Perianal fistulas in Crohn’s disease (CD) are a major problem. In majority of patient, inflammati... more Perianal fistulas in Crohn’s disease (CD) are a major problem. In majority of patient, inflammation involves the rectum. Perianal fistulas in CD pose a diagnostic and therapeutic challenge due to severe symptoms and worse prognosis compared to cryptogenic fistulas. The accurate diagnosis is crucial for an effective treatment of CD-related perianal fistulas, and the following should be determined: anatomy of the fistula, possible strictures and inflammation of the alimentary tract, including the rectum and the anal canal. Treatment of fistulas might be challenging and requires cooperation between the colorectal surgeon and the gastroenterologist. The combination of surgical and pharmacological therapy is more effective than surgical or pharmacological therapy alone. In conservative treatment, aminosalicylates or steroids have little significance. In everyday practice, antibacterial chemotherapeutics, antibiotics and thiopurines are applied. The most effective are TNF-neutralizing antibodies, i.e. infliximab (IFX), adalimumab (ADA) and certolizumab (CER). Surgical management can be urgent including drainage. Elective procedures include dissection of the fistula (simple fistula) or more complex interventions such as mucosal flap or ligation of the intersphincteric portion of the fistula. Surgical interventions can be enhanced using the video-assisted anal fistula treatment (VAAFT) or negative-pressure therapy. In extreme cases, creation of a stoma may be necessary. Also, tissue glues or so-called plugs may be applied in managing perianal fistulas. The use of stem cells seems promising, i.e. application of multipotent non-hematopoietic stem cells around the fistula in order to induce immunomodulation and wound healing.
There are at least three, well-known, different groups of motor activity disturbances of the uppe... more There are at least three, well-known, different groups of motor activity disturbances of the upper part of alimentary tract which can induce the development of gastroesophageal reflux disease (GERD) and enlarge the risk of excessive exposure of the esophageal mucous membrane on gastric juice and/or biliary contents. Most important is insufficiency of the lower esophageal sphincter (LES), which causes gastroesophageal reflux at 50-60% of patients suffering from GERD. Other reasons include impairment of stomach function (increase of intra-gastric pressure, late emptying and/or hypersecretion), and impairment of esophageal clearance. The question: does motility impairment of the esophagus occur primary or secondary to the gastroesophageal reflux, is still not enough clarified. Motor activity of the esophagus before and after the antireflux operation was prospectively assessed in 57 patients. Motility of the esophagus was determined by estimation: the efficacy of LES, general motor activity of the body of the esophagus and motor activity of the body during the reflux episodes, basing on 24-h manometry. Comparison of general pre- and postoperative data revealed significantly positive influence of Nissen-Rossetti fundoplication on improvement of motor activity of the esophagus, but the results differed in relation to the height of the measurements. Moreover comparison of the data during gastroesophageal reflux episodes revealed negative changes of the manometric parameters in the upper and middle esophagus. We conclude that post-operative improvement of esophageal motility confirms the secondary dysfunction in the peristalsis, connected with pathological reflux. However, lack of the complete normalization in motor activity after operation suggests that disorder may partially occur as primary impairment of motor activity or as the secondary dysfunction, which is fixed in the course of GERD.
We are presenting a case report of 57-year-old patient operated on due to primary malignant melan... more We are presenting a case report of 57-year-old patient operated on due to primary malignant melanoma of the esophagus. Melanoma was misdiagnosed in biopsy taken during endoscopy. Final precise establishing the character of the lesion was able during histopathological examination of the specimen obtained during surgery. The outcome of the treatment was poor--survival time did not exceed 14 months. Patient died because of pulmonary metastases.
Neoangiogenesis has been proved to be crucial in neoplasmatic tumor growth and metastases. Over t... more Neoangiogenesis has been proved to be crucial in neoplasmatic tumor growth and metastases. Over the last few years, the factors that have both a positive (angiogenic) and negative (antiangiogenic) influence on tumor growth have been identified. The potential use of natural and synthetic factors that suppress vasculature formation as anticancer drugs is currently under intense investigation. Recently, several antiangiogenic compounds, including TNP-470 or matrix metalloproteinase inhibitors, have entered clinical trials. This review will describe the main groups of angiogenesis inhibitors, their mechanisms of action and some data from clinical studies.
It is suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor... more It is suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in tumor-induced angiogenesis. The purpose of this study was to estimate the correlation between VEGF and bFGF levels and tumor pathological status according to pTNM classification in patients with squamous cell oesophageal cancer. A group of 25 healthy controls and 32 consecutive patients with oesophageal cancer were included in this study. Serum VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Serum VEGF and bFGF levels were significantly elevated in the patient groups (VEGF: 146.0 pg/ml, 79.0-386.3 pg/ml vs. 38.0 pg/ml, 6.5-135.1 pg/ml, p<0.005, and bFGF: 5.2 pg/ml, 1.2-10.6 pg/ml vs. 2.06 pg/ml, 0.07-4.0 pg/ml, p<0.02 Fisher test). The highest correlation between serum VEGF and bFGF levels were found in patients with advanced cancers, especially with: T4, N1, and M1 factors. The VEGF and bFGF levels were significantly higher in patients with pT4 (p<0.01). Patients with N1 lymph node invasion, compared with N0 factor, have higher levels of angiogenetic factors (p<0.04). Also in patients with advanced cancers with liver metastases the serum levels VEGF and bFGF were significantly higher (M1 vs. M0, VEGF p<0.001 and bFGF p<0.05). Consecutive monitoring of VEGF and bFGF serum levels may be a useful prognostic marker for patients with squamous cell oesophageal cancer.
Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal... more Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. See related commentary by Salvagno and Cubillos-Ruiz, p. 1623. This article is highlighted in the In This Issue feature, p. 1601
Perianal fistulas in Crohn’s disease (CD) are a major problem. In majority of patient, inflammati... more Perianal fistulas in Crohn’s disease (CD) are a major problem. In majority of patient, inflammation involves the rectum. Perianal fistulas in CD pose a diagnostic and therapeutic challenge due to severe symptoms and worse prognosis compared to cryptogenic fistulas. The accurate diagnosis is crucial for an effective treatment of CD-related perianal fistulas, and the following should be determined: anatomy of the fistula, possible strictures and inflammation of the alimentary tract, including the rectum and the anal canal. Treatment of fistulas might be challenging and requires cooperation between the colorectal surgeon and the gastroenterologist. The combination of surgical and pharmacological therapy is more effective than surgical or pharmacological therapy alone. In conservative treatment, aminosalicylates or steroids have little significance. In everyday practice, antibacterial chemotherapeutics, antibiotics and thiopurines are applied. The most effective are TNF-neutralizing antibodies, i.e. infliximab (IFX), adalimumab (ADA) and certolizumab (CER). Surgical management can be urgent including drainage. Elective procedures include dissection of the fistula (simple fistula) or more complex interventions such as mucosal flap or ligation of the intersphincteric portion of the fistula. Surgical interventions can be enhanced using the video-assisted anal fistula treatment (VAAFT) or negative-pressure therapy. In extreme cases, creation of a stoma may be necessary. Also, tissue glues or so-called plugs may be applied in managing perianal fistulas. The use of stem cells seems promising, i.e. application of multipotent non-hematopoietic stem cells around the fistula in order to induce immunomodulation and wound healing.
There are at least three, well-known, different groups of motor activity disturbances of the uppe... more There are at least three, well-known, different groups of motor activity disturbances of the upper part of alimentary tract which can induce the development of gastroesophageal reflux disease (GERD) and enlarge the risk of excessive exposure of the esophageal mucous membrane on gastric juice and/or biliary contents. Most important is insufficiency of the lower esophageal sphincter (LES), which causes gastroesophageal reflux at 50-60% of patients suffering from GERD. Other reasons include impairment of stomach function (increase of intra-gastric pressure, late emptying and/or hypersecretion), and impairment of esophageal clearance. The question: does motility impairment of the esophagus occur primary or secondary to the gastroesophageal reflux, is still not enough clarified. Motor activity of the esophagus before and after the antireflux operation was prospectively assessed in 57 patients. Motility of the esophagus was determined by estimation: the efficacy of LES, general motor activity of the body of the esophagus and motor activity of the body during the reflux episodes, basing on 24-h manometry. Comparison of general pre- and postoperative data revealed significantly positive influence of Nissen-Rossetti fundoplication on improvement of motor activity of the esophagus, but the results differed in relation to the height of the measurements. Moreover comparison of the data during gastroesophageal reflux episodes revealed negative changes of the manometric parameters in the upper and middle esophagus. We conclude that post-operative improvement of esophageal motility confirms the secondary dysfunction in the peristalsis, connected with pathological reflux. However, lack of the complete normalization in motor activity after operation suggests that disorder may partially occur as primary impairment of motor activity or as the secondary dysfunction, which is fixed in the course of GERD.
We are presenting a case report of 57-year-old patient operated on due to primary malignant melan... more We are presenting a case report of 57-year-old patient operated on due to primary malignant melanoma of the esophagus. Melanoma was misdiagnosed in biopsy taken during endoscopy. Final precise establishing the character of the lesion was able during histopathological examination of the specimen obtained during surgery. The outcome of the treatment was poor--survival time did not exceed 14 months. Patient died because of pulmonary metastases.
Neoangiogenesis has been proved to be crucial in neoplasmatic tumor growth and metastases. Over t... more Neoangiogenesis has been proved to be crucial in neoplasmatic tumor growth and metastases. Over the last few years, the factors that have both a positive (angiogenic) and negative (antiangiogenic) influence on tumor growth have been identified. The potential use of natural and synthetic factors that suppress vasculature formation as anticancer drugs is currently under intense investigation. Recently, several antiangiogenic compounds, including TNP-470 or matrix metalloproteinase inhibitors, have entered clinical trials. This review will describe the main groups of angiogenesis inhibitors, their mechanisms of action and some data from clinical studies.
It is suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor... more It is suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in tumor-induced angiogenesis. The purpose of this study was to estimate the correlation between VEGF and bFGF levels and tumor pathological status according to pTNM classification in patients with squamous cell oesophageal cancer. A group of 25 healthy controls and 32 consecutive patients with oesophageal cancer were included in this study. Serum VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Serum VEGF and bFGF levels were significantly elevated in the patient groups (VEGF: 146.0 pg/ml, 79.0-386.3 pg/ml vs. 38.0 pg/ml, 6.5-135.1 pg/ml, p<0.005, and bFGF: 5.2 pg/ml, 1.2-10.6 pg/ml vs. 2.06 pg/ml, 0.07-4.0 pg/ml, p<0.02 Fisher test). The highest correlation between serum VEGF and bFGF levels were found in patients with advanced cancers, especially with: T4, N1, and M1 factors. The VEGF and bFGF levels were significantly higher in patients with pT4 (p<0.01). Patients with N1 lymph node invasion, compared with N0 factor, have higher levels of angiogenetic factors (p<0.04). Also in patients with advanced cancers with liver metastases the serum levels VEGF and bFGF were significantly higher (M1 vs. M0, VEGF p<0.001 and bFGF p<0.05). Consecutive monitoring of VEGF and bFGF serum levels may be a useful prognostic marker for patients with squamous cell oesophageal cancer.
Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal... more Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. See related commentary by Salvagno and Cubillos-Ruiz, p. 1623. This article is highlighted in the In This Issue feature, p. 1601
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