independent predictor of recurrence; however, CEA testing was not a reliable surveillance tool to identity recurrence after liver resection.

Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells.

RATIONALE: Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown. OBJECTIVE: In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca(2+) oscillations. METHODS AND RESULTS: We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca(2+), mediated by IP3 receptor activation, which condition asymmetrical stem cell division and myocyte lineage specification. CONCLUSIONS: Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca(2+) spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.

[A case of postoperative colon cancer with peritoneal dissemination in which a long-term response was achieved using panitumumab maintenance therapy].

A 66-year-old man underwent a sigmoidectomy for advanced sigmoid colon cancer. The pathological examination revealed that the tumor was T3, N0, M0, and KRAS wild type. Fifteen months after surgery, the patient was hospitalized with stenosis of the anastomosis due to recurrent disease that had disseminated to the peritoneum, and which was unresectable. After transverse colostomy, the patient received 8 courses of mFOLFOX6+panitumumab (Pmab), and 39 courses of infusional 5-fluorouracil (5-FU) + Leucovorin (LV)+ Pmab. A partial remission (PR) was maintained for 27 months. The utility of maintenance therapy with an anti-epidermal growth factor receptor (EGFR) antibody-based regime has not previously been demonstrated. In this case, a long PR was achieved using infusional 5-FU+LV+Pmab, suggesting that this is a useful maintenance therapy following mFOLFOX6 + Pmab. However, the side effects resulting from Pmab treatment reduced the patient's quality of life (QOL). We suggest that Pmab maintenance therapy can be established by controlling the side effects of the anti-EGFR antibody.

[Three cases of anal squamous cell carcinoma treated with chemoradiotherapy].

We reviewed the clinical records of 3 patients with anal squamous cell carcinoma treated with chemoradiotherapy (CRT). Case 1: The patient was diagnosed with StageI (T1N0M0) and treated with cisplatin (CDDP)+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. She achieved partial response(PR), and underwent a salvage surgery. Seven months after the surgery, she died from other comorbidities. Case 2: The patient was diagnosed with Stage I (T1N0M0) and treated with CDDP+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. He achieved PR, and underwent a salvage surgery. Three years and 7 months after the surgery, he died from other comorbidities. Case 3: The patient was diagnosed with Stage IIIB (T4N1M0) and treated with MMC+S-1+radiation. Chemotherapy was discontinued after the first course because of adverse effects. She achieved complete response (CR) and is still surviving without cancer recurrence. We conclude that CRT is an effective treatment for anal squamous cell carcinoma.

[Resection for the treatment of bleeding caused by ovarian metastasis after hepatectomy for metachronous liver metastasis from sigmoid colon cancer].

We describe the case of a 75-year-old woman who underwent bilateral oophorectomy for bleeding due to right ovarian metastasis after hepatectomy for metachronous liver metastasis from sigmoid colon cancer. She underwent curative resection for sigmoid colon cancer( T4a, N2, M0, Stage IIIC). She received adjuvant chemotherapy of tegafur/uracil(UFT) plus leucovorin for 6 months. The patient underwent hepatectomy for liver metastasis 13 months after the primary resection for sigmoid colon cancer. One year after liver resection, the patient underwent emergency surgery for the treatment of bleeding due to ovarian metastasis. She received adjuvant capecitabine chemotherapy for 6 months after oophorectomy. The patient was alive with no evidence of disease 36 months after her oophorectomy. In the present report, we describe the case of a patient who underwent repeated resection for distant metastases after sigmoidectomy. These findings suggest that therapeutic strategies including surgical resection will be very important in the future.

[A case of advanced rectal cancer treated with leucovorin, fluorouracil, and oxaliplatin plus panitumumab preoperative chemotherapy].

