Chemotherapy-induced Reversion of Mutant RAS to Wild-type RAS in Metastatic Colorectal Cancer.

BACKGROUND/AIM: Secondary mutation of mutated RAS, induced by chemotherapy, is thought to be rare. However, introduction of liquid biopsy (LB) has made it possible to monitor RAS status in patients' plasma throughout the course of chemotherapy for metastatic colorectal cancer (mCRC), and disappearance of the RAS mutation (RAS-mt), i.e., the NeoRAS-wt phenomenon, has been reported and is receiving attention, especially with respect to treatment implications. PATIENTS AND METHODS: A prospective study of 129 patients undergoing chemotherapy for mCRC (RAS-wt, n=65; RAS-mt, n=64) was carried out. Plasma RAS status was monitored in these patients by LB. Relations between secondary genetic change, chemotherapy, and 6-month disease outcomes were analyzed. The effect of anti-EGFR mAb therapy on NeoRAS-wt mCRC was also examined. RESULTS: NeoRAS-wt was detected in 27 (43.5%) RAS-mt patients overall and in all patients with a G12S or Q61H mutation. First-line treatment was more effective among NeoRAS-wt patients than non-NeoRAS-wt patients (70.9% vs. 48.6% overall response rate, p=0.087), and the time from treatment to LB was shorter in this group. Six-month outcomes were significantly better in the NeoRAS-wt group (p<0.001), and conversion to NeoRAS-wt was found to be predictive of a good outcome (OR=7.886, 95% CI=2.458-25.30; p<0.001). Anti-EGFR mAb therapy was found to restrict disease progression in NeoRAS-wt patients. CONCLUSION: Conversion to NeoRAS-wt is relatively frequent, and it may predict good responses to treatment. Anti-EGFR mAb therapy was effective for our NeoRAS-wt patients. Detection of NeoRAS-wt by LB may significantly change the indication for anti-EGFR mAb therapy and the mCRC treatment strategy.

Preoperative Pre-albumin Concentration as a Predictor of Short-term Outcomes in Elderly Patients With Colorectal Cancer.

BACKGROUND/AIM: Population aging results in increasing numbers of elderly persons undergoing surgery for colorectal cancer. We sought to identify objective preoperative indicators of outcomes, with a view toward development of safe, effective treatments for such patients. PATIENTS AND METHODS: The study included 99 patients aged 80 years or more, who were treated surgically for stage I- III colorectal cancer. Preoperative nutritional status was compared retrospectively between those who suffered postoperative complications (n=40) and those who did not (n=59). RESULTS: Univariate analysis revealed low prealbumin (PreAlb) concentration (p=0.032) and low platelet-to-lymphocyte ratio (p=0.116) as risk factors for postoperative complications. Multivariate analysis showed preoperative PreAlb concentration to be an independent risk factor (OR=0.884; 95% confidence interval=0.791-0.989; p=0.024) associated with postoperative length of hospital stay (coef.=-0.336, p=0.002). CONCLUSION: PreAlb, a rapid turnover protein, shows promise as a simple predictor of postoperative complications in elderly patients treated for colorectal surgery.

Signet-ring Cell Carcinoma Component as an Indicator of Anaplastic Lymphoma Kinase Mutations in Colorectal Cancer.

OBJECTIVES: Molecular profiling of marker mutations has become an essential aspect in the treatment planning for colorectal cancer (CRC). Anaplastic lymphoma kinase (ALK) mutations could be used as markers in CRC molecular profiling. However, the extremely low frequency of these mutations makes their confirmation in all patients inefficient. Thus, to determine whether ALK positivity could be indicated by morphological features, we have analyzed ALK positivity in CRC tissues with a signet-ring cell carcinoma (SRCC) component. METHODS: We screened cases of patients who underwent CRC surgical resection at the Department of Gastrointestinal Surgery of the Kanagawa Cancer Center between January 2015 and December 2019. The selected samples were then assessed immunohistochemically using an antibody against p80 ALK. RESULTS: In total, we were able to retrieve 29 cases of CRC with the SRCC component from the database; however, 5 cases were excluded owing to the absence of formalin-fixed paraffin-embedded tissue sections or the absence of the SRCC component when the tissues were observed. In the immunohistochemical analysis, two cases showed diffused positive immunoreactivity for ALK and were defined as ALK-positive CRC. Thus, the ALK positivity rate in CRC with SRCC was determined to be 8.3%. CONCLUSIONS: This present study sheds light on the morphological features of ALK-positive CRC. Our findings could contribute to the effective screening and improvement of front-line therapy for CRC.

Automated non-invasive identification of pelvic autonomic nerves with a handheld Raman spectrometer and potential application to nerve-sparing colorectal surgery: a preliminary study in surgical specimens.

