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.

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.

Two submucosal nerve plexus in human intestines.

We examined the architecture of human submucosal nerve networks of gut segments derived from 12 individuals (each six from small and large intestines). Twelve undivided submucosal wholemounts were prepared and immunohistochemically stained for peripherin (nerve elements) and for alpha-smooth muscle actin (remnants of attached muscle bundles). We found two ganglionic nerve networks. The plexus submucosus externus was generally monolayered and located under the outermost surface of the submucosal wholemounts. Its nerve fibre strands frequently joined each other in acute or obtuse angles, the meshes of the network were relatively wide and frequently polyangular shaped. The plexus submucosus internus was generally multi-(mostly two- or three-)layered and occupied at least the inner half of the thickness of the wholemount, sometimes extending abluminally beyond the great submucosal vessels. Its meshes were irregular. The shapes of ganglia of the two plexus were generally different, those of the internal plexus were frequently grape-like whereas the neurons of external ganglia were mostly embedded in the contoures of the joining nerve fibres. Both plexus were intensely connected via coiled interconnecting strands, either with or without intercalated ganglia. For use of eponyms for two different submucosal plexus, the names of Meissner (inner) and Schabadasch (outer) are historically justified.

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.

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.

Thyroid metastases of renal cell carcinoma: clinical course in 45 patients undergoing surgery. Assessment of factors affecting patients' survival.

BACKGROUND: Metastases of renal cell carcinoma (RCC) to the thyroid gland are uncommon. There is no clear consensus regarding the role of surgery in metastatic disease to the thyroid since most clinical studies include small numbers of patients. Also, risk factors associated with disease progression following thyroidectomy are not yet defined. We examined the determinants of the outcome in patients undergoing surgery for thyroid metastases of RCC. METHODS: The medical records of 45 patients undergoing resection of thyroid metastases of RCC at 15 institutions in Germany and Austria were reviewed retrospectively. The outcome parameters assessed were overall survival and tumor-related survival. Factors associated with disease progression following thyroid surgery have been calculated. RESULTS: The overall 5-year survival rate following thyroid metastasectomy was 51%. Nineteen patients died during the study: 14 of disseminated disease and 5 of non-tumor-related causes. In the multivariate analysis, the prognosis was significantly worse in patients older than > or = 70 years and in patients who had undergone nephrectomy for metastases in the contralateral kidney during the course of the disease. Nine patients developed a thyroid recurrence following surgery. No local disease relapse occurred if resection margins were documented to be free of the tumor. Of the 45 patients with thyroid metastases, 14 (31%) developed pancreatic metastases during the course of disease. Ten of these patients also underwent pancreatic surgery with a 5-year survival rate of 43% in this subgroup. CONCLUSIONS: The overall survival of patients undergoing thyroidectomy for metastases of RCC is affected rather by general health status than by tumor-related factors. There is a significant coincidence of thyroid and pancreatic metastases of RCC.

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.

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.

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.

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.

Closing a Tracheal Defect with an Omental Pedicled Gastric Flap; A Technical Note.

Due to an adenocarcinoma of the right upper lobe with infiltration of the main bronchus a 49-years-old female patient underwent an upper bilobectomy with sleeve resection. After two completed chemotherapy bouts and signs of sepsis another thoracotomy was inevitable.  As a complicating factor a supracarinal, necrotic and perforating lesion of the trachea appeared. The defect can be initially repaired with a suture and covered with azygos vein material. However surgical revision showed an enlargement of the tracheal necrosis. Then the lesion was occluded with a diaphragmatic pedicled flap. Nevertheless after the operation a tracheal insufficiency with massive ventilation leakage was observed. It was generated by the death of the diaphragmatic flap. As an ultimate therapeutic measure a transplantation of a pedicled omental gastric flap was performed, which in case of a failure of the conventional operative techniques, is an additional option in closing tracheal defects caused by infections. Especially in cases of massive infected thoracic cavity and tracheal necrosis omentum majus is, compared to muscle flaps, the better biological tissue to close and heal the tracheal defect. This case report firstly describes a successfully closure of a tracheal defect using the technique mentioned above.

The geriatric polytrauma: Risk profile and prognostic factors.

BACKGROUND: In the German population, the percentage of elderly patients is increasing, and consequently there are more elderly patients among trauma cases, and particularly cases of polytrauma. The aim of this study was to present clinical results and a risk profile for geriatric polytrauma patients. METHODS: Review of 140 geriatric (over 65 years of age) polytrauma patients who received prehospital treatment was performed. Severity of trauma was retrospectively assessed with Hannover Polytrauma Score (HPTS). Age, hemoglobin (Hb) level, systolic blood pressure (BP), Glasgow Coma Scale (GCS) score, timing of and necessity for intubation were analyzed in relation to mortality and in comparison with younger patients. RESULTS: Geriatric polytrauma patients (n=140) had overall mortality rate of 65%, whereas younger patients (n=1468) had mortality rate of 15.9%. Despite equivalent severity of injury (HPTS less age points) in geriatric and non-geriatric groups, mortality rate was 4 times higher in geriatric group. Major blood loss with Hb <8 g/dL was revealed to be 3 times more fatal than moderate or minor blood loss (Hb ≥8 g/dL). GCS score <12 corresponded to double mortality rate (39% vs 83%). CONCLUSION: Age by itself is significant risk factor and predictor of increased mortality in polytrauma patients. Additional risk factors include very low GCS score and systolic BP <80 mm Hg, for instance, as potential clinical indicators of massive bleeding and traumatic brain injury. Such parameters demand early and rapid treatment at prehospital stage and on admission.

A retrograde y-stenting of the trachea for treatment of mediastinal fistula in an unusual situation.

INTRODUCTION: Stents have been used for quite some time for the treatment of benign and malignant airway stenosis. Silicon stents are preferred for benign situations, whereas metallic self-expanding stents are preferred for malignant comorbidities. PATIENT AND METHODS: In general, stents can be placed in different approach directions, although in pulmonary medicine it is logical to apply only antegrade techniques - until now. A 63-year-old patient, 168 cm height and 53 kg weight on referral, suffered chronical diseases. The patient was diagnosed with a papillary thyroid carcinoma in 1989, which was treated by resection and radiotherapy. In the following years, she developed a stenosis of the esophagus. The decision to try endobronchial stenting was made upon the plan to close that fistula with a pedicled omentum majus replacement through the diaphragmal opening of the esophagus. This surgical plastic needed an abutment and a secured continuous airway replacement above the tracheostoma level. A Freitag stent (FS), 11 cm in length (110-25-40) and an inner diameter of 13 mm, was placed successfully retrograde into the trachea and completely bridged the big fistula. Unfortunately the patient passed away due to pulmonary infections after several weeks. DISCUSSION: In this case report, a successful but unusual case of retrograde stent placement of a modified FS is presented.