COVID-19 symptom-onset to diagnosis and diagnosis to treatment intervals are significant predictors of disease progression and hospitalization in high-risk patients: A real world analysis.

BACKGROUND: Coronavirus disease (COVID-19) is overwhelming healthcare systems worldwide. This study aimed to elucidate factors that influence disease progression to pneumonia and hospitalization before and after antiviral treatment for COVID-19 in an outpatient setting. METHODS: A total of 206 high-risk patients with COVID-19 were treated with sotrovimab, remdesivir, and molnupiravir at the Toshiwakai clinic between January 4 and April 30, 2022. Of these, 49 patients visited the Toshiwakai clinic directly and were treated immediately after diagnosis (Toshiwakai-clinic study group). The remaining patients were diagnosed elsewhere, and of these, 102 patients were quarantined at home (health-center study group) and 55 at designated facilities (quarantine-facility study group) before being referred to Toshiwakai clinic. Patients were categorized into those with mild and moderate COVID-19, based on the presence of pneumonia at the initial visit to Toshiwakai clinic. RESULTS: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals were significant predictors of moderate disease. Age, dyspnea, and diagnosis-to-treatment interval at the first visit to Toshiwakai clinic were significant predictors for hospitalization even after antiviral treatment. Although the symptom-onset-to-diagnosis interval did not differ among the three study groups, the diagnosis-to-treatment and symptom-onset-to-treatment intervals were significantly longer in the health-center and quarantine-facility study groups than in the Toshiwakai-clinic study group. CONCLUSION: The symptom-onset-to-diagnosis and diagnosis-to-treatment intervals reflect diagnostic and interventional delays, respectively, which are closely related to the current COVID-19 clinical management protocol. Easy access to the clinics and immediate antiviral treatment after diagnosis may be the best methods to prevent disease progression and hospitalization in high-risk patients.

Highly sensitive diagnostic method for colorectal cancer using the ratio of free DNA fragments in serum.

OBJECTIVES: The correlations of the ratio of long-/short-chain DNA fragments in blood with the existence of cancer and the clinicopathological features of colorectal cancer (CRC) were examined. The potential use of this ratio for diagnostic screening was evaluated. METHODS: DNA concentrations were amplified using Alu247 for long-chain DNA fragments and Alu115 for long- and short-chain DNA fragments. The Alu247/115 ratio was calculated for 60 patients with CRC and 24 healthy volunteers. The correlation of the Alu247/115 ratio with clinicopathological variables and the efficacy of this ratio as a tumor marker were examined. The Alu247/115 ratio cut-off value was set using a receiver operating characteristic (ROC) curve. RESULTS: The Alu247/115 ratio was significantly higher in patients with CRC than in healthy volunteers (P<0.001). The Alu247/115 ratio was also significantly higher in patients with Dukes stage A or B CRC than in healthy volunteers (P=0.034) as well as in patients with Dukes C or D CRC than in those with Dukes A or B CRC (P=0.016). Among patients with CRC, the Alu247/115 ratio was significantly higher in those with than without venous invasion (P=0.031). Using the cut-off value set from the ROC curve, the sensitivity of the Alu247/115 ratio was significantly higher than that of the carcinoembryonic antigen level (P=0.004) or the carbohydrate antigen 19-9 level (P<0.001). CONCLUSION: Our data suggest that the Alu247/115 ratio is a promising tool for highly sensitive and early detection of CRC.

Laparoscopic sigmoidectomy combined with uterus excision for colouterine fistula caused by sigmoid colon diverticulitis: A case report.

A case of colouterine fistula caused by colonic diverticulitis that was successfully treated laparoscopically is presented. A 74-year-old woman visited us with lower abdominal discomfort and vaginal excretion with minor fecal contamination. Mild tenderness was observed in her lower abdomen. Blood examinations revealed elevated white blood cell count and C-reactive protein. Sigmoid colon diverticulitis was revealed on CT, and her condition was diagnosed as colouterine fistula. Hinchey classification was stage I. After 2 weeks of conservative therapy, her symptoms were reduced, and the white blood cell count and C-reactive protein level decreased. However, fecal contaminated vaginal excretion continued. The patient underwent laparoscopic sigmoidectomy combined with uterus excision, and she has been in good health for the 3 years since the operation. Although colouterine fistula is usually treated with open surgery, patients with controlled and well-localized inflammation may be good candidates for a laparoscopic approach.

How Far Can We Go with Laparoscopic Liver Resection for Hepatocellular Carcinoma? Laparoscopic Sectionectomy of the Liver Combined with the Resection of the Major Hepatic Vein Main Trunk.

