Improvement of a Clinical Score for Necrotizing Fasciitis: 'Pain Out of Proportion' and High CRP Levels Aid the Diagnosis.

Necrotizing fasciitis (NF) is a rare mono-/polymicrobial skin infection that spreads to underlying tissues. NF is quickly progressing and leads to life threatening situations. Immediate surgical debridement together with i.v. antibiotic administration is required to avoid fatal outcome. Early diagnosis is often delayed due to underestimation or confusion with cellulitis. We now compared the initial clinical and laboratory presentation of NF and cellulitis in detail to assess if a typical pattern can be identified that aids timely diagnosis of NF and avoidance of fatal outcome. 138 different clinical and laboratory features of 29 NF patients were compared to those of 59 age- and gender matched patients with severe erysipelas requiring a subsequent hospitalization time of ≥10 days. Differences in clinical presentation were not obvious; however, NF patients suffered significantly more often from strong pain. NF patients exhibited dramatically elevated CRP levels (5-fold, p>0.001). The overall laboratory risk indicator for necrotizing fasciitis (LRINEC) score was significantly higher in NF patients as compared to cellulitis. However, a modification of the score (alteration of laboratory parameters, addition of clinical parameters) led to a clear improvement of the score with a higher positive predictive value without losing specificity. In summary, clinical differentiation of NF from cellulitis appears to be hard. 'Pain out of proportion' may be an early sign for NF. An improvement of the LRINEC score emphasizing only relevant laboratory and clinical findings as suggested may aid the early diagnosis of NF in the future leading to improvement of disease outcome by enabling rapid adequate therapy.

Confocal chromolaser endomicroscopy: a supplemental diagnostic tool prior to transanal endoscopic microsurgery of rectal tumors?

PURPOSE: Due to diagnostic advancements, preoperative staging of rectal tumors was significantly improved. However, difficulties in obtaining accurate results can sometimes be observed in the staging of adenomas and early rectal carcinomas (pT1/2). The aim of this study was to test if confocal chromolaser endomicroscopy (cCLEM) can help minimize this diagnostic gap. METHODS: cCLEM generates optical transversal sections at x1,000 magnification and allows for evaluation of the mucosal microarchitecture and differentiation of normal mucosa from adenomas and carcinomas. Cases with conflicting preoperative findings (adenoma vs. > or =uT2 categories), undetectable tumors after inadequate (R1/RX) snare polypectomy of carcinomas, and extremely flat adenoma areas were studied. RESULTS: By cCLEM, in > or =uT2 carcinomas with an adenoma histology, malignoma-suspicious areas were identified and selected biopsies were done. In addition, re-epithelialized polypectomy areas of carcinomas were visualized and targeted reoperations could be carried out. Furthermore, the dignity and extension of extremely flat adenomas were determined and marked by clips for additional therapy. CONCLUSIONS: In cases with rectal tumors, conflicting or unclear findings, and flat extending adenomas, the utilization of cCLEM should be considered. Especially in cases with early rectal carcinomas, unnecessary second operations and also recurrences can be minimized or even avoided by selective usage of cCLEM.

Diagnosis and treatment of pancreatic metastases of a papillary thyroid carcinoma.

BACKGROUND: Apart from regional lymph node metastases, systemic metastases occur sporadically in papillary thyroid carcinomas (PTC). The lung and bones are the most frequent localizations. Additionally known but extremely rare locations are metastases of the skeletal muscles, ovaries, submandibular gland, sphenoidal sinus, brain, adrenals, and, as shown in only two previously published cases to date, the pancreas. SUMMARY: In this article we report about two additional patients with pancreatic metastases from PTC. There is almost no prior experience about therapeutic approaches to this type of metastases. In both patients distant metastases within the pancreas were successfully removed. Postoperative histology confirmed the diagnoses. Supplemental genetic analysis did not demonstrate a BRAF V600E mutation or expression of a RET/PTC1 rearrangement in one case, but revealed a BRAF V600E mutation in the second case. Surgery avoided impending complications maintaining quality of life. One patient had a tumor-specific survival of 42 months. The other patient has occult disease. CONCLUSIONS: Our two patients benefited of a calculated aggressive surgical action. Thus, if low perioperative mortality and morbidity can be warranted, surgical measures are justifiable in selected cases.

