Impact of the COVID-19 pandemic on colorectal cancer surgery in Japan: Clinical Study Group of Osaka University-A multicenter retrospective study.

Aim: Due to the overwhelming spread of SARS-CoV-2 and its disruption of the healthcare system, delays and reduced numbers were reported for colorectal cancer screening, colonoscopies, and surgery during the COVID-19 pandemic. This multicenter retrospective study investigated the still poorly understood impact of the COVID-19 pandemic on colorectal cancer treatment in Japan. Methods: This study was organized by the Clinical Study Group of Osaka University, which comprised 32 major institutions in Osaka. We retrospectively analyzed the number of surgeries and colonoscopies performed and the characteristics of patients who underwent surgery for colorectal cancer between March 2019 and February 2021. We compared data collected before and during the COVID-19 pandemic. We also assessed the methods used for detecting colorectal cancer, including fecal occult blood test, abdominal symptoms, and anemia. Results: The COVID-19 pandemic caused reductions in the annual numbers of surgeries (3569 vs 3198) and colonoscopies (67 622 vs 58 183) performed in the 2020 fiscal year, compared to the 2019 fiscal year. During the COVID-19 pandemic, a significantly lower proportion of patients were treated for clinical stages ≤I (24.2% vs 26.9%; P = .011), compared to the proportion treated before the pandemic. Fecal occult blood tests for detecting colorectal cancer were used significantly less frequently during the COVID-19 pandemic (26.2% vs 29.6%; P = .002). These trends were more significant in larger institutions. Conclusion: The COVID-19 pandemic reduced the number of colonoscopies and surgeries performed for colorectal cancer and hindered the detection of asymptomatic early-stage cancers, and its impact varied by hospital size.

Subjective symptoms and their association with psychiatric symptoms 3 months after ICU discharge: sub-analysis of a single-center prospective observational study.

BACKGROUND: Despite a growing volume of literature on post-intensive care syndrome, we know little about how subjective symptoms affect intensive care unit survivors in the long term. AIMS: This study aimed to elucidate the prevalence of subjective symptoms and to determine the clinical importance of post-intensive care syndrome by evaluating the association between these symptoms and psychiatric symptoms. We evaluated new-onset or worsening subjective symptoms and psychiatric symptoms in 81 patients at 3 months after discharge from an intensive care unit. RESULTS: More than half of patients had at least one subjective symptom, such as weakness (n = 31), fatigue (n = 23), malaise (n = 14), body pain (n = 14), or insomnia (n = 9). CONCLUSIONS: The presence of subjective symptoms is associated with worse psychiatric symptoms (post-traumatic stress disorder, anxiety, and depression) at 3 months after ICU discharge. We found insomnia was particularly strongly associated with psychiatric symptoms in our study group. TRIAL REGISTRATION: UMIN Clinical Trial Registry no. UMIN000023743, September 1, 2016.

Carbon ion radiotherapy using fiducial markers for prostate cancer in Osaka HIMAK: Treatment planning.

PURPOSE: Carbon ion radiotherapy for prostate cancer was performed using two fine needle Gold Anchor (GA) markers for patient position verification in Osaka Heavy Ion Medical Accelerator in Kansai (Osaka HIMAK). The present study examined treatment plans for prostate cases using beam-specific planning target volume (bsPTV) based on the effect of the markers on dose distribution and analysis of target movements. MATERIALS AND METHODS: Gafchromic EBT3 film was used to measure dose perturbations caused by markers. First, the relationships between the irradiated film density and absolute dose with different linear energy transfer distributions within a spread-out Bragg peak (SOBP) were confirmed. Then, to derive the effect of markers, two types of markers, including GA, were placed at the proximal, center, and distal depths within the same SOBP, and dose distributions behind the markers were measured using the films. The amount of internal motion of prostate was derived from irradiation results and analyzed to determine the margins of the bsPTV. RESULTS: The linearity of the film densities against absolute doses was constant within the SOBP and the amount of dose perturbations caused by the markers was quantitatively estimated from the film densities. The dose perturbation close behind the markers was smallest (<10% among depths within the SOBP regardless of types of markers) and increased with depth. The effect of two types of GAs on dose distributions was small and could be ignored in the treatment planning. Based on the analysis results of internal motions of prostate, required margins of the bsPTV were found to be 8, 7, and 7 mm in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. CONCLUSION: We evaluated the dose reductions caused by markers and determined the margins of the bsPTV, which was applied to the treatment using fiducial markers, using the analysis results of prostate movements.