A 58-year-old woman had a very large advanced rectal cancer( with wild-type K-RAS expression). Abdominal computed tomography( CT) revealed a space-occupying lesion in the pelvis and an enlarged lymph node. We established a diagnosis of unresectable rectal cancer and subsequently performed transverse colostomy. The patient received 6 courses of Leucovorin, fluorouracil, and oxaliplatin( mFOLFOX6) plus panitumumab( Pmab), 2 courses of simplified Leucovorin plus 5-fluorouraci(l sLV5-FU) plus Pmab, and 1 course of Pmab. The size of the primary tumor decreased remarkably after chemotherapy. Low anterior resection was performed. The pathological stage was T4a, N0, M1, Stage IVa. The results from this case suggest that mFOLFOX6 plus Pmab preoperative chemotherapy is a useful regimen for the treatment of locally advanced K-RAS wild-type rectal cancer.

[A case of advanced rectal cancer with bone metastasis successfully treated with chemo-radiation therapy].

A 62-year-old man presented to a hospital with left buttock pain, and sacral neoplasia was suspected. He was referred to our hospital. Colonoscopy( CS) and bone biopsy showed rectal cancer with metastasis to the sacrum. There was no bleeding or ileus associated with the primary lesion, and the sacral metastasis was unresectable; therefore, we decided to provide palliative care for pain relief. Radiation therapy( 40 Gy) was performed on the sacral metastasis and included the primary lesion, and zoledronate was administered concomitantly. Both CS and computed tomography (CT) showed tumor regression of both the primary and metastatic lesions, and the patient's carcinomatous pain was alleviated. Irinotecan, 5- fluorouracil, and Leucovorin (FOLFIRI)+cetuximab was administered to reduce the progression of the primary lesion. After 3 months, CT showed significant tumor regression of both the primary and metastatic lesions. The sacral metastasis was no longer evident on the CT images, and positron emission tomography( PET)-CT did not show fluorodeoxyglucose (FDG) accumulation. The primary lesion had shrunk and become flat, but biopsy indicated residual lesion. Although clinically the frequency of bone metastasis of colon cancer has been reported to be 8.6 to 10.7%, single metastasis is not often seen. In this report, we present a case of advanced rectal cancer with bone metastasis, which was successfully treated with chemo-radiation therapy.

[A case of recurrent rectal cancer successfully treated for a long period with capecitabine plus oxaliplatin and bevacizumab therapy].

A 62-year-old woman was diagnosed as having rectal cancer and underwent low anterior resection. The final pathological diagnosis was RS, type 3, circ, mod>muc>por>,pSE, ly1, v1, pN2, sH0, sP0, cM0, fStage IIIb, with KRAS mutation. Adjuvant chemotherapy with tegafur-uracil( UFT) plus Leucovorin( LV) was administered for 6 months. Ten months after surgery, right internal iliac and common iliac lymph node metastasis and peritoneal dissemination were diagnosed. In October 2009, capecitabine plus oxaliplatin (CapeOX) plus bevacizumab (Bmab) therapy was initiated. In May 2010, diagnostic imaging revealed a complete response after 42 months. In the present report, we describe the case of a patient with rectal cancer who experienced postoperative recurrence and achieved long-term complete response with CapeOX plus Bmab therapy. We also include a brief review of the literature.

[A case of neuroendocrine carcinoma of the anal canal with multiple bone metastases successfully treated with combined modality therapy].

Neuroendocrine carcinoma (NEC) of the anal canal is a comparatively rare tumor with a poor prognosis. We report herein a case of NEC of the anal canal with multiple bone metastases that was successfully treated with combined therapy. A 63-year-old man was referred to our hospital with the chief complaint of anal and back pain. A tumor was found in the anal canal, and pathologic examination revealed it to be NEC( Ki-67 expression>50%); fluorodeoxyglucose( FDG) positron emission tomography (PET)-computed tomography (CT) showed multiple bone metastases. Initially, a l-leucovorin/5- fluorouraci(l 5-FU)/oxaliplatin( L-OHP)(: mFOLFOX6)/bevacizumab( Bmab) regimen and octreotide were administered to treat the unresectable and advanced NEC. Strontium-89 and zoledronate were used to treat pain related to the bone metastases. After 3 months, the tumor and bone metastases became difficult to identify. The patient experienced grade 2 neurotoxicity after 5 months, and thus, we stopped L-OHP administration. After 10 months, we reintroduced L-OHP because of additional progression of the bone metastases.

