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PubMed1995

A modified bioassay for energy utilization in newly hatched chicks. 2. Determination of feed input and procedures to estimate endogenous energy loss.

Two experiments were conducted to develop a modified bioassay system to determine bioavailability of dietary energy in newly hatched chicks based on the TME assay system. Broiler chicks aged 0, 1, 3, 7, and 14 d old were force-fed or consumed feed ad libitum following 24 h of feed withdrawal to determine the optimum level for feed input. In the second experiment, 7-d-old chicks were force-fed various diets and feedstuffs at three levels following 24 h of feed deprivation. Linear regressions (P < .01) between energy input (X) and excreted energy (Y) were demonstrated irrespective of diets and feedstuffs at any age in Experiments 1 and 2. Endogenous energy loss (EEL), estimated by the regression method and approximated over a small range was lower than EEL estimated using feed-deprived chicks. The TME and TMEn values of diets and feedstuffs calculated using EEL estimated by the regression method were not modulated by the feed input level, whereas those estimated by feed-deprived chicks tended to increase with decreases in the level of feed input. Thus, a modified method for determination of energy utilization in newly hatched chicks based on TME assay is proposed, which seems to have proper physiological and chemical bases.

Age Factors↗

PubMed1995

Metabolizable energy and amino acid availability of full-fat seeds, meals, and oils of flax and canola.

The TME, true amino acid availability (TAAA), AME, and apparent amino acid availability (AAAA) were determined in full-fat seeds, meals, oils, and meal-oil mixtures of flax and canola using Single Comb White Leghorn roosters by the force feeding and total excreta collection assay. The metabolizable energy values were corrected to zero nitrogen balance to obtain AMEn and TMEn. The AMEn and TMEn contents of canola seed (4.46 and 4.56 kcal/g) were respectively higher (P < .05) than those of flax seed (3.75 and 3.75 kcal/g). Flax meal contains contents of AMEn (2.07 kcal/g) and TMEn (2.07 kcal/g) similar to those (1.98 and 2.09 kcal/g) of canola meal. There were no differences in AMEn and TMEn values between flax oil (8.10 and 8.28 kcal/g) and canola oil (8.25 and 8.46 kcal/g). No differences were observed among AME, AMEn, TME, and TMEn values within each test ingredient except canola meal: its TME value was higher (P < .05) than its AMEn value. The TAAA values were higher for full-fat seeds than for the meals and also higher for canola seed and meal than for flax seed and meal. The AAAA values, although lower than TAAA values, followed similar patterns as TAAA values. Both AAAA and TAAA values were higher when the ingredients were fed with a basal diet than when fed alone.

Amino Acids↗

PubMed2000

Local recurrences and primary surgery in rectal carcinoma.

BACKGROUND: The authors analyze retrospectively a consecutive series of rectal carcinomas operated on with different surgical strategies at Third Surgical Department of "La Sapienza" University of Rome, between January 1985 and December 1997, by one expert surgeon (GDM), and report the incidence of the local recurrence correlated to the surgical technique development. METHODS: In most recent groups of patients treated for extraperitoneal neoplasm from January 1992 with curative (R0) total mesorectal excision (TME) and nerve sparing technique (NST) (Group C, n = 47) and with curative TME plus lateral pelvic lymphadenectomy (LPL) and NST (Group D, n = 7), sacrificing the pelvic autonomic nervous system only in case of neoplastic infiltration, the local recurrence was 8.5% (4 cases, with mean interval of 30.5 months) and 0 respectively at mean follow-up of 44.9 and 55 months. RESULTS: In none of the local recurrences of the Group C a re-resection (neither curative nor palliative) was possible and the survival was 50% at 14 months from the diagnosis of relapse. Instead, in local recurrences of rectal carcinoma in patients who underwent a first anterior resection with less extended dissection in other Department (Group E), a re-resection was possible for 3 cases out of 4 (R0, R1 and R2 operations); re-resected patients are now alive at mean follow-up of 33.6 months (82, 12 and 7 months, respectively). In Group A patients, treated between January 1985 and December 1988 with partial mesorectal excision (R0) also for extraperitoneal localization, the incidence of local relapses is 21.9% (9/41 cases) vs 11.2% (11/98 cases) in Group B patients, treated from January 1989 with curative TME for extraperitoneal tumors. CONCLUSIONS: The incidence of local recurrences of extraperitoneal rectal cancer can be reduced by total mesorectal excision. The total sparing of pelvic autonomic nervous system in advanced rectal carcinoma doesn't increase the incidence of local recurrences.