Perforation into the peritoneal cavity during transanal endoscopic microsurgery for rectal cancer is not associated with major complications or oncological compromise.

BACKGROUND: This study was designed to investigate short-term and long-term consequences from perforation to the peritoneal cavity during transanal endoscopic microsurgery (TEM) for rectal cancer, with special emphasis on local recurrence and complications. METHODS: Data from TEM procedures with peritoneal perforations were collected from six prospective databases. Patient, procedure, and follow-up data were extracted. Participating centers were the United Kingdom TEM database, the German TEM database from Mainz, the National Danish TEM database, and databases from the three major Norwegian TEM centers. A total of 888 TEM procedures were registered, and 22 perforations were identified. RESULTS: Median age was 82 years. Tumor stages were 14 pT1, 4 pT2, 3 pT3, and 1 pTx. The mean tumor size was 4.1 cm. Radical resection was achieved in 17 patients. All perforations were handled endoscopically. There were no severe complications and no deaths related to the procedure. The mean time of observation was 37 (median 36; range 3-164) months. Local recurrence occurred in two patients, three patients died from the cancer (distant metastasis), and six died from other causes. CONCLUSIONS: Breaching the peritoneum during TEM is not associated with major short-term complications or long-term oncological consequences provided that primary endoscopic repair is undertaken.

Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer.

This study aimed to define the co-expression pattern of target receptor tyrosine kinases (RTKs) in human esophageal adenocarcinoma and squamous cell cancer. The co-expression pattern of vascular endothelial growth factor receptor (VEGFR)1-3, platelet-derived growth factor receptor (PDGFR)alpha/beta and epidermal growth factor receptor 1 (EGFR1) was analyzed by RT-PCR in 50 human esophageal cancers (35 adenocarcinomas and 15 squamous cell cancers). In addition, IHC staining was applied for the confirmation of the expression and analysis of RTK localisation. The adenocarcinoma samples revealed VEGFR1 (97%), VEGFR2 (94%), VEGFR3 (77%), PDGFRalpha (91%), PDGFRbeta (85%) and EGFR1 (97%) expression at different intensities. Ninety-four percent of the esophageal adenocarcinomas expressed at least four out of six RTKs. Similarly, squamous cell cancers revealed VEGFR1 (100%), VEGFR2 (100%), VEGFR3 (53%), PDGFRalpha (100%), PDGFRbeta (87%) and EGFR1 (100%) expression at different intensities. All esophageal squamous cell carcinomas expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRalpha and EGFR1 was expressed by tumor cells, PDGFRbeta was restricted to stromal cells, which also depicted a PDGFRalpha expression. Our results revealed a high rate of RTK co-expression in esophageal adenocarcinoma and squamous cell cancer and may encourage application of multi-target RTK inhibitors within a multimodal concept as a promising novel approach for innovative treatment strategies.

Oncological outcome after local excision of rectal carcinomas.