[A case of poorly differentiated adenocarcinoma of the uterine cervix treated with paclitaxel and carboplatin after positive PAX 8 immunostaining].

PAX 8 is a paired-box gene that plays an important role in the embryogenesis of the thyroid gland, Müllerian ducts, and renal/upper urinary tract. PAX 8 expression is observed in carcinomas from each of these sites. Accordingly, PAX 8 immunostaining has been reported to be useful for the diagnosis of these carcinomas. Here, we report a case in which PAX 8 was useful for the diagnosis of a patient with cervical adenocarcinoma and multiple metastases. A 55-year-old female patient complained of cough and genital bleeding. Examination revealed a uterine cervical mass, masses in both breasts, and enlargement of the lymph nodes and subcutaneous nodules. Histology of the uterine cervical mass biopsy revealed a poorly differentiated adenocarcinoma. Cytology of the aspiration biopsy specimens of the breast masses indicated scirrhous cancer. PAX 8 immunostaining of the uterine cervical mass and breast mass biopsies was positive. We determined that the breast masses were metastases of the cervical adenocarcinoma and decided to treat the patient with chemotherapy consisting of paclitaxel and carboplatin. A partial response was observed. A hysterectomy was performed 5 months after chemotherapy because corpus cancer was newly diagnosed. The cervical adenocarcinoma was undetectable in the surgical specimen. Fifteen months have passed since the completion of chemotherapy and the metastases has been under control.

Comparison of short-term outcomes between robot-assisted and laparoscopic rectal surgery for rectal cancer: A propensity score-matched analysis using the Japanese Nationwide diagnosis procedure combination database.

Background: The use of robot-assisted surgery for rectal cancer is increasing, but its short-term results remain unclear. We compared the short-term outcomes of robot-assisted and laparoscopic surgery for rectal cancer using a nationwide inpatient database. Methods: We analyzed patients registered in the Japanese Diagnosis Procedure Combination database who underwent robot-assisted or laparoscopic surgery for rectal cancer from April 2018 to March 2020. Postoperative complication rates, anesthesia time, length of hospital stay, and cost were compared using propensity score matching for low anterior resection (LAR), high anterior resection (HAR), and abdominoperineal resection (APR). Results: Among 38 090 rectal cancer cases, 1992 LAR, 357 HAR, and 310 APR pairs were generated by propensity score matching and analyzed. Anesthesia time was longer for robot-assisted surgery compared with laparoscopic surgery (LAR: 388.6 vs. 452.8 min, p < 0.001; HAR: 300.9 vs. 393.5 min, p < 0.001; APR: 4478.5 vs. 533.5 min, p < 0.001). Robot-assisted surgery was associated with significantly shorter hospital stay for LAR (22.3 vs. 20.0 days, p < 0.001) and APR (29.2 vs. 25.9 days, p = 0.029). Total costs for LAR were significantly lower for robot-assisted surgery (2031511.6 vs. 1955216.6 JPY, p < 0.001). The complication rates for robot-assisted surgery tended to be fewer than laparoscopic surgery for all procedures, but the differences were not significant. Conclusions: Although the anesthesia time was longer for robot-assisted surgery, the procedure resulted in shorter hospital stay for LAR and APR, and lower costs for LAR compared with laparoscopic surgery. Robot-assisted surgery can thus help to reduce costs and can be performed safely.

Advantages of preoperative counseling with video for robotic rectal cancer surgery compared with conventional counseling: A randomized controlled trial.

