DOG1 overexpression is associated with mismatch repair deficiency and BRAF mutations but unrelated to cancer progression in colorectal cancer.

INTRODUCTION: The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations. METHODS: A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry. RESULTS: DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p<0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes. CONCLUSION: Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity.

High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

BACKGROUND: Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking. METHODS: More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results. RESULTS: At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p < 0.0001). The number of intratumoral CD8+ lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8+ lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0; p < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2; p < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8+, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion (p < 0.0001 each). CONCLUSION: The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.

Elevated MUC5AC expression is associated with mismatch repair deficiency and proximal tumor location but not with cancer progression in colon cancer.

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relationship of MUC5AC expression with parameters of tumor aggressiveness and mismatch repair deficiency (dMMR) in colorectal cancer, a tissue microarray containing 1812 colorectal cancers was analyzed by immunohistochemistry. MUC5AC expression was found in 261 (15.7%) of 1,667 analyzable colorectal cancers. MUC5AC expression strongly depended on the tumor location and gradually decreased from proximal (27.4% of cecum cancers) to distal (10.6% of rectal cancers; p < 0.0001). MUC5AC expression was also strongly linked to dMMR. dMMR was found in 21.3% of 169 cancers with MUC5AC positivity but in only 4.6% of 1051 cancers without detectable MUC5AC expression (p < 0.0001). A multivariate analysis showed that dMMR status and tumor localization predicted MUC5AC expression independently (p < 0.0001 each). MUC5AC expression was unrelated to pT and pN status. This also applied to the subgroups of 1136 proficient MMR (pMMR) and of 84 dMMR cancers. The results of our study show a strong association of MUC5AC expression with proximal and dMMR colorectal cancers. However, MUC5AC expression is unrelated to colon cancer aggressiveness.

Thoracic compartment syndrome after penetrating heart and lung injury.

Thoracic injuries are the most lethal penetrating injuries. After attempting suicide, two patients with a penetrating thoracic wound were admitted to our emergency department. During CT scan they became hemodynamically unstable, which is why we had to perform an emergency thoracotomy. In both cases, a perforation in the left ventricle as well as multiple lesions of the lung parenchyma and vessel injuries were found. After the treatment of the different injuries, a massive edema of the heart and lung prevented a primary closure of the thorax. Due to massive diffuse bleeding, a "packing" of the pleural cavity became necessary. To prevent a thoracic compartment syndrome, the thoracic wall was left open and the skin was closed with a plastic sheet. Due to the "open chest" procedure combined with "packing" of the thoracic cavity, the majority of patients with an edema of the heart and lung after a penetrating chest injury can be saved. Pitfalls of preclinical and clinical treatment, aspects of diagnostics and surgery are discussed.

Prehospital tracheotomy in a case of avulsion of the larynx with a comminuted fracture of the jawbone.

Emergency physicians in the field are sometimes confronted with cases wherein patients cannot be intubated and ventilated. In some cases, cricothyrotomy, the method of choice for securing an emergency airway, may not have a successful outcome. We report a rare case of a 35-yearold male patient with avulsion of the larynx and a comminuted fracture of the jawbone, due to entrapment in a dung excavator. Prehospital tracheotomy was successfully performed. In cases with crush injuries to the larynx, anatomic structures, including the ligamentum conicum, are destroyed. In addition, massive subcutaneous emphysema blurs the anatomical key structures; hence, only a tracheotomy can prevent a lethal outcome.

Delayed Cardiac Rupture Induced by Traumatic Myocardial Infarction: Consequence of a 45-Magnum Blast Injury; A Comprehensive Case Review.

A penetrating chest trauma, a myocardial contusion or a myocardial infarction can lead to a cardiac rupture, which is linked to an extreme high death rate. Only few cases with delayed perforation of the myocardium have been reported in literature. We report about a penetrating gunshot injury, which led to a myocardial contusion with secondary delayed rupture of the left ventricle and the left inferior lobe of the lung. The leakage of the lesion in the left ventricle could be sealed sufficiently with fibrin-coated collagen fleeces after adapting stitches with Prolene 2-0. For additional stabilization of the vulnerable myocardium area, a bovine patch has been placed on the damaged ventricle. Fibrin fleeces are used successfully in cardiac surgery, as in our case, to seal the leakage of the lesion in the left ventricle. The implantation of a bovine patch in the pericardium could prevent a cardiac compartment syndrome with a fatal pericardial tamponade. To prohibit a thoracic compartment syndrome a modified Bogota bag could be sewed in for temporarily closure of the chest. In most cases penetrating cardiac injuries can be treated without heart-lung-machines. An immediate transfer to a cardio-surgical center is, due to the acute situation, not possible. If a surgeon with thoraco-surgical expertise is present a transfer is not absolutely necessary.

A case of severe acute necrotizing pancreatitis in a 38-year-old woman postpartum due to a parathyroid adenoma.

Lethal necrotizing pancreatitis postpartum due to primary hyperparathyroidism caused by a parathyroid adenoma can be considered as a rarity. Due to the unspecific clinical signs and uncommonness this disorder may be overseen very easily. The reported case illustrates the very importance of early diagnosis of this endocrine disorder in pregnancy in order to avoid a lethal course.

Large thoracic defect due to shotgun violation - surgical emergency management.

Shotgun injuries from a short distance (<3 m) may cause massive bleeding and tissue destruction. Only immediate aggressive (surgical) therapy prevents lethal outcome. We report about a 27-year-old patient, who was wounded on the left chest wall by a straight-cut shotgun from a short distance. In cases of this special traumatic pattern damage control measures are necessary. The measures should take place in preclinical emergency management (by the on-site emergency physician). We report about the emergency management from admission to our hospital and the following surgical treatment until discharge from the hospital.

Tension pneumopericardium in a multiply injured child.

Tension pneumopericardium is a rare disease that is very difficult to diagnose. A 3-year old child was run over by a minibus. Computed tomography showed bilateral pneumothorax, multiple rib fractures on both sides, and a hepatic laceration. The massive blunt thoracic trauma caused entrapped air in the pericardium, and a tension pneumoprecordium developed abruptly. We report this unique case of tension pneumopericardium in a child, and the subsequent emergency surgery and damage control measures.