Aged↗

PubMed2000

Sexual and bladder dysfunction after total mesorectal excision for benign diseases.

PURPOSE: An evaluation was made of sexual and bladder dysfunction combined with quality of life (QoL) score after a proctocolectomy with total mesorectal excision (TME) for benign diseases. METHODS: An in-depth questionnaire was mailed to all patients (n = 94) who had undergone a proctocolectomy with TME followed by an ileal pouch-anal anastomosis (IPAA) in the period from 1989 through 1994. Seventy-six patients responded (81%) with a mean age of 34 +/- 10.6 years and a mean follow-up of 33 +/- 18.3 months. RESULTS: Sexual activity, satisfaction and libido were preserved better in males than in females. Severe sexual dysfunction was found in two males (permanent retrograde ejaculation) and in one female (complete vaginal dryness). No severe bladder dysfunction was found, although minor dysfunction, such as stress and urge incontinence, occurred frequently. QoL was significantly increased postsurgery. Moreover, no evident correlation was demonstrated between QoL and sexual and bladder dysfunction. CONCLUSION: A relatively low incidence of severe sexual and bladder disorders was found following proctocolectomy with TME and IPAA, whereas minor dysfunction was a relatively common finding. Nevertheless, a significant increase was found in postoperative QoL compared to preoperative QoL.

Adult↗

PubMed2001

Lateral pelvic lymphadenectomy and total nerve sparing for locally advanced rectal cancer in Western patients.

BACKGROUND: In an attempt to improve the results of locally advanced rectal cancer treatment, we performed an extended surgical technique consisting of total mesorectal excision (TME), lateral pelvic lymphadenectomy (LPL) and total nerve sparing (NS). Resection of the autonomic nerves was realized only when these fibres were involved by the tumour. METHODS: Nine cases (9.2%) of a personal series of 98 western patients with rectal carcinoma operated on between January 1992 and December 1997 at Third Department of Surgery, University La Sapienza, Rome, underwent TME, LPL and NS procedures for locally advanced extraperitoneal disease. RESULTS: Two out of seven patients in stage II/III suffered postoperatively from urinary retention with mild irregular flow as tested on urodynamics, but no long-term urinary disturbances persisted. Retrograde ejaculation occurred postoperatively in one of two patients who experienced urinary disturbances. Another patient had erection dysfunctions. These sexual dysfunctions did not improve during the long-term follow-up. Seven patients with stage II or stage III disease achieved a 5-year survival rate of 80.0% and a 5-year disease-free survival rate of 68.6% after a mean follow-up period of 64.7 months. None of them experienced local recurrence, but one patient died of diffuse metastatic disease 50 months after surgery. Two patients with stage IV rectal carcinoma died of local and distant disease 13 months and 35 months after operation. One patient underwent liver resection for solitary metastasis 25 months after primary operation. CONCLUSIONS: TME, LPL, and NS with resection of autonomic nerves only when these fibres are involved by the disease can achieve satisfactory results in terms of survival and functional outcome in selected western patients with locally advanced rectal cancer.

Adult↗

PubMedDate not supplied

[Adjuvant radiotherapy in rectal cancer and total mesorectal excision].

Local recurrence (LR) after surgical resection for adenocarcinoma of the rectum still remains an unsolved problem. Local relapse often occurs when tumor spreads in perirectal fat (mesorectum) or along the lateral iliac lymph nodes also when surgery is considered radically. There is a close relationship between local recurrence rate and lymphatic involvement, local tumor extension and tumour grading. Total mesorectal excision (TME) appears to be associated with a reduced LR rate when resection of perirectal fat is done "en-bloc" and when a negative radial margins is obtained. TME allows autonomic nerve sparing and sphincter preservation too, but lateral nodes are not treated by TME. Extended lymphadenectomy with lateral dissection for advanced rectal cancer has been often associated with an increase rate of long term morbidity, particularly regarding urinary and sexual function. Concomitant preoperative chemo-radiation for advanced rectal cancer is a relatively safe procedure with an acceptable morbidity and mortality. This approach is associated with a considerable clinical and pathologic tumor downstaging. Tumor resectability is improved and lateral spreading is also better controlled. An improving in survival and a longer disease free period has been reported. More radical sphincter saving operations are also allowed.

Digestive System Surgical Procedures↗

PubMed2002

[Laparoscopic total mesorectal excision for low or ultralow anterior resection of rectal cancer with anal sphincter preservation].