PURPOSE: Surgeons should provide patients with appropriate explanations before surgery and obtain informed consent. However, this process requires time and effort and can be a great burden. The purpose of this study was to compare preoperative counseling with video (VC) and conventional counseling (CC) for rectal cancer patients. METHODS: Rectal cancer patients indicated for surgery were included between April 2021 and March 2022, and eligible patients were randomly assigned to the CC and VC groups. The primary outcomes were the comprehension, satisfaction, and anxiety levels, and the secondary outcome was the preoperative counseling time. This exploratory study protocol was registered with the UMIN Clinical Trials Registry (UMIN000038133). RESULTS: We included 13 patients in the CC group and 17 in the VC group. All eligible patients were scheduled for robotic rectal cancer surgery. There were no significant differences between the two groups, including patients' general condition, preoperative diagnosis, and planned procedures. Although the comprehension, satisfaction, and anxiety test scores were not significantly different between the groups, the preoperative counseling time was significantly shorter in the VC group than in the CC group (20 vs. 35 minutes, P = .002). A 4-year college degree significantly increased the counseling time, whereas VC significantly decreased it. CONCLUSION: Using videos in preoperative counseling for rectal cancer patients is useful. This novel method could reduce the burden on surgeons during preoperative counseling in the era of robotic surgery and work style reforms.

Human cardiac stem cell differentiation is regulated by a mircrine mechanism.

BACKGROUND: Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes that fail to acquire the differentiated phenotype. However, the interaction of CSCs with postmitotic myocytes results in the formation of cells with adult characteristics. METHODS AND RESULTS: On the basis of results of in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499), which is barely detectable in hCSCs but is highly expressed in postmitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart. CONCLUSIONS: The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.

IL-27 inhibits hyperglycemia and pancreatic islet inflammation induced by streptozotocin in mice.

Inflammation driven by immune cells and pro-inflammatory cytokines is implicated in pancreatic ß-cell injury, leading to the development of diabetes mellitus. IL-27, a cytokine consisting of IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), binds a membrane-bound heterodimeric receptor consisting of the IL-27 receptor α chain (WSX-1) and gp130. IL-27 has anti-inflammatory properties that regulate T-cell polarization and cytokine production. We evaluated blood glucose and islet proinsulin concentrations, inflammatory cell infiltration in islets, and expression of IL-1ß mRNA in pancreas in wild-type (WT), EBI3(-/-), and WSX-1(-/-) mice treated with streptozotocin (STZ). Hyperglycemia was augmented in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. Islet proinsulin levels after STZ treatment were lower in EBI3(-/-) and WSX-1(-/-) mice than in WT mice. The infiltration of islets by F4/80(+)CD11c(-)7/4(-) macrophages, CD4(+) T cells, and CD8(+) T cells was increased in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. The administration of recombinant IL-27, compared with control, decreased the blood glucose level, immune cell infiltration into islets, and IL-1ß mRNA expression in the pancreas and increased islet proinsulin levels in WT and EBI3(-/-) mice. Thus, IL-27 inhibits STZ-induced hyperglycemia and pancreatic islet inflammation in mice and represents a potential novel therapeutic approach for ß-cell protection in diabetes.

Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.

RATIONALE: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. OBJECTIVE: In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. METHODS AND RESULTS: We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a gamma-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. CONCLUSIONS: Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.

Clonality of mouse and human cardiomyogenesis in vivo.

