Differences in the Difficulty of Accessing Various 3-Dimensional Locations Under Mirror-Image Conditions During Laparoscopic Surgery.

BACKGROUND: Laparoscopic colon surgery frequently requires performing maneuvers under mirror-images conditions; the complexity differs depending on the surgical site location in the abdominal cavity. However, no previous reports have examined this. METHODS: Eleven surgeons participated in this study. Operations were performed on 25 points placed at the bottom and sides of a laparoscopic training box under mirror-image conditions. The mean time-point required to operate at each point and variation between surgeons were evaluated. RESULTS: When the right hand was used, time-points to touch the right side-superficial ends were 0.50 to 0.58 and 0.27 to 0.45 for the other sites. With the left hand, time-points to touch the left side-superficial ends were 0.58 to 0.63 and 0.28 to 0.51 for the other sites, indicating that the most difficult manipulation was at the proximal site of the surgical port. The variation in the difficulty according to the spots increased with a decrease in the surgeon's experience (right hand, r=-0.248; left hand, r=-0.491). CONCLUSIONS: In performing laparoscopic surgery under mirror-image conditions, the technical difficulty varies by location, and operating in locations close to the forceps port is the most difficult.

Insights into the heterogeneity of iNKT cells: tissue-resident and circulating subsets shaped by local microenvironmental cues.

Invariant natural killer T (iNKT) cells are a distinct subpopulation of innate-like T lymphocytes. They are characterized by semi-invariant T cell receptors (TCRs) that recognize both self and foreign lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. iNKT cells play a critical role in stimulating innate and adaptive immune responses, providing an effective defense against infections and cancers, while also contributing to chronic inflammation. The functions of iNKT cells are specific to their location, ranging from lymphoid to non-lymphoid tissues, such as the thymus, lung, liver, intestine, and adipose tissue. This review aims to provide insights into the heterogeneity of development and function in iNKT cells. First, we will review the expression of master transcription factors that define subsets of iNKT cells and their production of effector molecules such as cytokines and granzymes. In this article, we describe the gene expression profiles contributing to the kinetics, distribution, and cytotoxicity of iNKT cells across different tissue types. We also review the impact of cytokine production in distinct immune microenvironments on iNKT cell heterogeneity, highlighting a recently identified circulating iNKT cell subset. Additionally, we explore the potential of exploiting iNKT cell heterogeneity to create potent immunotherapies for human cancers in the future.

Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by the Tissue Microenvironment.

Recently, considerable attention has been directed toward innate-like T cells (ITCs) and innate lymphoid cells (ILCs) owing to their indispensable contributions to immune responses, tissue homeostasis, and inflammation. Innate-like T cells include NKT cells, MAIT cells, and γδ T cells, whereas ILCs include NK cells, type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), and type 3 ILCs (ILC3s). Many of these ITCs and ILCs are distributed to specific tissues and remain tissue-resident, while others, such as NK cells and some γδ T cells, circulate through the bloodstream. Nevertheless, recent research has shed light on novel subsets of innate immune cells that exhibit characteristics intermediate between tissue-resident and circulating states under normal and pathological conditions. The local microenvironment frequently influences the development, distribution, and function of these innate immune cells. This review aims to consolidate the current knowledge on the functional heterogeneity of ITCs and ILCs, shaped by local environmental cues, with particular emphasis on IL-15, which governs the activities of the innate immune cells involved in type 1 immune responses.

Local excision versus radical surgery for anal squamous cell carcinoma: a multicenter study in Japan.

BACKGROUND: The standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of over-treatment for early-stage disease. cTisN0 and cT1N0 disease is currently indicated for local excision, but it is unclear whether the indication of local excision can be expanded to cT2N0 disease. METHODS: 126 patients with cTis-T2N0 anal cancer treated at 47 centers in Japan between 1991 and 2015 were included. Patients were first classified into the CRT group and surgical therapy group according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups. We compared prognoses among the groups, and analyzed risk factors for recurrence after local excision. RESULTS: The CRT group (n = 87) and surgical therapy group (n = 39) showed no difference in relapse-free survival (p = 0.29) and overall survival (p = 0.94). Relapse-free survival curves in the LE (n = 23) and RS groups (n = 16) overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p = 0.33). By contrast, there was no difference in overall survival between the two groups (p = 0.98). In the LE group, the majority of recurrences distributed in locoregional areas, which could be managed by salvage treatments. Muscular invasion was associated with recurrence after local excision (hazard ratio: 22.91, p = 0.011). CONCLUSION: LE may be applied to selected patients with anal cancer of cTis-T2N0 stage. Given the high risk of recurrence in cases with muscular invasion, it may be important to consider close surveillance and additional treatment in such patients.