Although the reports of laparoscopic major liver resection are increasing, hepatocellular carcinomas (HCCs) close to the liver hilum and/or major hepatic veins are still considered contraindications. There is virtually no report of laparoscopic liver resection (LLR) for HCC which involves the main trunk of major hepatic veins. We present our method for the procedure. We experienced 6 cases: 3 right anterior, 2 left medial, and 1 right posterior extended sectionectomies with major hepatic vein resection; tumor sizes are within 40-75 (median: 60) mm. The operating time, intraoperative blood loss, and postoperative hospital stay are within 341-603 (median: 434) min, 100-750 (300) ml, and 8-44 (18) days. There was no mortality and 1 patient developed postoperative pleural effusion. For these procedures, we propose that the steps listed below are useful, taking advantages of the laparoscopy-specific view. (1) The Glissonian pedicle of the section is encircled and clamped. (2) Liver transection on the ischemic line is performed in the caudal to cranial direction. (3) During transection, the clamped Glissonian pedicle and the peripheral part of hepatic vein are divided. (4) The root of hepatic vein is divided in the good view from caudal and dorsal direction.

Pure laparoscopic hepatectomy as repeat surgery and repeat hepatectomy.

AIM: To assess clinical outcomes of laparoscopic hepatectomy (LH) in patients with a history of upper abdominal surgery and repeat hepatectomy. METHODS: This study compared the perioperative courses of patients receiving LH at our institution that had or had not previously undergone upper abdominal surgery. Of the 80 patients who underwent LH, 22 had prior abdominal surgeries, including hepatectomy (n = 12), pancreatectomy (n = 3), cholecystectomy and common bile duct excision (n = 1), splenectomy (n = 1), total gastrectomy (n = 1), colectomy with the involvement of transverse colon (n = 3), and extended hysterectomy with extensive lymph-node dissection up to the upper abdomen (n = 1). Clinical indicators including operating time, blood loss, hospital stay, and morbidity were compared among the groups. RESULTS: Eighteen of the 22 patients who had undergone previous surgery had severe adhesions in the area around the liver. However, there were no conversions to laparotomy in this group. In the 58 patients without a history of upper abdominal surgery, the median operative time was 301 min and blood loss was 150 mL. In patients with upper abdominal surgical history or repeat hepatectomy, the operative times were 351 and 301 min, and blood loss was 100 and 50 mL, respectively. The median postoperative stay was 17, 13 and 12 d for patients with no history of upper abdominal surgery, patients with a history, and patients with repeat hepatectomy, respectively. There were five cases with complications in the group with no surgical history, compared to only one case in the group with a prior history. There were no statistically significant differences in the perioperative results between the groups with and without upper abdominal surgical history, or with repeat hepatectomy. CONCLUSION: LH is feasible and safe in patients with a history of upper abdominal surgery or repeat hepatectomy.

Recent advances in the surgical treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation (LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed.

Recent advances in liver resection for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The association of HCC with chronic liver disease (CLD) is well known and making treatment complex and challenging. The treatment of HCC must take into consideration, the severity of CLD, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC. Better liver function assessment, increased understanding of segmental liver anatomy using more accurate imaging studies, and surgical technical progress are the important factors that have led to reduced mortality, with an expected 5 year survival of 38-61% depending on the stage of the disease. However, the procedure is applicable to <30% of all HCC patients, and 80% of the patients after LR recurred within 5 years. There are recent advances and prospects in LR for HCC in several aspects. Three-dimensional computed tomography imaging assisted preoperative surgical planning facilitates unconventional types of LR. Emerging evidences of laparoscopic hepatectomy and prospects for the use of newly developing chemotherapies as a combined therapy may lead to expanding indication of LR. LR and liver transplantation could be associated rather than considered separately with the current concepts of "bridging LR" and "salvage transplantation."

Pure laparoscopic hepatectomy for hepatocellular carcinoma with chronic liver disease.

Pure laparoscopic hepatectomy is a less invasive procedure than conventional open hepatectomy for the resection of hepatic lesions. Increases in experiences with the technique, in combination with advances in technology, have promoted the popularity of pure laparoscopic hepatectomy. However, indications for usage and potential contraindications of the procedure remain unresolved. The characteristics and specific advantages of the procedure, especially for hepatocellular carcinoma (HCC) patients with chronic liver diseases, are reviewed and discussed in this paper. For cirrhotic patients with liver tumors, pure laparoscopic hepatectomy minimizes destruction of the collateral blood and lymphatic flow from laparotomy and mobilization, and mesenchymal injury from compression. Therefore, pure laparoscopic hepatectomy has the specific advantage of minimal postoperative ascites production that leads to lowering the risk of disturbance in water or electrolyte balance and hypoproteinemia. It minimizes complications that routinely trigger postoperative serious liver failure. Under adequate patient positioning and port arrangement, the partial resection of the liver in the area of subphrenic space, peri-inferior vena cava area or next to the attachment of retro-peritoneum is facilitated in pure laparoscopic surgery by providing good vision and manipulation in the small operative field. Furthermore, the features of reduced post-operative adhesion, good vision, and manipulation within the small area between the adhesions make this procedure safer in the context of repeat hepatectomy procedures. These improved features are especially advantageous for patients with liver cirrhosis and multicentric and/or metachronous HCCs.

