Visceral Fat Associated with Worsening of Recurrent Esophageal Varices in Alcoholic/Nonalcoholic Steatohepatitis-Related Liver Cirrhosis.

BACKGROUND: Alcoholic steatohepatitis and nonalcoholic steatohepatitis-related liver cirrhosis (ASH/NASH-LC) are major causes of esophageal varices (EVs). However, the association between high visceral fat and exacerbation of EVs remains unclear. The aim of this study was to clarify the association of visceral fat and recurrence rate of EVs in ASH/NASH-LC and to identify independent predictors associated with recurrence. METHODS: We retrospectively evaluated data from 94 patients who underwent endoscopic injection sclerotherapy for EVs with ASH/NASH-LC. Using the receiver operating characteristic curve for the cut-off value of visceral fat index (VFI; 46.4 cm2/m2), we classified patients as having a high VFI (n = 53) or low VFI (n = 41). Propensity score matching was used to align for background factors, and the recurrence rate of EVs was compared between the two groups. Predictors associated with esophageal variceal recurrence were identified by multivariate analysis. The recurrence rate in patients with viral LC was also investigated. RESULTS: In the overall analysis, the recurrence rate was significantly higher in the high VFI group than in the low VFI group (P = 0.023). The recurrence rate was also higher in the high VFI group than in the low VFI group after propensity score matching, in which 19 patients were matched in each group (P = 0.048). VFI and Child-Pugh score were independently associated with recurrence. Recurrence rates were comparable between the two groups in viral LC patients. CONCLUSIONS: Worsening of variceal recurrence was observed in high visceral fat patients in ASH/NASH-LC but not in viral LC. Furthermore, high visceral fat was an independent predictor associated with variceal recurrence.

Predictive Postoperative Inflammatory Response Indicators of Infectious Complications Following Gastrectomy for Gastric Cancer.

BACKGROUND: Perioperative factors are useful for predicting postoperative infectious complications (PIC) in gastric cancer. Specifically, postoperative inflammatory response indicators (PIRI), [C-reactive protein (CRP) level, body temperature (BT), and white blood cell (WBC) count], are widely used in clinical practice. We investigated predictive factors for PIC, including PIRI, to establish a simple and practical indicator of postoperative complications after gastrectomy. METHODS: We retrospectively collected clinical data from 200 patients with fStage I-III gastric cancer. Univariate/multivariate analysis was performed to evaluate the relationship of predictive factors [host factors, clinicopathological factors, and PIRI (BT, WBC count, and CRP level on postoperative day (POD) 1 and 3) ]. Cut-off values of the predictive factors were analyzed using receiver operating characteristic (ROC) curve modulated by the presence/absence of PIC Grade II, III (Clavien-Dindo classification). RESULTS: Age [Odds ratio (OR): 5.67], smoking history (OR: 3.51), and CRP level (OR: 5.65), WBC count (OR: 8.96), and BT (OR: 3.37) on POD3 were selected as independent factors from multivariate analysis. Cut-off values were 77 years, 14.8 mg/dL, 116.0×102/µL, and 37.4°C, respectively. CONCLUSIONS: Predictive factors relative to PIC in gastric cancer were CRP level ≥ 14.8 mg/dL, WBC count ≥ 116.0×102/µL, and BT ≥ 37.4°C all on POD3. Age ≥ 77 years, and history of smoking were relative to PIC, suggesting a simple and practical indicator applicable in clinical practice.

Preoperative and Postoperative C-Reactive Protein to Albumin Ratio (CAR) as a Prognostic Marker for Survival of Esophageal Squamous Cell Carcinoma Patients After Surgery.