Efficacy of Negative Pressure Wound Therapy Followed by Delayed Primary Closure for Abdominal Wounds in Patients with Lower Gastrointestinal Perforations: Multicenter Prospective Study.

OBJECTIVES: The efficacy of negative pressure wound therapy (NPWT) and its application to severely contaminated wounds sustained during surgery remain to be established. Here, we evaluated the efficacy of utilizing NPWT until delayed primary closure (DPC) by assessing the infection rates in patients with lower gastrointestinal perforations. METHODS: This prospective multicenter cohort study included 56 patients that underwent abdominal surgery for lower gastrointestinal perforations in eight institutions, from February 2016 to May 2017. All patients received NPWT after surgery before attempting DPC. The extent of peritonitis was categorized according to Hinchey's classification. Patients in stages II-IV were included. RESULTS: Five patients had surgical site infections (SSIs) during NPWT and did not receive a DPC (9%). Of the 51 patients that received DPCs, 44 had no infection (91%) and 7 developed SSIs after the DPC (13.7%). For stages II, III, and IV, the SSI rates were 0%, 22.6%, and 35.7%, respectively; the median (range) times to wound healing were 15 (10-36), 19 (11-99), and 19 (10-53) days, respectively. There were no significant differences between the stages. CONCLUSIONS: NPWT followed by DPC resulted in low infection rates in each peritonitis stage. This approach appears promising as an alternative to traditional DPC alone for treating lower gastrointestinal perforations.

Prehospital and in-hospital quick Sequential Organ Failure Assessment (qSOFA) scores to predict in-hospital mortality among trauma patients: an analysis of nationwide registry data.

AIM: The quick Sequential Organ Failure Assessment (qSOFA) score can be used to predict in-hospital mortality in trauma patients. We sought to determine whether repeatedly calculating the qSOFA score improves its discriminative ability in predicting in-hospital mortality in trauma patients. METHODS: We undertook a multicenter retrospective study, analyzing 90,974 trauma patients registered in the Japan Trauma Data Bank (a nationwide trauma registry) from 2004 to 2017. Patients included were ≥18 years old and transferred directly to hospitals from their respective scenes of injury. We calculated the qSOFA score at two time points: at the scene (prehospital qSOFA score) and on arrival at the hospital (hospital qSOFA score). We evaluated the discriminative ability of repeated calculations of the qSOFA score. The primary outcome in consideration was in-hospital mortality. RESULTS: In-hospital mortality occurred in 5604 patients (6.2%). The predictive accuracy of the hospital qSOFA score was higher than that of the prehospital qSOFA (area under the receiver operating characteristics curve [AUROC] 0.74 vs. 0.69, P < 0.0001) in predicting in-hospital mortality. However, the mean qSOFA score had the highest predictive accuracy (AUROC 0.76, P < 0.0001). If the hospital qSOFA score was increased compared to the prehospital score, this indicated an approximately 2-fold to 4-fold increase in in-hospital mortality. CONCLUSIONS: Repeated calculations of qSOFA score improved its ability to predict in-hospital mortality in trauma patients. Specifically, we should consider an increasing qSOFA score as a "red flag" to clinicians in the emergency department.

Prehospital quick sequential organ failure assessment score to predict in-hospital mortality among patients with trauma.

OBJECTIVE: The quick sequential organ failure assessment (qSOFA) score is calculated from three variables measured at the scene of trauma-systolic blood pressure, respiratory rate and consciousness. This study aimed to evaluate the discriminative ability of the prehospital qSOFA score for in-hospital mortality in patients with trauma. METHODS: This retrospective multicenter study used data from 42,722 patients with trauma included in a Japanese nationwide trauma registry. All included patients were aged ≥18 years old and transferred to hospitals from the scenes of injury. The primary outcome was in-hospital mortality. RESULTS: The included patients had a mean age of 59.4 ±â€¯21.5 years and a male predominance (63%). In-hospital mortality occurred in 2612 patients (6%), while 2-day mortality occurred in 1189 of 42,339 patients (3%). When patients were stratified by qSOFA scores, in-hospital mortality rates of 0.9% (105/11783), 5% (941/17839), 12% (1280/11132) and 15% (286/1968) were associated with qSOFA scores of 0, 1, 2 and 3, respectively (P < 0.0001 for trend). The area under the receiver operating characteristics curve of the qSOFA score for in-hospital mortality was 0.70 (95% confidence interval: 0.69-0.71). A qSOFA score cutoff value ≥1 yielded a sensitivity and specificity of 0.96 and 0.29, respectively, overall, and a sensitivity of 0.99 in patients younger than 65 years. CONCLUSIONS: The prehospital qSOFA score was strongly associated with in-hospital mortality in patients with trauma. A prehospital qSOFA score cutoff of ≥1 can be used to identify patients at a very low risk of death, especially in younger age groups.