Caudal approach to pure laparoscopic posterior sectionectomy under the laparoscopy-specific view.

AIM: To study our novel caudal approach laparoscopic posterior-sectionectomy with parenchymal transection prior to mobilization under laparoscopy-specific view. METHODS: Points of the procedure are: (1) Patients are put in left lateral position and posterior sector is not mobilized; (2) Glissonian pedicle of the sector is encircled and clamped extra-hepatically and divided afterward during the transection; (3) Dissection of inferior vena cava (IVC) anterior wall behind the liver is started from caudal. Simultaneously, liver transection is performed to search right hepatic vein (RHV) from caudal; (4) Liver transection proceeds to the bifurcation of the vessels from caudal to cranial, exposing the surfaces of IVC and RHV. Since the remnant liver sinks down, the cutting surface is well-opend; and (5) After the completion of transection, dissection of the resected liver from retroperitoneum is easily performed using the gravity. This approach was performed for a 63 years old woman with liver metastasis close to RHV. RESULTS: RHV exposure is required for R0 resection of the lesion. Although the cutting plane is horizontal in supine position and the gravity obstructs the exposure in the small subphrenic space, the use of specific characteristics of laparoscopic hepatectomy, such as the good vision for the dorsal part of the liver and IVC and facilitated dissection using the gravity with the patient positioning, made the complete RHV exposure during the liver transection easy to perform. The operation time was 341 min and operative blood loss was 1356 mL. Her postoperative hospital stay was uneventfull and she is well without any signs of recurrences 14 mo after surgery. CONCLUSION: The new procedure is feasible and useful for the patients with tumors close to RHV and the need of the exposure of RHV.

A case of solitary necrotic nodule treated with laparoscopic hepatectomy: spontaneous regression of hepatocellular carcinoma?

Solitary necrotic nodule of the liver is a rare benign lesion with a completely necrotic core and a hyalinized fibrotic capsule containing elastic fibers. The pathogenetic mechanism is still unclear. We here describe a case of SNN, whose central reticulin fibers within the nodule suggest the origin as hepatocellular carcinoma or other hepatocyte-origin tumors, treated with laparoscopic anatomical segmentectomy of the liver. A 76-year-old Japanese female, with no prior medical history and no symptom, visited our hospital with the heterogeneous hypoechoic lesion in the liver segment VI incidentally pointed out in abdominal ultrasonography. Computed tomography with contrast demonstrated a 1.1 cm sized low-density lesion with mild ring enhancement on the rim in the arterial phase. Since the possibility of malignant tumor with necrotic change could not be ruled out, she underwent laparoscopic anatomical segmentectomy of the liver. In the histological examination of the surgical specimen, the liver nodule was necrotic tissue without viable cells and signs of inflammation, which had fibrous capsule and central cystic change and showed trabecular pattern alignment of ghost cells and reticulin fibers orthogonal to the capsule. Also, the findings of chronic hepatitis were observed in the background liver.

Gene expression and effects of orally active derivatives of fluoropyrimidine on gastric and colorectal cancer.

The effects of chemotherapy on gastrointestinal cancer are influenced by the chemotherapeutic sensitivity of the cancer cells. Determining the expression of genes related to chemotherapeutic sensitivity has been used as a molecular method. The aim of the study was to clarify the relationships between the expression of genes related to chemotherapeutic sensitivity and the effects of orally active derivatives of fluoropyrimidine on gastric and colorectal cancer. Forty-five patients who underwent adjuvant chemotherapy containing orally active derivatives of fluoropyrimidine after undergoing curative surgery for gastric or colorectal cancer were enrolled. Twenty-four patients had colorectal cancer and 21 patients had gastric cancer. Total RNA was extracted from formalin-fixed, paraffin-embedded specimens of the resected tumors, and the expression of 11 genes was measured using the RT-PCR method. We then analyzed the relationships between the gene expression and the postoperative relapse rate as well as the relationships between clinicopathological factors and postoperative relapse rate. The median observation period of the subjects was 41 months. Twelve out of the 21 gastric cancer patients (57%) and 11 out of the 24 colorectal cancer patients (46%) relapsed. Although the results of a univariate analysis revealed that expression of none of the evaluated genes was related to relapse in the gastric cancer patients, excision repair cross-complementing gene 1 (ERCC1) overexpression was related to the relapse rate in colorectal cancer patients (p=0.023). When 1.295 was set as the cut-off value for ERCC1 overexpression using the receiver operating characteristic (ROC) curve, 67% of patients with ERCC1 overexpression and 25% of patients without ERCC1 overexpression relapsed. The relapse-free survival rate was lower in the group with ERCC1 overexpression than in the group without ERCC1 overexpression (p=0.046). ERCC1 overexpression appears to be a useful predictor of relapse in colorectal cancer patients receiving adjuvant therapy with regimens including orally active derivatives of fluoropyrimidine.

Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine.

E-selectin is expressed on the surfaces of stimulated vascular endothelial cells and is sometimes involved in cancer cell metastasis. The H2-receptor antagonist cimetidine inhibits the increase in E-selectin expression on vascular endothelial cells that is induced by interleukin-1beta (IL-1beta) and cimetidine. It also inhibits the adhesion of sialyl-Lewis-antigen-positive cancer cells to vascular endothelial cells, ultimately inhibiting hematogenous metastasis. Anticancer drugs are essential to cancer therapy, but whether they can alter the expression of E-selectin in vascular endothelial cells remains unclear. Whether cimetidine inhibits the expression of E-selectin in the same manner in the presence or absence of anticancer drugs also remains unknown. Human umbilical vein endothelial cells were cultured with 5-fluorouracil (5-FU), doxorubicin (DXR), cisplatin (CDDP), or IL-1beta and with or without cimetidine. The expression of E-selectin at the mRNA and protein levels was then determined using quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining, respectively. The E-selectin mRNA level increased in cells exposed to 5-FU, DXR, or CDDP, but the addition of cimetidine had no effect on the E-selectin mRNA level. The expression of E-selectin protein was also significantly higher after the addition of 5-FU, DXR, or CDDP, compared with that of a negative control. However, when cimetidine was added prior to the addition of 5-FU, DXR, or CDDP, the expression of E-selectin was significantly suppressed. Thus, cimetidine significantly inhibited the expression of E-selectin at the protein level without affecting its expression at the mRNA level in cells treated with anticancer drugs. In conclusion, anticancer drugs increased the expression of E-selectin and this increase was inhibited by cimetidine. These findings suggest that the administration of cimetidine during treatment with anticancer drugs might be useful for preventing metastasis.

[Effect of cimetidine on E-selectin expression on the vascular endothelium stimulated by anti-cancer drug].

Various anticancer drug treatments have contributed to elongating survival of cancer patients. However, cancer often metastasizes and recurs in spite of anti-cancer drug treatment. It is important to control metastasis in order to achieve a favorable outcome. In this study, we confirmed that an expression of E-selectin in human umbilical vein endothelial cells (HUVEC) was stimulated by 5-FU, and that the expression of E-selectin was inhibited by cimetidine which was a H2 receptor antagonist.

[An interesting change of E-selectin in cimetidine administration during anticancer drug use].

E-selectin is an adhesion molecule developed as an important material for hematogenous metastasis of cancer cells on vascular endothelial cells. It is expected that if we can restrain a manifestation of E-selectin then hematogenous metastasis can be restrained. We divided gastric cancer and the colorectal cancer patients, who performed chemotherapy, into two groups of cimetidine administrated group and a non-administration group, and reviewed whether cimetidine inhibited an expression of E-selectin on vascular endothelial cells by measuring E-selectin in plasma. We experienced one example that showed an interesting change of E-selectin and the quantity of E-selectin in plasma fell during the cimetidine dosage. However, we report that E-selectin has risen after the cimetidine dosage was cancelled in the cimetidine administrated group.

[Trial of outpatient anti-cancer chemotherapy with infusion of 5-FU and cisplatin for advanced gastric and colorectal cancers].

We carried out a pilot study on the clinical efficacy and safety of outpatient anti-cancer chemotherapy with 5-FU and CDDP for 5 patients with advanced cancer of the stomach or colon, using two disposable balloon pumps. The protocol was combined chemotherapy with continuous intravenous infusion of 5-FU (500 mg/body/day) and CDDP (10 mg/body/day) in 5-day courses for 1 week, and the therapy was repeated as long as possible. Pharmacokinetic study showed that the mean serum concentration of 5-FU was 64.3+/-9.2 ng/ml, and the serum concentration of total Pt increased continuously during CDDP injection. Thus, both drugs were injected, safely and surely. One patient had a clinically evaluable lesion, and the anti-tumor effect of this case was SD. But the serum CEA level was decreased in 3 cases. The side effect of Grade 3 and 4 was not seen, but nausea, vomiting, anorexia, and weight loss were observed frequently. This therapy enabled the patients to stay home 51.6+/-10.0 days longer than with the usual methods in hospital, and this therapy was thought to improve their quality of life. Thus, this therapy is feasible and quite useful, but much attention must be paid to the patient's oral uptake during the therapy, and the clinical effects should be evaluated in randomized control trials.