BACKGROUND/AIM: Recent studies have reported that the C-reactive protein (CRP) to albumin ratio (CAR) may be a useful prognostic biomarker in various types of cancer patients. However, the mechanism underlying this observation is unclear. The present study aimed to clarify why the CAR can predict post-esophagectomy prognosis, the relationship between pre- and postoperative CAR, and whether postoperative CAR can predict the prognosis of esophageal cancer patients. PATIENTS AND METHODS: We investigated 158 esophagectomy patients with esophageal squamous cell carcinoma. Hematological examinations were performed on postoperative days (POD) 1, 3, 5, 7, 10, and 14. RESULTS: Preoperative CAR was a significant independent prognostic factor of overall survival (OS) [hazard ratio (HR)=2.247; p=0.0005], and there was a strong correlation between preoperative CAR and tumor depth. The preoperative high-CAR (pre-high-CAR) group had significantly higher CAR on all postoperative days (POD). We then divided the patients as follows: those with at least two low-CAR days on POD 5, 7, and 10 were assigned to the modified post-low-CAR (mPost-low-CAR) group, and others were assigned to the modified post-high-CAR (mPost-high-CAR) group. The 5-year OS rate was significantly higher in the mPost-low-CAR group than in the mPost-high-CAR group, which predicted a more accurate prognosis (p<0.0001, HR=2.769). CONCLUSION: Preoperative CAR was associated with tumor depth and diameter, and patients in the pre-high-CAR group continued to have significantly higher CAR postoperatively. These factors were presumed to reflect disease prognosis. Furthermore, grouping by CAR on POD 5, 7, and 10 reflected patient prognosis more accurately than preoperative CAR.

[Evaluation of Bridge to Surgery(BTS) after Stenting for Malignant Colorectal Stenosis].

OBJECTIVE: To evaluate the current status and postoperative course of nutritional management in bridge to surgery(BTS) after colorectal stenting for malignant colorectal stenosis. SUBJECTS AND METHODS: The study included 242 colorectal cancer cases, 27 cases with malignant colorectal stenosis who underwent BTS group, 24 cases with malignant colorectal stenosis who fasted until the day of surgery and consumed drinking water and Elenthal®(no oral intake group), and 191 cases with non-stenotic colorectal cancer (diet group). The study items selected were nutritional management methods before colorectal cancer resection, nutritional assessment, surgical factors, and postoperative course. RESULTS: The BTS, no oral intake, and diet groups were compared in 27, 0, and 191 patients, respectively. In contrast, the intake of Elenthal® was compared in 4, 20, and 5 patients and total parenteral nutrition in 3, 15, and 1 patients, respectively. There were no differences in nutritional sufficiency during hospitalization. The Onodera Nutritional Index(PNI)was significantly lower in the BTS and no oral intake groups than the diet group at the first outpatient visit before surgery. The PNI was significantly lower in the no oral intake group than in the diet group immediately before surgery. Blood loss was higher in the BTS and no oral intake groups than in the diet group, but there was no difference in operative time. The postoperative course was poorer in the no oral intake group than in the diet group. However, there was no difference between the diet and BTS groups. CONCLUSION: In patients with obstructive colorectal cancer in whom BTS could be performed, the results suggest that preoperative nutritional management with a high sufficiency rate using the intestinal tract may lead to a postoperative course comparable to that in non-stenotic cases.

Preoperative Subcutaneous Fat is an Useful Indicator for Learning Totally Extraperitoneal Repair.

BACKGROUND: Totally extraperitoneal (TEP) repair is a recommended procedure for inguinal hernia repair in European hernia guidelines. However, technical challenges have limited its uptake in Japan, where transabdominal preperitoneal (TAPP) repair is more common. We evaluated the association of preoperative subcutaneous fat area (preSFA) with surgical outcomes and identified factors associated with the difficulty of TEP repair. METHODS: Clinical data from 62 patients undergoing TEP repair were collected retrospectively. Using the median for the preoperative subcutaneous fat index (preSFI; 45.9 cm2/m2), we classified patients as having a high SFI (HSFI) (n=31) and low SFI (LSFI) (n=31). Surgical outcomes and perioperative complications were then compared between these groups. Additionally, TEP repair was divided into five phases (e.g., Phase 1: dissection of the caudal side of the preperitoneal space), and operative time was measured during each phase. Phase 1 was divided into two sub-phases (1A: insertion of the first port, 1B: reaching Cooper's ligament). RESULTS: Operative time was longer (133 min vs 111 min, P = 0.028) and the peritoneal injury rate was higher (35.5% vs 9.7%, P = 0.015) for the HSFI patients. Furthermore, operative time for HSFI patients was significantly longer during Phase 1 (P = 0.014) and Phase 1A (P = 0.022). CONCLUSIONS: preSFA was associated with a higher peritoneal injury rate and longer operative time in HSFI patients, suggesting that the presence of abundant subcutaneous fat increases the difficulty of TEP repair.