Benefits of using a self-expandable metallic stent as a bridge to surgery for right- and left-sided obstructive colorectal cancers.

PURPOSE: To assess the benefit of placing a self-expandable metallic stent (SEMS) as a bridge to surgery for obstructive colorectal cancer (OCRC) according to the tumor site. METHODS: The subjects of this retrospective multicenter cohort study were 201 patients with OCRC, but without initial bowel perforation, who were treated either with a self-expandable metallic stent (SEMS) as a bridge to surgery (n = 109) or with primary surgery (PS; n = 92) between 2014 and 2016. The cohort consisted of 68 patients with right-sided and 133 left-sided OCRC. We evaluated the short-term surgical outcomes for each side. RESULTS: The SEMS group of patients with left-sided OCRC had significantly higher rates of primary resection, primary resection with anastomosis, stoma-free surgery, and laparoscopic surgery than the PS group of patients with left-sided OCRC. In contrast, the SEMS group of patients with right-sided OCRC had only a significantly higher rate of laparoscopic surgery than the PS group of patients with right-sided OCRC, but they had a longer overall hospital stay. There were no significant differences between the two treatment groups in the rates of morbidity or mortality, for either right-sided or left-sided OCRC. CONCLUSION: The benefit of a SEMS as a bridge to surgery may be less for right-sided than for left-sided obstructions in colon cancer patients.

Implantation of esophageal cancer onto post-dissection ulcer after gastric endoscopic submucosal dissection.

A case in which implantation of esophageal squamous cell carcinoma onto a post-dissection gastric ulcer was strongly suspected is presented. A 72-year-old man with alcoholic liver cirrhosis underwent esophagogastroduodenoscopy (EGD). Esophageal cancer (EC) (Mt, 20 mm, 0-Is) and gastric cancer (GC) (antrum, 15 mm, 0-IIc) were identified. Biopsy specimens revealed moderately differentiated squamous cell carcinoma (SCC) and differentiated adenocarcinoma, respectively. The GC was resected by endoscopic submucosal dissection (ESD) [14 mm × 9 mm, type 0-IIc, tub1, pT1a(M), ly0, v0, HM(-), VM(-)]. Two months after ESD, radiation therapy was started for the EC, and an almost complete response was obtained. Nine months after the ESD, a follow-up EGD showed a submucosal tumor-like lesion with ulceration, located immediately under the post-ESD scar, and biopsy specimens showed moderately differentiated SCC. There were no similar lesions suggesting hematogenous or lymphatic metastasis in the stomach.

Water immersion colonoscopy facilitates straight passage of the colonoscope through the sigmoid colon without loop formation: randomized controlled trial.

BACKGROUND AND AIM: One of the major causes of pain during colonoscopy is looping of the instrument during insertion through the sigmoid colon, which causes discomfort by stretching the mesentery. There are many studies in colonoscope techniques, but they have not been assessed objectively with respect to colonoscope passage through the sigmoid colon without loop formation. The aim of the present study was to determine whether cap-fitted colonoscopy and water immersion increase the success rate of insertion through the sigmoid without loop formation. METHODS: A total of 1005 patients were randomized to standard colonoscopy, cap-fitted colonoscopy or water immersion technique. All examinations were carried out under a magnetic endoscope imaging device. Main outcome was the success rate of insertion without loop formation. RESULTS: Success rate of insertion without loop formation was 37.5%, 40.0%, and 53.8% in the standard, cap, and water groups, respectively (standard vs water P = 0.00014, cap vs water P = 0.00186). There were no significant differences among the groups regarding cecal intubation rate, cecal intubation time and number of polyps ≥5 mm per patient. CONCLUSIONS: Water immersion increases the success rate of insertion through the sigmoid colon without loop formation. This practical technique, requiring only preparation of a cap and water, is useful without compromising cecal intubation rate, cecal intubation time, or polyp detection rate.

Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 ß1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

Feasibility of five days of consecutive leukocytapheresis for the treatment of ulcerative colitis: a preliminary study.

Leukocytapheresis (LCAP) has been applied for the treatment of steroid refractory ulcerative colitis (UC). A standard protocol employs one or two sessions of LCAP per week. Our aim was to determine whether five consecutive LCAP sessions can be performed safely and effectively for UC patients. Six patients with moderately active UC were enrolled. The patients received five days of consecutive LCAP in which the processing volume of blood was limited to 1500 mL per session. The hemoglobin levels in each patient gradually decreased, and the platelet count by the fifth session reached half of the value before the first session. The clinical activity index in two patients improved daily, and they went into remission with an improvement in the colonic endoscopic appearance after one week. This preliminary study showed that five consecutive LCAP sessions are safe and feasible for active UC patients. The therapeutic efficacy and suitable patients for this treatment protocol should be confirmed by further studies.

Usefulness of bispectral monitoring of conscious sedation during endoscopic mucosal dissection.

AIM: To assess the usefulness of bispectral index (BIS) monitoring in order to carry out endoscopic submucosal dissection (ESD) safely and with patients' satisfaction. METHODS: Three hundred sixty-six patients with an early-stage neoplasm of the digestive tract were enrolled. The BIS monitor (A-1050: Aspect medical systems/NIHON KOHDEN, Tokyo, Japan) was used. The appropriate sedative condition was set at 55 to 75 BIS levels (BIS value) during the endoscopic procedures. RESULTS: Among 366 cases, 13 were accompanied by adverse events during and/or after ESD. All episodes occurred in cases with BIS value between 56 and 65. Hypotension was observed in four cases, and bradycardia in six. Respiratory distress was observed in two cases with chronic pulmonary obstructive disease. All patients with adverse events were able to leave the hospital without extension of the hospitalization. CONCLUSION: BIS monitoring is useful to safely perform ESD. A BIS value of 70 to 75 is suitable for ESD.

Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease.

BACKGROUND AND AIM: There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients. METHODS: Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography. RESULTS: The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations. CONCLUSION: The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.

Acute cytomegalovirus infection superimposed on corticosteroid-naïve ulcerative colitis.

Most cases of cytomegalovirus (CMV) colitis that develop in patients with inflammatory bowel disease (IBD) are caused by a reactivation of a latent virus; acute CMV infections are rare. Treatment with immunosuppressive agents further increases the infection risk. Here, we present a 32-year-old man with acute CMV-mononucleosis and colitis, superimposed on corticosteroid-naïve ulcerative colitis (UC). The diagnosis was confirmed by a viral-like prodrome, positive CMV antigenemia (C7-HRP), a positive CMV IgM titer, the presence of atypical lymphocytes, mild transaminase elevation, and immunohistological detection of CMV positive cells in his colonic mucosa. Gancyclovir was intravenously administered, and all symptoms were improved.

A unique B2 B cell subset in the intestine.

Over 80% of the body's activated B cells are located in mucosal sites, including the intestine. The intestine contains IgM(+) B cells, but these cells have not been characterized phenotypically or in terms of their developmental origins. We describe a previously unidentified and unique subset of immunoglobulin M(+) B cells that present with an AA4.1(-)CD21(-)CD23(-) major histocompatibility complex class II(bright) surface phenotype and are characterized by a low frequency of somatic hypermutation and the potential ability to produce interleukin-12p70. This B cell subset resides within the normal mucosa of the large intestine and expands in response to inflammation. Some of these intestinal B cells originate from the AA4.1(+) immature B2 cell pool in the steady state and are also recruited from the recirculating naive B cell pool in the context of intestinal inflammation. They develop in an antigen-independent and BAFF-dependent manner in the absence of T cell help. Expansion of these cells can be induced in the absence of the spleen and gut-associated lymphoid tissues. These results describe the existence of an alternative pathway of B cell maturation in the periphery that gives rise to a tissue-specific B cell subset.

[Case report: periodical infliximab administration enabled closure of colostomy in fistulating perianal Crohn's disease].