BACKGROUND: Although minimally invasive surgery for colorectal cancer, whether performed as standard laparoscopic or robotic surgery, has been established as an oncologically safe procedure, postoperative urinary dysfunction and sexual dysfunction remain matters of concern, even when so-called nerve-sparing surgery is performed. We have hypothesized that Raman spectroscopy can be used intraoperatively as a non-invasive label-free means of objective identification of the pelvic nerves, and we conducted a preliminary study by applying a newly developed handheld Raman spectrometer to surgical specimens. METHODS: Samples of nervous tissue, colon cancer tissue, and tissues from surrounding pelvic organs were obtained from 25 patients undergoing colectomy. Raman spectra were obtained by irradiation with the Progeny™ Raman spectrometer. We looked for characteristic Raman shifts to distinguish nervous tissue from cancer tissue. To improve discrimination between nervous tissue and other tissues, the spectral data were subjected to principal component analysis. RESULTS: We detected characteristic differences in the spectra at 1,309 cm-1, 1,442 cm-1, and 1,658 cm-1. A significant difference was detected at 1,442 cm-1, and accuracy of the modality for identification of nervous tissue was 75%. The addition of principle component analysis (4 components) yielded 100% sensitivity, 85% specificity, and 90%, notably increasing accuracy from 75% to 90% in discriminating between nervous tissue and cancer tissue. CONCLUSIONS: Raman spectroscopy holds promise for non-invasive intraoperative recognition of nervous tissue. We expect the modality to become a powerful clinical tool, compensating for the lack of tactile feedback intrinsic to minimally invasive colectomy and thus thwarting the risk of postoperative urinary and/or sexual dysfunction.

[Case of Spindle Cell Carcinoma of the Breast Resistant Neoadjuvant Chemotherapy].

We report a rare case of spindle cell carcinoma of the breast which grew rapidly during neoadjuvant chemotherapy. A 72- year-old female was presenting with chief complaint of a mass in the right breast; a tumor about 20 mm in size. Core needle biopsy of tumor revealed invasive ductal carcinoma and fine needle aspiration cytology of axillary lymph node was Class Ⅴ. So she was diagnosis breast cancer as cT2N1M0, cStage ⅡB. The tumor subtype was triple negative breast cancer (TNBC). She received the neoadjuvant chemotherapy by FEC100. After FEC 4 courses, we detected a huge and rapid growing breast mass of 40 mm by CT. She was administered received mastectomy and axillary lymph node dissection after 4 months from initial contact. Pathological finding was spindle cell carcinoma of the breast. Postoperatively, she was treated with weekly PTX for a total of 12 courses and radiation therapy for a right chest wall and supraclavicular fossa. Although the tumor was resistant for neoadjuvant chemotherapy, she is alive and well without metastasis for more than 3 years.

[Four Cases of Appendiceal Mucinous Neoplasm Treated with Laparoscopic Surgery].

Appendiceal mucinous neoplasm has a risk for pseudomyxoma peritonei caused by appendiceal perforation.It has been reported that laparoscopic surgery is more risky than open surgery.We investigated 4 patients who underwent laparoscopic surgery for appendiceal mucinous neoplasm.The median age was 69.5(49-85).There were 3 males and 1 female.Three cases of partial laparoscopic resection of the cecum and 1 case of ileocecal resection with lymph node dissection were performed. The pathology was low-grade mucinous neoplasm in all cases.The median hospital stay was 6 days, and there were no postoperative complications(CD Grade 3 or higher)or hospital death.As for long-term results, peritoneal pseudomyxoma developed in 1 case, which had already ruptured at the time of surgery.There were no recurrences in other cases.This result suggests that laparoscopic surgery for appendiceal mucinous neoplasm is safe with optimal selection of the procedure and a protective technique.

[A Case of Perforated Intestinal Malignant Lymphoma Induced to Remission by Multidisciplinary Therapy].

A 61-year-old man had a sudden severe abdominal pain and visited our hospital. He was diagnosed with intestinal perforation, given the peritoneal irritation symptoms, the thickening of the intestinal wall and free air as shown on enhanced abdominal computed tomography. He then underwent emergent surgery. A tumor with small perforation was found on the intestine about 15 cm distant from the terminal ileum. Partial resection of the ileum was performed. Microscopically, a type 2 tumor of 70×50mm in diameter, was observed in the resected intestine. The tumor was diagnosed as diffuse large B-cell lymphoma via immunochemical staining. He received 6courses of R-CHOP therapy after surgery without recurrence. A primary intestinal malignant lymphoma is easily perforated, which lead to poor prognosis of the patient. We report a case of perforated intestinal malignant lymphoma, which was induced to remission by multidisciplinary therapy.

[A Case of Long-Term Survival with Multidisciplinary Treatment in Unresectable Advanced Gastric Cancer Found with Ovarian Tumor].