Range of protein induced by vitamin K absence or antagonist-II levels in neonates at birth.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is avitamin K (VK) deficiency indicator in neonates. However, PIVKA-II detection frequency in neonatal blood at birth and the correlation between PIVKA-II and gestational age are unclear. We retrospectively analyzed infants admitted to our institution between June 1, 2018, and March 31, 2022, whose clinical and PIVKA-II data were available, and classified them into preterm and term infant groups. Overall incidence of PIVKA-II-positive cases (≥ 50 mAU/mL) was 42.8%, including 0.6% apparent VK deficiency (≥ 5000 mAU/mL), 3.1% experimental VK deficiency (1000-4999 mAU/mL), and 10.7% latent VK deficiency (200-999 mAU/mL) cases. Incidence of PIVKA-II-positive cases was significantly higher in the term group than in the preterm group (49.4% vs. 29.7%, p < 0.001). Gestational age correlated with PIVKA-II levels (r2 = 0.117, p < 0.0001). Median serum PIVKA-II levels and incidence of PIVKA-II-positive cases (≥ 50 mAU/mL, 16.4%) were lower at 5 days after birth than at birth, possibly reflecting the postnatal VK prophylaxis impact. Only one infant was diagnosed with VK deficiency bleeding (PIVKA-II levels, at birth: 10,567 mAU/mL; at day 5: 2418 mAU/mL). Thus, serum PIVKA-II levels after birth weakly correlated with gestational age. VK deficiency was more common in term infants than in preterm infants.

Essential anatomy for lateral lymph node dissection.

In Western countries, the gold-standard therapeutic strategy for rectal cancer is preoperative chemoradiotherapy (CRT) following total mesorectal excision (TME), without lateral lymph node dissection (LLND). However, preoperative CRT has recently been reported to be insufficient to control lateral lymph node recurrence in cases of enlarged lateral lymph nodes before CRT, and LLND is considered necessary in such cases. We performed a literature review on aspects of pelvic anatomy associated with rectal surgery and LLND, and then combined this information with our experience and knowledge of pelvic anatomy. In this review, drawing upon research using a 3-dimensional anatomical model and actual operative views, we aimed to clarify the essential anatomy for LLND. The LLND procedure was developed in Asian countries and can now be safely performed in terms of functional preservation. Nonetheless, the longer operative time, hemorrhage, and higher complication rates with TME accompanied by LLND than with TME alone indicate that LLND is still a challenging procedure. Laparoscopic or robotic LLND has been shown to be useful and is widely performed; however, without a sufficient understanding of anatomical landmarks, misrecognition of vessels and nerves often occurs. To perform safe and accurate LLND, understanding the landmarks of LLND is essential.

Unexplained increases in serum carcinoembryonic antigen levels in colorectal cancer patients during the postoperative follow-up period: an analysis of its incidence and longitudinal pattern.

BACKGROUND: Carcinoembryonic antigen (CEA) monitoring facilitates the detection of recurrence in patients with colorectal cancer (CRC) after resection. False-positive CEA has been reported in CRC patients with certain comorbidities or smokers. However, limited information is currently available on the frequency of and changes in falsely elevated CEA levels in patients without these conditions. MATERIALS AND METHODS: We retrospectively examined CRC patients who underwent surgical resection at our hospital between 2001 and 2017, had no recurrence for at least five years, and were free of known factors that may increase CEA. Postoperative CEA levels were retrieved until 2 years before the last contact. For comparison, we similarly selected patients who developed recurrence after resection of CRC during the same period, and CEA levels at initial presentation, at nadir, and at the time of recurrence were reviewed. The patterns of elevated CEA (>5 ng/ml) were classified as transient, repeated, or persistent based on longitudinal changes. The relationships between CEA and carbohydrate antigen 19-9, transaminases, creatinine, and C-reactive protein were examined. RESULTS: CEA elevation occurred in 90 (20%) out of 446 eligible patients without recurrence at least once during the mean postoperative period of 50.5 months, whereas CEA was >5 ng/ml in 117 (53%) of 221 patients when they developed recurrence. Twenty-seven patients without recurrence showed a transient elevation in CEA, 45 repeated elevations, and 18 a persistent elevation; the frequency of a high preoperative CEA level increased in this order. The majority (98%) of false elevations ranged between 5 and 15 ng/ml. CEA was not associated with other laboratory data. CONCLUSIONS: Unexplained CEA elevations were observed in 20% of recurrence-free CRC patients after surgery, and were classified into three patterns based on longitudinal changes. A more detailed understanding of patient-specific fluctuations in CEA will prevent unnecessary imaging studies and reduce medical costs.

Limited information is currently available on the frequency of and changes in falsely elevated carcinoembryonic antigen (CEA) levels after surgery for colorectal cancer. Unexplained postoperative CEA elevations were detected in 20% of colorectal cancer patients. The patterns of these elevations were classified into transient, repeated, and persistent.