[A Case of Resected Diffuse Large B-Cell Lymphoma Diagnosed with Liver Metastasis and Peritoneal Dissemination after Surgery for Sigmoid Colon Cancer].

We experienced a case of diffuse large B-cell lymphoma(DLBCL)that developed around the kidney about 1 year after surgery for sigmoid colon cancer. In this case, imaging findings suggestive of liver metastasis were also observed at the same time of diagnosis, therefore, diagnosis was difficult because the possibility of peritoneal dissemination could not be ruled out. The lesion was excised by surgery and a definitive diagnosis was obtained by tissue diagnosis, leading to appropriate treatment. However, one wrong step could lead to the wrong treatment policy. Therefore, when there is any doubt about the diagnosis, it is considered important to proactively perform tissue diagnosis.

[The Effects of Bridge to Surgery(BTS)for Malignant Colorectal Stenosis on the Nutritional and Immunological Status].

OBJECTIVE: This study aimed to clarify the effects of bridge to surgery(BTS)for malignant colorectal stenosis on the nutritional and immunological status. SUBJECTS AND METHODS: A total of 19 patients with colorectal cancer who underwent BTS were included. We examined the technical success of stenting, clinical improvement, treatment progress after BTS, and nutritional and immunological status changes before and after BTS. RESULTS: There were 19 technically successful cases and 18 clinically improved cases. One patient(Score 0)had an obstruction after BTS, which improved after stent repositioning. The CROSS Score before and after stenting improved in all patients. Scores 0 to 4 improved in 12 patients, Scores 0 to 3 in 5 patients, and Scores 3 to 4 in 2 patients. The median time to resume eating was 3 days, and the median surgery time was 25 days. The final diet before operation for colorectal consisted of a rokubugayu(rice gruel: polished rice content 12%)in 1 case, zengayu(rice gruel: polished rice content 20%)in 8 cases, soft diet in 5 cases, and regular diet in 5 cases. Before and after BTS, the nutritional and immunological status decreased significantly(p<0.05)with albumin levels ranging from 3.9- 3.5 g/dL, BUN/Cr from 24.8-12.5, and neutrophil-to-lymphocyte ratio from 3.8-2.5; however, no significant fluctuations in the prognostic nutritional index were observed. CONCLUSION: BTS enabled the nutritional management using the intestinal tract and improved the patient's immune status.

[A Case of Rectal Cancer Diagnosed Based on Brain Metastasis and Had a Long-Term Prognosis by Radical Resections].

The patient was a 57-year-old man who visited the department of neurosurgery for headache and lightheadedness. He was admitted with a diagnosis of brain tumor based on imaging findings. Severe brain dysfunction and mild ataxia were observed, and craniotomy tumor resection was performed 5 days after admission. He was diagnosed with brain metastasis of colorectal cancer based on histopathological examination and endoscopic findings, and was therefore referred to our department. No extracranial metastases were observed, laparoscopic-assisted low anterior resection was performed 1 month after the craniotomy. The final diagnosis was rectal cancer(Ra), pT3N0M1a(BRA), Stage Ⅳa. Three months after the craniotomy, subsequent MRI examination revealed a new metastatic lesion inferior to the tumor excision cavity, and gamma knife radiosurgery was performed. However, because an increasing tendency was noted, craniotomy was performed again 7 months after the first craniotomy. Following operative treatment, follow up has been performed without adjuvant chemotherapy or prophylactic irradiation, the patient has survived without recurrence at 34 months postoperatively. Here, we report a valuable rare case of solitary brain metastasis of colorectal cancer in which prognosis could be expected by radical resections.

[A Case of Multiple Lung Metastases of Pancreatic Cancer with 50 Months Survival by Sequential Chemotherapy].

We hereby report a case in which a patient with multiple lung metastases of pancreatic cancer continued chemotherapy and maintained good performance status(PS)for 48 months after recurrence. But her disease progressed rapidly after withdrawal of chemotherapy, resulting in her death in a short period of time. The patient was a 66-year-old woman who underwent a substomach preserving pancreaticoduodenectomy for pancreatic head cancer at the age of 60 years. She was diagnosed as fT3N1M0, fStage ⅡB. During postoperative adjuvant chemotherapy S-1, multiple lung metastases were noted on CT scan 2 years after surgery. Thereafter, she was treated with gemcitabine(GEM)alone, GEM plus nab-paclitaxel(GnP), nal-CPT-11 plus 5-FU plus Leucovorin, and FOLFIRINOX for 48 months sequentially. Each of which achieved a best overall response SD or better. However, Trousseau syndrome developed following community-acquired pneumonia during chemotherapy withdrawal due to myelosuppression. The disease progressed rapidly and resulted in her death 50 months after relapse. The results suggest that chemotherapy may have contributed significantly to disease control in this case.