Although chemotherapy is the standard treatment for unresectable advanced gastric cancer, its prognosis is poor and the median survival time is only around 10 months. With some literature consideration, we report that ovarian metastasis triggered the diagnosis of unresectable advanced gastric cancer with long-term survival through multidisciplinary treatment. This is the case of a 69-year-old woman, who was diagnosed with ovarian tumor and underwent right extracorporectomy and omentum resection in 2011. Pathological diagnosis suspected adenocarcinoma. In February 2012, EGD found a type 4 tumor in the upper portion of the pyloric area of the stomach. She was diagnosed with gastric cancer with Stage IV(T4aN0M1 [ovary])ovarian metastasis. Because the primary tumor was HER2 positive, XP plus HER therapy(capecitabine 1,000mg/m2 twice a day for 14 days, CDDP 80mg/m2 every 3 weeks on the first day, and trastuzumab 8 mg/kg every 3 weeks on the first day)was administered since March 2012. No metastasis was found in the imaging examination after 8 courses of chemotherapy, and we also confirmed the reduction of the primary tumor in the EGD. Based on the images, primary resection was already possible. In December 2012, after a diagnostic laparoscopy, total gastrectomy with D2 lymph node dissection was performed. Postoperative pathology was diagnosed as Stage IV(pT4aN0M1). To control postoperative micrometastasis, capecitabine therapy(1,000mg/m2 twice a day for 14 days)was administered for 12 months starting from February 2013. Then, recurrence and metastasis were not observed during follow-up. However, in January 2017, a circumstellar stenotic tumor was found in the rectum and was diagnosed as recurrence of peritoneal dissemination through images. In February 2017, artificial ostomy(in the sigmoid colon, double-mouth type)was made. Then, the patient underwent an outpatient chemotherapy, with hospital visits, and she survives.

[Three Cases of Long-Term Surviving Stage IV Gastric Cancer after Conversion Surgery].

The standard therapy for Stage IV gastric cancer is chemotherapy. It is not certain, but conversion surgery is expected to be effective. We report the cases of 3 patients who achieved long-term survival after conversion surgery. Case 1 was of a 59- year-old woman. The tumor was classified as L-Less Post, Type 2, tub1, cT3N2M1(#16a2lat), Stage IV. Then, we initiated S-1 plus cisplatin and the LN achieved PRafter 4 courses. We performed distal gastrectomy with D2 lymph node dissection in February 2011. It was classified as ypT2N2 and the primary lesion was histologically classified as Grade 1a. Case 2 was of a 74- year-old man. The tumor was classified as UM-Less Ant, Type 3, por1, cT3N2H0P1CY1, Stage IV. Then, we initiated docetaxel plus cisplatin plus S-1 and the primary tumor achieved PRafter 6 courses. There were no new tumors and we conducted a laparoscopic examination. After the decision of P0CY0, we performed total gastrectomy with D2 lymph node dissection in April 2012. It was classified as ypT3N1 and the primary lesion was histologically classified as Grade 2. Case 3 was of a 64-yearold woman. The tumor was classified as UM-Less, Type 3, por1, cT3N2H1M0(liver), Stage IV. Then, we initiated capecitabin plus cisplatin and liver metastasis achieved PRafter 6 courses. We performed total gastrectomy with D2 lymph node dissection in July 2012. It was classified as ypT3N1 and the primary lesion was histologically classified as Grade 1b. All postoperative chemotherapy courses were of only S-1. In case 1, the para aortic LN exhibited recurrence 6 months postoperatively. We initiated weekly paclitaxel as second-line therapy. It achieved CRafter 6 courses, and the same trend was maintained. In cases 2 and 3, no therapy was administered after 8 S-1 courses, but no recurrences occurred. All patients survived after 62-77 months postoperatively. A new clinical trial is needed to prove the improvement in prognosis for Stage IV gastric cancer after conversion surgery.

[A Case of Retroperitoneal Liposarcoma Resected 6 Times in 24 Years].

We report a long-surviving case of retroperitoneal liposarcoma requiring 6 operations in 24 years. A 56-year-old female was diagnosed with liposarcoma and it was resected for the first time in 1991. The pathological diagnosis was well-differentiated liposarcoma. Thereafter, we resected recurrences in the retroperitoneum in July 2008, with the left half of the colon in June 2011. Then, we resected the pancreatic tails, spleen, accessory spleen, left adrenal gland, left kidney, and part of the diaphragm in October 2012, and part of the diaphragm, descending colon, and jejunum in October 2014. At this time, there were growing recurrences removed from the pancreatic tails. There is no evidence of recurrence after 24 years after the first resection. In this case, it was thought that the factor correlated with long survival was actively resecting recurrences and recognizing high-grade dedifferentiated type liposarcoma at an early stage.