An analysis of the clonality of cardiac progenitor cells (CPCs) and myocyte turnover in vivo requires genetic tagging of the undifferentiated cells so that the clonal marker of individual mother cells is traced in the specialized progeny. CPC niches in the atria and apex of the mouse heart were infected with a lentivirus carrying EGFP, and the destiny of the tagged cells was determined 1-5 months later. A common integration site was identified in isolated CPCs, cardiomyocytes, endothelial cells (ECs), and fibroblasts, documenting CPC self-renewal and multipotentiality and the clonal origin of the differentiated cell populations. Subsequently, the degree of EGFP-lentiviral infection of CPCs was evaluated 2-4 days after injection, and the number of myocytes expressing the reporter gene was measured 6 months later. A BrdU pulse-chasing protocol was also introduced as an additional assay for the analysis of myocyte turnover. Over a period of 6 months, each EGFP-positive CPC divided approximately eight times generating 230 cardiomyocytes; this value was consistent with the number of newly formed cells labeled by BrdU. To determine whether, human CPCs (hCPCs) are self-renewing and multipotent, these cells were transduced with the EGFP-lentivirus and injected after acute myocardial infarction in immunosuppressed rats. hCPCs, myocytes, ECs, and fibroblasts collected from the regenerated myocardium showed common viral integration sites in the human genome. Thus, our results indicate that the adult heart contains a pool of resident stem cells that regulate cardiac homeostasis and repair.

[Long-surviving patient with hilar cholangiocarcinoma by gemcitabine monotherapy].

An 80-year-old woman visited our department with the complaint of icterus and brown urine. After detailed examination, she was diagnosed with cT4N0M (-), cStage IVa, hilar cholangiocarcinoma. We believed that she could be cured with surgery, but she and her family did not agree to the surgical procedure. Chemotherapy was scheduled, and gemcitabine (GEM) therapy was started in April 2011. GEM therapy reduced significantly the level of the CA 19-9 tumor marker, and diagnostic imaging allowed a judgment of partial response or stable disease after 18 months. In the present report, we describe a case of a patient with hilar cholangiocarcinoma who achieved long-term survival with GEM therapy. We also include a brief literature review.

[A case of recurrent gastric cancer responding to CPT-11].

A 68-year-old man underwent total gastrectomy for gastric cancer(Stage II). Adjuvant chemotherapy with S-1 was administered. At 21 months after the operation, he received a nephron catheter because of hydronephrosis caused by para-aortic lymph node metastases. Then, weekly paclitaxel was given as a second-line treatment. However, his tumor marker level increased and he therefore received CPT-11 (160 mg/m2) as a third-line treatment at 28 months after the operation. At 7 days after the first CPT-11 administration, he was hospitalized because of a severe adverse event involving nausea and general fatigue, which caused a continuous fever of 39°C and renal failure at 14 days after administration. However, hydration enabled him to recover several days later. Computed tomography scan revealed the lymph node metastases to be partial remission.

[A patient with sigmoid colon cancer( cStage IV) who responded to preoperative chemotherapy with mFOLFOX6 plus bevacizumab and was subsequently able to undergo a radical operation].

There are a growing number of reports of unresectable, advanced colorectal cancer and multiorgan invasive colorectal cancer for which extended surgery was avoided or a radical operation was performed after down-staging, or tumor size reduction, was achieved by chemotherapy. Here we describe a case of sigmoid colon cancer (cStage IV) for which preoperative chemotherapy improved the outcome of surgery. The patient was a 57-year-old man with sigmoid colon cancer of sufficient size to block the passage of the endoscope. The cancer was found to be widely infiltrated and adherent to the peritoneum over the bladder, with effusion around the tumor that made peritoneal disseminated metastasis a strong possibility. Moreover, many regional and periaortic lymph nodes were swollen. Sigmoid colon cancer at Stage IV was diagnosed. After preoperative chemotherapy [mFOLFOX6+bevacizumab (Bev)] was administered, tumor size decreased sufficiently to allow the endoscope to pass through. The effusion around the tumor disappeared, and lymph node swellings were reduced. The surgical findings revealed no evidence of peritoneal metastasis, and tumor adhesion to the peritoneum over the bladder was small, which limited the extent of combined peritonectomy. Ultimately, the histopathological diagnosis was Stage II,and histological evaluation of the drug therapy effects was that the tumor was then Grade 1b. Although clinical studies are currently conducted on preoperative chemotherapy for locally advanced colorectal cancer, preoperative chemotherapy is not established as standard treatment due to lack of clear evidence. The evaluation of the usefulness of preoperative chemotherapy is warrants future clinical studies.