[A Case of Pathological Complete Response after Neoadjuvant Therapy for Resectable Pancreatic Cancer].

We report a case of resectable pancreas tail cancer treated with 2 courses of neoadjuvant therapy which is gemcitabine and S-1 therapy, and pathological diagnosis of the resected specimen revealed pathological complete response. A 56-year- old woman was referred to our hospital because she had back pain after eating for 5 months and her previous abdominal ultrasonography revealed an enlarged pancreatic tail. The tumor size was reduced from 30 mm to 12 mm, and the chemotherapy response was judged to be partial response. The patient underwent distal pancreatectomy, splenectomy, and D2 lymph node dissection. Intraoperative findings showed a pancreatic tail with a depression and surface erythema, thus we also diagnosed the patient as having pancreatic capsular invasion(S1). Postoperative histopathological examination revealed a 10×10 mm area of pancreatic parenchyma, which was replaced by fibrous tissue, with no evidence of active cancer cells. The patient was discharged from the hospital on the 14th after surgery.

Feasibility of augmented rectangle technique in laparoscopic distal gastrectomy: comparison with hemi-double stapling technique in a single-center retrospective cohort study.

PURPOSE: Augmented rectangle technique (ART) anastomosis is a totally intracorporeal anastomosis of laparoscopic distal gastrectomy (LDG), Billroth I (B1) reconstruction for gastric cancer, which secures a wide anastomotic stoma. Since the conventional extracorporeal hemi-double stapling technique (HD) may have a narrow anastomotic stoma, our aim of this study was to evaluate the feasibility and usefulness of ART anastomosis by comparing the surgical outcomes with HD anastomosis. METHODS: Clinical data of 89 patients undergoing LDG with B1 reconstruction were retrospectively collected. Patients were divided into ART group (n = 40) and HD group (n = 49). Surgical outcomes including short-term outcomes, postoperative endoscopic findings, and nutritional factors 1 year after surgery were compared between the groups. RESULTS: Baseline characteristics were similar between the groups. In terms of short-term outcomes, blood loss was less (11.5 mL vs 40 mL, P = 0.011) and postoperative hospital stay was shorter (10 days vs 12 days, P = 0.022) in the ART group. In terms of endoscopic findings, residual food was less (P = 0.032) in the ART group. In terms of nutritional factors, percent decrease of visceral fat area (- 27.6% vs - 40.5%, P = 0.049) and subcutaneous fat area (- 25.7% vs - 39.3%, P = 0.050) 1 year after surgery attenuated in the ART group. CONCLUSIONS: ART anastomosis is superior in perioperative course such as postoperative hospital stay. Moreover, a better nutritional recovery is expected by securing a wide anastomotic stoma leading to a favorable food passage.

[Relationship between Degree of Obstruction of Colorectal Cancer and Nutritional and Immune Status].

This study examined the impact of the degree of occlusion in colorectal cancer during the perioperative period. The subjects included 207 patients who underwent elective colorectal cancer resection. The degree of obstruction at the first medical examination was evaluated using the ColoRectal Obstruction Scoring System(CROSS). We classified the subjects into two groups(CROSS score 0-2, CROSS score 3-4)and assessed their associations with clinicopathological factors, nutritional immune status, and postoperative course. Compared to the CROSS score 3-4 group, the CROSS score 0-2 group(42 subjects [20.3%])had a higher proportion of subjects with ≥2 lesions, T4, Stage classification Ⅳ, CEA >5.0 ng/mL, prognostic nutritional index( PNI)≤40, controlling nutritional status( CONUT) score ≥2, modified Glasgow prognostic score (mGPS)2, weight loss rate>2.3, mini nutritional assessment-short form(MNA®-SF)score <12, neutrophil lymphocyte ratio(NLR) ≥4.0, postoperative complications, and postoperative hospital stay >16 days( p<0.05). Our findings suggest that the degree of occlusion in colorectal cancer is associated with clinicopathological and nutritional/immune factors and is reflected by the postoperative course.