OBJECTIVE: To assess the feasibility of laparoscopic total mesorectal excision (TME) for low or ultralow anterior resection of rectal cancer. METHODS: Excision of the mesorectum and low (ultralow) colo-anal anastomoses were performed laparoscopically in 62 patients with low rectal cancer based on the concept of TME and double stapling technique (DST). RESULTS: Sixty-two operations with TME and DST were performed in a totally laparoscopic manner, and only one was converted to open procedures because of dysfunction of coagulation. The operative time was 125 min (110-210 min) and the operative blood loss 20 ml (5-80 ml). The time for bowel function recovery and post-operatively dietary intake was 1-2 days. Twenty-eight patients received postoperative analgesics. Average hospital stay was 8 days (5-14 days). Complications were observed in only 2 of the 62 patients, one had suffered from urinary retention and the other, anastomotic leakage. CONCLUSIONS: Totally laparoscopic excision of the mesorectum for low or ultralow anterior resection of rectal cancer is a minimally invasive technique with sphincter preservation, less postoperative pain, and rapid recovery.

Adult↗

PubMed2004

Total mesorectal excision: technical aspects.

Total mesorectal excision (TME) is a precise dissection of the rectum and all pararectal lymph nodes within an oncologic package: the mesorectal envelope. This article is a brief description of the technical aspects of the dissection, illustrated by cadaver dissection. Here the TME dissection is organized into 6 steps to facilitate learning: (1) left retroperitoneum; (2) superior rectal and inferior mesenteric vessels; (3) upper mesorectum; (4/5) right and left mid-mesorectum; and (6) distal mesorectum and anorectal junction. The relationship of the autonomic nerves, blood vessels and adjacent organ structures are described at each step. The 6 steps are recommended for learning and performing TME dissection in cadavers and patients.

Digestive System Surgical Procedures↗

PubMed1991

Modulation of cytolytic T lymphocyte functions by an inhibitor of serine/threonine phosphatase, okadaic acid. Enhancement of cytolytic T lymphocyte-mediated cytotoxicity.

A specific and potent inhibitor of protein phosphatases 1 and 2A, okadaic acid (OA), and its inactive analog, tetramethyl ether (OA-TME), were tested in the cytotoxicity and granule exocytosis assays of CTL activation. At low concentrations OA enhanced, whereas at higher concentrations OA inhibited, CTL responses. The Ag-specific and retargeted cytotoxicity, granule exocytosis induced by target cell (TC), anti-TCR mAb, or PMA and A23187, and conjugate formation with TC were inhibited by pretreatment of CTL with OA as expected if protein phosphatases and protein dephosphorylation were indeed involved in the TCR-mediated signal transduction and effector responses of CTL. Cytotoxicity and granule exocytosis were unaffected by pretreatment of CTL with OA-TME. The inhibitory effect of OA on the exocytic response of CTL induced by TC and anti-TCR mAb can be dissociated from the inhibition of the response to PMA and A23187, suggesting the involvement of a serine and/or threonine protein phosphatase in the early events of transmembrane signaling. At lower concentrations, OA, but not OA-TME, was able to enhance the Ag-specific cytotoxicity and TC-induced exocytosis from CTL clones. The enhancement of these TCR-mediated responses of CTL was observed only if the activation was induced by the Ag on the TC surface, because OA did not enhance either the anti-TCR mAb-induced exocytosis of granules from the CTL clone or lysis of the Ag-nonbearing TC by CTL in a retargeting assay. The biphasic character of the effects of OA on CTL-TC interactions suggests the existence of at least two functionally distinct phosphatases in CTL. The ability of OA to enhance the Ag-specific response is unique and indicates the presence of an inhibitory phosphoprotein phosphatase that should be considered as a participant in the down-regulation of the cell-cell interactions between CTL and TC. The inhibitory effects of OA on both TC-induced and anti-TCR mAb-triggered CTL responses at higher concentrations point to the importance of yet another phosphatase in the CTL-TC interactions and in the TCR-mediated transmembrane signaling. The use of OA may help to decipher the details of biochemical changes involved in T lymphocyte effector functions.

Animals↗

PubMed2006

[Recent progress in diagnosis and treatment of rectal cancer].