A 29-year old woman with Crohn's disease was performed colostomy due to severe perianal abscess. Her disease had been easy to recur and she was admitted to hospital for intestinal bleeding caused by acute exacerbation in Crohn's disease on October 2006. The bleeding was stopped rapidly and clinical remission was maintained with bimonthly administration of infliximab. Finally, her colostomy was closed after 5 years 8 months. Periodical treatment of infliximab not only prevented recurrence but also enabled closure of colostomy in fistulating perianal Crohn's disease.

Chemoradiation therapy followed by endoscopic submucosal dissection for esophageal cancer.

We performed chemoradiation therapy (CRT) followed by an endoscopic submucosal dissection (ESD) for three patients with esophageal cancer. One patient refused surgery, and two patients were complicated with severe cardiopulmonary diseases. In all patients, CRT was effective in reducing tumor size, and the residual tumors were completely resected by ESD. All patients were recurrence-free for 6 months to 2.5 years. The combination of CRT plus subsequent ESD may be useful for treating patients with esophageal cancer who are not fit to undergo surgery.

TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality.

BACKGROUND & AIMS: Ligation of tumor necrosis factor (TNF) receptors (TNFRs) with TNF plays a critical role in the pathogenesis of human inflammatory bowel disease (IBD). However, it remains unclear which cell types activated through TNFR-associated signaling cascades are involved in the pathogenesis of colitis. METHODS: Recombination activating gene-1 (RAG) knockout (KO) (no T or B cells)-based TNFR double and triple KO mice were generated. Bone marrow (BM) chimera mice in which BM-derived myeloid cells, but not colonic epithelial cells (CECs), express TNFRs were also generated. Colitis was induced by administration of dextran sodium sulfate (DSS) in distilled water. Murine lines and chimeras were assessed for disease severity, histopathology, apoptotic cell rate, epithelial proliferation, and bacterial invasion rate. RESULTS: Following DSS administration, mice lacking both RAG and TNFR1 exhibited a high mortality (>80%) rate with an impaired CEC regeneration compared with RAG KO and RAG x TNFR2 double KO (DKO) mice. Transplantation of RAG KO-derived BM cells restored CEC regeneration and rescued the majority of recipient RAG x TNFR1 DKO mice from DSS-induced mortality. After BM transplantation, RAG x TNFR1 DKO mice exhibited an increased rate of apoptosis in the colonic lamina propria macrophages in association with the activation of caspases. In addition, BM reconstitution directly or indirectly enhanced the proliferation of CECs by activating mitogen-activated protein kinase and phosphoinositide-3 kinase/Akt pathways. CONCLUSIONS: TNFR1-signaling cascade in colonic myeloid lineage cells contributes to the suppression of acute damage-associated mortality presumably by controlling CEC homeostasis.

IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis.

Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium-induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene-delivery system for treating UC.

Protein kinase C theta plays a fundamental role in different types of chronic colitis.

BACKGROUND & AIMS: Dysregulated host/microbial interactions induce the development of colitis by activating deleterious acquired immune responses. Activation of CD4(+) T cells is mainly induced through signaling machinery associated with immunologic synapse (IS). A key molecule associated with the IS is protein kinase C (PKC) theta. However, the role of PKCtheta in the pathogenesis of colitis has not fully been defined. METHODS: The role of PKCtheta for the acquired-immune responses involved in the development of different types of colitis (CD45RB model, T-cell receptor [TCR] alpha knockout [KO] mice and interleukin [IL]-2KO mice) was examined by generating double KO mice and by utilizing cell transfer approaches. RESULTS: Adoptive transfer of PKCtheta-deficient naïve CD4(+) T cells failed to induce T helper cell (Th) 1-mediated colitis in the immune-deficient host (CD45RB model). Development of Th2-mediated colitis in TCRalphaKO mice was also inhibited by the absence of PKCtheta. In IL-2KO mice, which develop colitis because of dysregulated T-cell homeostasis, deficiency of PKCtheta in CD4(+) T cells failed to induce the development of severe colitis. Interestingly, absence of PKCtheta led to a remarkable decrease in the proliferation, but not apoptosis, of colonic memory CD4(+) T cells. This impaired proliferation resulted in a marked decrease in the colonic CD4(+) T cells that are capable of producing IL-17. In addition, deficiency of PKCtheta inhibited the production of Th2 cytokines by colonic CD4(+) T cells. CONCLUSIONS: PKCtheta serves as a common and fundamental signaling molecule in the development of different types of colitis and may represent an attractive target for treating inflammatory bowel disease.