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.

Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.

Benefits of a laparoscopic approach for second colorectal resection after colectomy or proctectomy -a retrospective study.

BACKGROUND: A laparoscopic approach generally provides several benefits in patients who undergo colon or rectal surgery without jeopardizing oncological outcomes. However, there is a paucity of studies on comparative outcomes of laparoscopic versus open approaches for second primary colorectal lesions after colectomy or proctectomy. METHODS: From patients with colorectal disease who underwent surgery between 2008 and 2022 at our hospital, we collected 69 consecutive patients who had previous colorectal surgery for this retrospective study. Based on the second surgery approach (laparoscopic or open), patients were classified into the Lap (n = 37) or Op group (n = 32). Patients' baseline data and perioperative and postoperative outcomes were compared between the two groups. RESULTS: Four patients (11%) of the Lap group needed conversion to laparotomy. The intraoperative blood loss was lower in the Lap group than the Op group (median: 45 ml vs. 205 ml, p = 0.001). The time to first bowel movement was shorter in the Lap group than the Op group (median: 2.8 days vs. 3.6 days, p = 0.007). The operative time, frequencies of postoperative morbidities, and overall survival did not differ between the two groups. CONCLUSION: Laparoscopic surgery appeared feasible and beneficial for selected patients undergoing second colorectal resection after colectomy or proctectomy regarding blood loss and bowel function recovery without affecting other outcomes.

Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.

Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.

Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches.

Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.

Preoperative chemoradiotherapy using tegafur/uracil, oral leucovorin, and irinotecan (TEGAFIRI) followed by oxaliplatin-based chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: the study protocol for a phase II trial.

BACKGROUND: Total neoadjuvant therapy (TNT) is a novel treatment strategy that is an alternative to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, an optimal protocol for TNT has not yet been established. The present study will be an open-label, single-arm, single-center trial to develop a new protocol. METHODS: Thirty LARC patients at high risk of distant metastasis will receive CRT consisting of long-course radiation, concurrent with tegafur/uracil, oral leucovorin, irinotecan (TEGAFIRI), followed by mFOLFOX-6 or CAPOX before undergoing surgery. DISCUSSION: Since previous findings showed a high percentage of grade 3-4 adverse events with the TEGAFIRI regimen for CRT and TNT, the primary outcome of this study will be safety and feasibility. Our regimen for CRT consists of the biweekly administration of irinotecan for good patient compliance. The novel combination approach of this treatment may improve the long-term outcomes of LARC. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031210660.

Neuroendocrine carcinoma associated with chronic ulcerative colitis: a case report and review of the literature.

Adenocarcinoma is a common histological type of ulcerative colitis-associated cancer (UCAC), whereas neuroendocrine carcinoma (NEC) is extremely rare. UCAC is generally diagnosed at an advanced stage, even with regular surveillance colonoscopy. A 41-year-old man with a 17-year history of UC began receiving surveillance colonoscopy at the age of 37 years; 2 years later, dysplasia was detected in the sigmoid colon, and he underwent colonoscopy every 3 to 6 months. Approximately 1.5 years thereafter, a flat adenocarcinoma lesion occurred in the rectum. Flat lesions with high-grade dysplasia were found in the sigmoid colon and surrounding area. The patient underwent laparoscopic total proctocolectomy and ileal pouch-anal anastomosis with ileostomy. Adenocarcinoma was diagnosed in the sigmoid colon and NEC in the rectum. One year postoperation, recurrence or metastasis was not evident. Regular surveillance colonoscopy is important in patients with long-term UC. A histological examination of UCAC might demonstrate NEC.

Prediction of lymph node metastasis of well-differentiated rectal neuroendocrine tumours using multiple diagnostic modalities.

AIM: The preoperative prediction of lymph node metastasis of well-differentiated rectal neuroendocrine tumours is highly desirable and useful in defining surgical indication more accurately. We aimed to evaluate lymph node metastasis in rectal neuroendocrine neoplasms using multiple imaging modalities. METHODS: The clinical records and radiological images of 70 patients with well-differentiated rectal neuroendocrine tumours who received treatment at the University of Tokyo Hospital between 2010 and 2022 were retrospectively analysed. The relationship between evaluation by multiple imaging modalities and pathological lymph node metastasis was analysed. RESULTS: The receiver operating characteristic curves showed that a maximum lymph node diameter ≥4 mm on computed tomography and ≥8 mm on magnetic resonance imaging were the optimal predictive factors for lymph node metastasis. Accumulation in the lymph nodes on somatostatin receptor scintigraphy (P = 0.058) and Delle's findings on colonoscopy (P = 0.014) were also significant predictors of pathological lymph node positivity, and combination of multiple modalities was useful. Pathologically, lymphatic (P = 0.0030)/venous (P = 0.0007) invasion were risk factors for lymph node metastasis. CONCLUSIONS: In addition to pathological risk factors, a combination of multiple radiological imaging modalities is useful for predicting lymph node metastasis in well-differentiated rectal neuroendocrine tumours.