Rectal cancer is an emerging health issue in Korea because its incidence is rapidly increasing with changes in life styles and diets. The optimal treatment of rectal cancer is based on multimodality. Among them, surgical treatment is the corner-stone. In the past, local recurrence rate has been reported as high as 30-40%, but the concept of total mesorectal excision (TME) lowered the rate of local recurrence down to less than 10%. TME focuses on sharp pelvic dissection and complete removal of rectal cancer with surrounding mesorectum inside the rectal proper fascia. TME is now considered as a standard procedure for surgical treatment of mid and low rectal cancer. With the introduction of pelvic magnetic resonance imaging (MRI) for preoperative staging of rectal cancer, risk factors for local recurrence can be predicted before surgery to distinguish patients who are in high risk for recurrence that requires preoperative neoadjuvant chemoradiation therapy. Early rectal cancer was assessed by transrectal ultrasonography (TRUS) and endorectal MRI with coil. Transanal local excision can be applied with anal sphincter preservation safely. Neoadjuvant chemoradiation therapy was performed in patients with locally advanced rectal cancer, and this resulted in tumor size reductions and histopathologic downstaging effect. As far as the quality of life is concerned, sexual and voiding function are much improved by techniques preserving nerve. Many experts have dealt with challenging practical problems of managing rectal cancer from diagnosis to quality of life. This issue contains recent progresses in the diagnosis and treatment of rectal cancer which will serve as a comprehensive reference for those who manage rectal cancer in their medical practice.

Humans↗

PubMedDate not supplied

Long-term survival and recurrences after total nerve-sparing surgery for rectal cancer.

BACKGROUND/AIMS: In advanced extraperitoneal rectal cancer Japanese surgeons perform the lateral pelvic nodal dissection with only partial pelvic autonomic nerves preservation; instead most Western surgeons prefer the total mesorectal excision (TME) with complete pelvic nerve sparing except for evident neoplastic nervous involvement. Long-term oncological results of the total nerve-sparing TME are reported. METHODOLOGY: From January 1992 to October 1998 71 [corrected] patients with extraperitoneal rectal carcinoma underwent TME with total nerve sparing except in two cases in which only a partial sparing was possible because of macroscopic neoplastic nervous infiltration: 54 anterior resections and 17 abdominoperineal resections were performed. Sixty-one curatively operated patients (9 stage I, 20 stage II, 29 stage III and 3 stage IV) were included. RESULTS: No postoperative death occurred. Postoperative radiochemotherapy was performed in 31 cases, radiotherapy in 9 cases and chemotherapy in 9 cases. The mean follow-up was 98.7 months. The 5-year overall and disease-free survival rates were 88.8% and 77.7%, 90% and 75.1%, 62.3% and 45% for stage I, II and III respectively. The 8-year actuarial overall and disease-free survival rates were 77.7% and 77.7%, 78.3% and 75.1%, 50.4% and 40% for stage I, II and III respectively. Local failures with or without distant metastases were 6 (9.8%). CONCLUSIONS: Total nerve-sparing surgery is not contraindicated unless grossly neoplastic involvement is present.

Adult↗

PubMed2007

Clinical factors in prediction of prognosis after anterior resection with total mesorectal excision for carcinoma of the rectum.

The aim of the study was to estimate the long-term results and the prognostic value of clinical and pathological factors following R0 anterior resection with total mesorectal excision (TME). Ninety-eight consecutive patients with histologically confirmed rectal cancer were studied prospectively with five-year follow-up. Survival was calculated using the Kaplan-Meier method and differences between curves were tested by the log-rank test. Multivariate analysis was performed using the Cox regression model. Recurrence-free survival (RFS) was 63.6%. Mean time of recurrence was 13.8 months (range 3-38). Local recurrence rate was 7.8% with the mean time of 12.7 months (range 3-25). In univariate analysis Dukes' stage (RFS for stage: A=93.2%; B=53.8%; C=26.3%) and preoperative CEA serum level (s-CEA) (for s-CEA 5 ng/ml RFS=5.9%) significantly influenced survival (P<0.005 and P<0.00001). These parameters were also found to be independent prognostic factors in multivariate analysis (P<0.05 and P<0.00001). Survival was worse in older female patients with low-localised poorly differentiated tumors; however, those variables had not significant impact on prognosis. Neither symptom duration nor mucinous histology was significantly related to survival. Using TME technique a low local recurrence rate resulting in improved survival can be achieved. Apart from clinicopathological staging, elevated s-CEA can identify patients with poor prognosis. In addition to TME adjuvant therapy for this high-risk group should be considered.

Adult↗

PubMed1995

Total mesorectal excision in the operative treatment of carcinoma of the rectum.