BACKGROUND: Local excision (LE) of T1 rectal cancer yields low recurrence rates. However, more frequent recurrences with unknown states of high-risk T1/T2 tumors are risk factors. The purpose of this study was to evaluate if, after LE, immediate reoperation is required, or awaiting salvage surgery is sufficient. METHODS: 150 T1 and 42 T2 tumors were treated by LE. Immediate reoperation was attempted for unfavorable pT1 (G3-4/L1/V1/R1/Rx/R < or =1 mm) and all pT2 tumors. Three groups were formed. Group A included low-risk pT1 tumors after complete (R0) LE; unfavorable pT1 and all T2 tumors were divided in groups B (immediate reoperation) and C (salvage surgery). RESULTS: Groups A (n = 93) and B (n = 39) showed high tumor-free (TFS) and tumor-related survival (TRS) rates: group A 92% and 98%; group B 86% and 89%. In group C (n = 43), the TFS und TRS were significantly lower with 54% and 72%. Group A showed low recurrence rates and a wide range of International Union Against Cancer (UICC) stages. In group B, similarly low recurrence rates were found, but, in contrast, all recurrences were UICC IV. Group C had significantly higher recurrences rates and, in addition, two-thirds of these patients showed advanced UICC stages (III-IV). CONCLUSIONS: LE of low-risk T1 tumors represents an adequate therapy. Immediate reoperation after LE of pT1 tumors with unfavorable histological finding or pT2 tumors can avoid local recurrences. Thereafter, high TFS rates can be expected in these patients, but metastases cannot be prevented and adjuvant measures are necessary. Awaiting recurrences as in group C leads to bad oncological outcomes with high recurrences and low survival rates.

Local excision for more advanced rectal tumors.

UNLABELLED: Over the past 20 years, local excision (LE) of T1 rectal cancer was increasingly established and represents an oncologically established technique. In contrast, the situation for T2 tumors is less clear and has only been investigated in small patient collectives. LE for T2 tumors is thus discussed controversially. MATERIALS AND METHODS: In addition to our own patients with T2 rectal cancer treated locally (n=40), we have analysed the local recurrence (LR) rates after LE alone (n=124), after immediate conventional radical reoperation (n=29), after adjuvant (chemo)-radiotherapy (n=294) and those after neoadjuvant chemoradiotherapy (nCRT) (n=269) using a PubMed search. RESULTS: LR rates of low-grade T2 tumors after R0 resection by LE alone was 19%. If additional prognostically unfavorable findings were present, the LR rate rose to 52%. By immediate radical reoperation the LR rate was decreased to 7%, whereas that after adjuvant therapy was 16%. In contrast, LE of more advanced tumors after nCRT resulted in LR rates of 9%. DISCUSSION: LE alone of T2 rectal cancer should not be performed, and after adjuvant chemoradiotherapy the risk of developing LR was also high. In cases with unexpected T2 finding after LE, immediate conventional reoperation can represent an adequate oncological therapy, because it reveals comparable results to those obtained by primary radical resection. First results after nCRT followed by LE showed favorable results with low LR rates. If the indication for LE of T2 cancers can be extended to patients after nCRT in the future will have to be determined in prospective mutlticentre studies.

Neoadjuvant chemoradiation and local excision for T2-3 rectal cancer.

BACKGROUND: Local excision (LE) of T1 low-risk (G1-2/L0/V0) rectal cancer is an established approach with local recurrence (LR) rates of approximately 5%, whereas LE of > or = T2 high-risk tumors or inadequate resections (R1/RX/R < or = 1 mm) showed high recurrence rates. Because of the favorable results after neoadjuvant chemoradiotherapy (nCRT) and radical surgery of disease that completely responds (CR) with almost absent LR even of T3-4 tumors, an extension of the indication for LE is controversially discussed, and therefore, we assessed this therapeutic option. METHODS: Including our own data, seven studies about LE after nCRT of cT2-3 tumors (n = 237) were analyzed after a PubMed search for cT categories, tumor height, nCRT regimens, schedule and technique of surgery, complications, freedom of stoma, response rates (ypT0-3), length of follow-up, LR, and metastases. RESULTS: Subgroups that we formed (retrospective vs. prospective/retractor vs. transanal endoscopic microsurgery) showed differences in the distribution of cT categories. However, neither the studies we considered nor our own patients showed LR in CR (ypT0). In addition, patients with ypT1 tumor consistently showed low LR rates of 2% (range, 0%-6%), whereas in ypT2 findings, less favorable LR rates of 6% to 20% were observed, and disease that did not respond to therapy (ypT3) displayed LR rates in up to 42%. CONCLUSIONS: Despite of a highly selected patient collective, an extended indication for LE of cT2-3 rectal cancer after nCRT may be considered. The strongest prognostic factors were a CR (ypT0) or responses on submucosa level (ypT1). These first results will have to be confirmed in a prospective trial with an appropriate sample size to ensure high statistical power.

Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma--a rationale for a molecular targeting strategy?

AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFR1-3, PDGFR alpha/beta and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFR alpha (82%) and PDGFR beta (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFR alpha revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFR beta was restricted to stromal pericytes, which also depicted a PDGFR alpha expression. CONCLUSION: Our results reveal a high rate of receptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy.

Transanal endoscopic microsurgical excision of pT2 rectal cancer: results and possible indications.

PURPOSE: In previous studies, local excision was predominantly established for "low-risk" pT1 rectal cancer. The results obtained with T2 tumors are unclear; recurrence rates of 0 to 67 percent were reported. This study was designed to determine the value of local excision for T2 rectal carcinomas, prognostic factors, and the need for reoperation. METHODS: After local excision of 649 patients with rectal tumors, pT2 carcinoma was found in 44 patients. In general, immediate reoperation was recommended; however, 24 patients declined further surgery or were not reoperated because of comorbidities. The results were analyzed separately for local R0 resection of low-risk carcinomas and for prognostically unfavorable criteria (R1/RX/R < or = 1mm/G3-4/L1/V1). Reoperation was performed within four weeks. Recurrences also were divided by previous local R0 resection of low-risk tumors as well as by unfavorable results and were analyzed in a long-term, follow-up study. Patients with palliative therapy were excluded, and follow-up was obtained in 90 percent (20 transanal endoscopic microsurgical excision alone, 17 transanal endoscopic microsurgical excision and reoperation). RESULTS: Local recurrence rates after local R0 resection alone of low-risk T2 carcinomas were 29 percent, whereas patients with unfavorable criteria developed recurrences in 50 percent. After immediate reoperation, the local recurrence risk in patients without lymph node filiae was significantly reduced to 7 percent. CONCLUSIONS: Local R0 resection of low-risk pT2 carcinomas represents an inadequate therapy. In pT2N0M0 rectal carcinomas, the recurrence rate can be reduced through immediate reoperation to a level similar to primary radical surgery. An initial poor local resection result (R1/RX/R < or = 1 mm/G3-4/L1/V1) has no negative influence on further oncologic outcome.

The influence of histopathologic criteria on the long-term prognosis of locally excised pT1 rectal carcinomas: results of local excision (transanal endoscopic microsurgery) and immediate reoperation.

PURPOSE: Local excision of early rectal cancer is a controversial issue, which is in part because of differences in the evaluation of histopathologic criteria. This prospective study was designed to determine prognostic factors for recurrences and the need for reoperation. METHODS: In 105 of 118 patients with pT1 carcinomas and local excision, results of recurrence rates and ten-year cancer-free survival were studied separately according to different histologic criteria (R0, R1, Rx, R < or = 1 mm, high-/low-risk situation), tumor localization (anterior, posterior, lateral wall and third of rectum), size, and degree of resection (full-thickness/partial wall). Patients were grouped into local excision (n = 89) and local excision followed by reoperation (n = 21). Risk classification was performed by division into "low-risk" carcinomas after local R0-resection (Group A) and unfavorable histologic results after local resection (R1, Rx, R < or = 1 mm, high-risk situation; Group B). RESULTS: Local recurrence rates after local R0-resection of low-risk carcinomas were 6 percent, whereas patients in Group B with local resection were 39 percent. The recurrence risk in those patients was significantly reduced to 6 percent by reoperation (P = 0.015). In addition, ten-year, cancer-free survival was 93 percent in Group B after reoperation compared with 89 percent in patients of Group A after local excision alone. CONCLUSIONS: Local R0-resection in cases with low-risk pT1 carcinomas represents an oncologically adequate therapy, which results in similar survival rates compared with primary radical surgery of pT1N0M0 rectal carcinomas. High recurrence rates are observed in tumors with unfavorable histologic result (Group B) requiring further treatment. In these cases immediate reoperation reduces the recurrence rate to 6 percent.