First successful case of percutaneous transabdominal thoracic duct embolization (PTTDE) for chylous ascites resulting from laparoscopic gastric cancer surgery.

A 61-year-old woman underwent laparoscopy-assisted distal gastrectomy (LADG) with extragastric lymph node dissection (D2). Two months later, she was readmitted to hospital to be treated for chylous ascites. Oral intake was discontinued and total parenteral nutrition started, but increasing body weight and decreasing serum albumin concentration was not controllable. Percutaneous transabdominal thoracic duct embolization (PTTDE) was performed on the 8th day after the readmission. Five days after PTTDE, oral intake was resumed. Seventeen days after PTTDE, the patient was discharged without recurrence of ascites. She has remained asymptomatic. We describe here the first patient with chylous ascites two months after LADG with D2 dissection for early gastric cancer who was successfully treated by PTTDE.

[Significance of Transitions in Neutrophil-to-Lymphocyte Ratio before and after Transcatheter Arterial Chemoembolizaton for Hepatocellular Carcinoma].

We investigated the significance of transitions in the neutrophil-to-lymphocyte ratio(NLR)before and after TACE for HCC could be a predictor of prognosis. The subjects were 108 patients with the first TACE performed from January 2010 to December 2019. NLR was calculated before and 1 month after TACE, and the relationship with therapeutic effect and prognosis was examined. When the transition of NLR before and after TACE was classified into 3 groups with a cut-off value of 5.0, group A(less than 5.0 after TACE): 52 cases(48.1%), group B(5.0 or more after TACE): 33 cases(30.6%)and C group(5.0 or more before and after TACE): 23 cases(21.3%). Median survival time were 25.0 months in group A, 18.5 months in group B, and 12.7 months in group C(p=0.0005). In multivariate analysis, treatment effect, NLR transition, AFP value, and serum albumin level were prognostic factors for HCC after TACE. Changes in NLR before and after TACE may help predict more detailed prognosis.

[Four Cases of Liver Resection for Liver Metastases from Renal Cell Carcinoma].

We report 4 cases of liver metastasis from renal cell carcinoma(RCC). Case 1: 72 years old, female. Pancreatic metastasis was resected 7 years after resection of left RCC, and hepatic posterior sectionectomy was performed for multiple liver metastases 2 years later. After that, multi-organ metastasis appeared and she died of the primary disease. Case 2: 72 years old, male. Liver metastasis and right RCC appeared 16 years after resection of left RCC, and hepatic posterior sectionectomy and partial resection of right kidney were performed. Nine months later, liver metastasis recurred and hepatic partial resection was performed. Case 3: 55 years old, male. After surgery for right RCC with tumor thrombus in the right atrium, multiple lung and liver metastases appeared, and hepatic central bisectionectomy was performed after chemotherapy. Case 4: 60 years old, male. Multiple pancreatic and lung metastases appeared 10 years after resection of left RCC, and most of them shrank or disappeared with chemotherapy. But increasing metastases appeared in the tail of pancreas and the right lobe of liver 16 months later, and hepatic subsegmentectomy and distal pancreatectomy were performed. Multidisciplinary treatment such as aggressive chemotherapy and excision is expected to improve the prognosis for liver metastasis from RCC.

Simultaneous Endoscopic Resection of Superficial Cancers of the Hypopharynx and Esophagus: A Case Report.

Diagnosis and treatment of superficial laryngopharyngeal cancers has recently received considerable attention. Here, we present a case of superficial hypopharyngeal cancer and superficial esophageal cancer treated with simultaneous endoscopic laryngopharyngeal surgery (ELPS) and endoscopic submucosal dissection (ESD). The patient was a 67-year-old man. During his follow-up for distal gastrectomy-performed earlier for stomach cancer-upper gastrointestinal endoscopy revealed three primary cancers: a superficial hypopharyngeal cancer, superficial esophageal cancer, and esophagogastric junction cancer. After total resection of the remnant stomach, combined hypopharyngeal ELPS with esophageal ESD was performed. He developed aspiration pneumonia after surgery but recovered and was discharged on the 16th day. Thus, safe and effective endoscopic therapy can be performed even for double superficial cancers of the laryngopharynx and esophagus.

[Assessment of Curative Resection in Patients with Multiple Relapses of Colorectal Cancer].