BACKGROUND: Total mesorectal excision (TME) is reported to reduce local recurrence and improve survival rates in patients with carcinoma of the rectum. STUDY DESIGN: Two hundred forty-six consecutive patients with Dukes' B (T3, N0, M0) and C (T(any), N1-2, M0) primary rectal carcinomas underwent operation according to the principle of TME. Kaplan-Meier estimates of survival and pelvic recurrence rates were calculated from a database of patients followed prospectively. RESULTS: The operative mortality rate was 0.8 percent (two of 246). The Kaplan-Meier five-year survival rate for patients with stages B and C was 74.2 percent; for patients with stage T3, N0, M0, 86.7 percent; for patients with stage T(any), N1-2, M0, 64.0 percent; and for patients with substage T3, N1-2, M0, 68.0 percent. Pelvic recurrences were observed in a total of 18 patients (7.3 percent) with or without metastases. In the 246 patients with Dukes' stages B and C, pelvic recurrence rates were 4.0 and 8.1 percent, respectively, in the presence or absence of distant metastases, and 3.0 and 5.8 percent, respectively, in the absence of distant spread. Statistically significant risk factors for pelvic recurrence were N2 disease and perineural invasion. Adjuvant radiation therapy was of no statistical benefit in preventing local recurrences. CONCLUSIONS: Total mesorectal excision cures carcinoma of the rectum and provides excellent local control through resection of the entire unit of regional spread that is excised, intact and with negative circumferential margins. Total mesorectal excision is compatible with autonomic nerve preservation and with sphincter preservation. The current role of combined modality adjuvant therapy, which is standard therapy following conventional surgery, should be reconsidered in patients who have undergone resection in accordance with TME.

Adult↗

PubMed1998

Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

Blood Coagulation↗

PubMed2025

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment. EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin. RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs. CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment. TRIAL REGISTRATION NUMBER: NCT03991403.

Aged↗

PubMed2026

Construction and validation of a β-hydroxybutyrylation-related molecular model for predicting prognosis of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) usually has a favorable prognosis, yet a subset of patients develops persistent, recurrent, or biologically aggressive disease. The clinical relevance of lysine β-hydroxybutyrylation (Kbhb)-related transcriptional programs in PTC remains unclear. Accordingly, this study aimed to characterize Kbhb-related molecular heterogeneity in PTC, construct a prognostic signature, and explore its association with the tumor microenvironment (TME). METHODS: Transcriptomic and clinical data from PTC samples within The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort were analyzed to identify Kbhb-related differentially expressed genes (DEGs), define molecular subtypes, construct a prognostic signature, and characterize tumor microenvironmental features. Single-cell RNA-sequencing data from PTC were further used to explore the cellular distribution of representative genes. RESULTS: We identified 51 Kbhb-related DEGs in PTC and defined two Kbhb molecular subtypes. The Kbhb_C2 subtype showed shorter progression-free interval (PFI) and a more immune- and stroma-enriched microenvironment. A six-gene prognostic signature comprising TARID, CDSN, PIMREG, KLRC1, SYT13, and NPR3 was then established. High-risk patients had significantly worse PFI in the full, training, and testing cohorts, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.715, 0.793, and 0.771, respectively, in the full cohort. High-risk tumors also exhibited higher stromal, immune, and ESTIMATE scores, altered immune infiltration, and increased expression of multiple immune checkpoint molecules. Single-cell analysis confirmed distinct cell-type-specific expression patterns of representative genes. CONCLUSIONS: Kbhb-related transcriptional programs define clinically relevant molecular heterogeneity in PTC and are closely associated with prognosis and TME remodeling. The identified six-gene signature provides a biologically interpretable framework for risk stratification in PTC.

Papillary thyroid carcinoma (PTC)↗

PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗

PubMed1995

Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer.

Total mesorectal excision (TME) appears to be associated with a reduced local recurrence rate following surgery for rectal cancer. Of 20 patients with rectal cancer in whom TME was performed, adenocarcinoma was found in the distal mesorectum in four. Distal mesorectal spread often extended further than intramural spread. Patients with tumour in the distal mesorectum had a worse outcome at 4-year follow-up, a greater risk of local recurrence and an increased frequency of distant metastasis. Distal tumour spread is, therefore, a marker of poor prognosis in rectal cancer. This study provides further evidence that incomplete excision of the mesorectum contributes to local recurrence in a proportion of patients with rectal cancer, particularly in those with tumours in the middle and lower third of the rectum.

Adenocarcinoma↗