Diverticular perforation of terminal ileum associated with chemotherapy for non-small cell lung carcinoma: a case report.

A 71-year-old man was diagnosed with advanced non-small cell lung carcinoma and treated with chemotherapy developed ileocecal diverticulitis three times over the last 2 months of receiving second-line treatment. During the fourth diverticulitis event, the patient presented with fever and abdominal pain, worsening after 5 days. Abdominal computed tomography showed ascites and intra-abdominal free air, suggesting bowel perforation with acute diffuse peritonitis. We performed emergency surgery; the surgical findings showed diverticulosis with perforated diverticula in the ileocecal region. We performed ileocecal resection, an ileostomy and a mucous fistula of the ascending colon. Histopathological examinations revealed pseudodiverticula at the perforation, where the mucosa was depressed through the muscularis propria. Hence, we diagnosed perforated ileal diverticulitis. Repeated diverticulitis triggered by chemotherapy might have resulted in perforation. Small bowel diverticula are rare, but diverticulitis can occur in patients receiving chemotherapy and with cases of unexplained fever and abdominal pain.

Metastasis of Ovarian Cancer to the Descending Colon.

Colonic metastasis from ovarian cancer is extremely rare, with only seven reported cases. A 77-year-old woman who had previously undergone surgery for ovarian cancer was admitted to a local hospital with anal bleeding. Histopathological analysis confirmed the presence of adenocarcinoma. Colonoscopy revealed a descending colon tumor. The patient was diagnosed with Union for International Cancer Control T3N0M0 descending colon cancer or colon metastasis of the ovarian cancer. Laparoscopic left colectomy was performed; intraoperative frozen section diagnosis confirmed metastasis from ovarian cancer, and the absence of invasion to the serosal surface suggested hematogenous metastasis. This is the first case of colonic metastasis from ovarian cancer that was diagnosed using an intraoperative frozen section and laparoscopically treated.

Vertical Transmission of Coxsackievirus A6 with Severe Congenital Pneumonia/Sepsis.

We report a case of vertical transmission of Coxsackievirus (CV)-A6 with severe congenital pneumonia/sepsis. A male infant presented with severe respiratory symptoms at birth and was treated with full cardiopulmonary support, including inhaled nitric oxide. Three days before delivery, his older brother was diagnosed with hand, foot, and mouth disease (HFMD). His mother developed transient fever 1 day before delivery and presented a blister on her thumb 2 days after delivery. A multiplex polymerase chain reaction test on day 2 was positive for human rhinovirus/enterovirus. CV-A6 was later detected in the serum, tracheal aspirate, and stool of the patient sampled on day 6, and in the maternal serum sampled on the day of delivery. He was diagnosed with congenital CV-A6 pneumonia/sepsis caused by vertical transmission, based on VP1 consensus sequences used for typing of the virus that demonstrated a 100% match between the mother and infant. Further, the strain was closely related to the lethal CV-A6-Changchun strains in the phylogenetic analysis of the P2 region, which contributes to the pathogenicity. In conclusion, congenital CV-A6 infection should be considered if a woman exhibits HFMD symptoms during the perinatal period. Detailed virologic examination is useful for understanding its pathogenesis.

Three-dimensional visualization of the total mesorectal excision plane for dissection in rectal cancer surgery and its ability to predict surgical difficulty.

Total mesorectal excision (TME) for rectal cancer is often technically challenging. We aimed to develop a method for three-dimensional (3D) visualization of the TME dissection plane and to evaluate its ability to predict surgical difficulty. Sixty-six patients with lower rectal cancer who underwent robot-assisted surgery were retrospectively analyzed. A 3D TME dissection plane image for each case was reconstructed using Ziostation2. Subsequently, a novel index that reflects accessibility to the deep pelvis during TME, namely, the TME difficulty index, was defined and measured. Representative bony pelvimetry parameters and clinicopathological factors were also analyzed. The operative time for TME was used as an indicator of surgical difficulty. Univariate regression analysis revealed that sex, body mass index, mesorectal fat area, and TME difficulty index were associated with the operative time for TME, whereas bony pelvimetry parameters were not. Multivariate regression analysis found that TME difficulty index (ß = - 0.398, P = 0.0025) and mesorectal fat area (ß = 0.223, P = 0.045) had significant predictability for the operative time for TME. Compared with conventional bony pelvimetry parameters, the TME difficulty index and mesorectal fat area might be more useful in predicting the difficulty of rectal cancer surgery.