We assessed the therapeutic effect of curative resection in patients with multiple relapses of colorectal cancer using the time to surgical failure(TSF)as an index. We included 24 patients who experienced recurrence after curative resection of primary colorectal cancer at our department between 1993 and 2015. Curative resection for multiple relapses was possible in these patients. The sites of recurrence included the liver, lungs, peritoneum, lymph nodes, localized, and brain in 9, 8, 3, 3, 2, and 1 patients, respectively. The relapse occurred in 2 organs in 2 patients. The TSF after curative resection of recurrent lesions was 25.6 months, with a 5-year TSF-free rate of 40.2%. The clinicopathological factors associated with poor prognosis were age B65 years at the time of recurrence, absence of distal metastasis at primary onset, and only 2 curative resections for relapses. However, there was no difference in prognosis because of the number of twice recurrent lesions. Therefore, curative resection should be proactively performed as long as feasible in colorectal cancer patients with multiple lesions or multiple relapses.

[A Case of Unresectable Ascending Colon Cancer Treated with a Newly Devised Bypass Method].

A 74-year-old man underwent a medical examination for anemia and had a positive fecal occult blood test. Ascending colon cancer was detected by colonoscopy. Since it was unresectable, a bypass operation was performed to prevent digestive symptoms prior to chemotherapy. The bypass was performed by cutting the ileum and attaching the oral side to the transverse colon with side to side anastomosis. The other end of the terminal ileum was anastomosed to the transverse colon on the oral side of the prior anastomosis, making a pretzel shaped bypass. There were no postoperative complications and the patient was treated with chemotherapy from postoperative day 23.

[A Case of Advanced and Recurrent Colon Cancer with Long-Term Survival after Seven Repeated Surgical Resections].

We hereby report a case of advanced and recurrent colon cancer with long-term survival after 7 repeated surgical resections. A 73-year-old woman initially underwent right hemicolectomy and partial hepatectomy for an ascending colon cancer with synchronous liver metastasis. Pathological diagnosis of the tumors were moderately differentiated adenocarcinoma and metastasis to the liver compatibly. Final clinical stage was diagnosed as fT3N2M1(H1), fStage Ⅳ. But she was interrupted oxaliplatin-based adjuvant chemotherapy after 6 courses of CAPOX because of adverse drug reaction. One year after first operation, partial resection of right lung was performed for lung metastasis. Two years after first operation, 2nd resection of liver was performed for 2 liver metastatic lesions. Three years after first operation, 3rd partial liver resection, 2nd and 3rd partial lung resections were performed for metachronous metastases during 1 year. After 3 years recurrence free period, she complained of an induration of right neck and diagnosed as neck and supra clavicular lymph nodes metastases. Lymph nodes resection was performed. After the last operation, she has no sign of cancer recurrence for 1 year and 7 months, eventually she has been alive for 7 years and 7 months after the initial operation.

[A Case of Lung Metastases from Rectal Cancer Treated for Quite Long with FOLFIRI plus Ramucirumab as a Late Line of Therapy].

We herein report a case of lung metastases from rectal cancer treated with FOLFIRI plus ramucirumab(Ram)therapy after salvage for a long time. A 44-year-old woman underwent low anterior resection for rectal cancer. Fifteen months after the surgery, mFOLFOX6 plus bevacizumab(BV)therapy was initiated for left obturator lymph node metastases. Although the target lesion shrunk, left lung metastasis was found 36 months after the surgery. Partial resection of the lung metastasis was performed, and carbon-ion radiotherapy for pelvic recurrence was administered. Following these treatments, mFOLFOX6 plus BV therapy was administered again for multiple lung metastases 42 months after the surgery. FOLFIRI plus BV therapy, TAS- 102 plus BV therapy, and regorafenib were then administered because of the disease progression. Although the best supportive care was provided after disease progression, FOLFIRI plus Ram therapy was initiated owing to the patient's wish. Although Grade 3 hematological toxicity was observed, severe digestive symptoms were not noted. Long-term administration(approximately 1 year, 21 courses)of the drugs was possible with withdrawal. The patient died due to disease progression 66 months after recurrence. We experienced a case in which FOLFIRI plus Ram therapy after salvage line could be administered for a quite long time. It has been suggested that anti-VEGF drugs with different targets may improve the prognosis even as a late line of therapy if it is tolerable.