Effective second-line treatment with cetuximab and bevacizumab in a patient with hepatic metastases of colorectal cancer and hyperbilirubinemia

Background: Irinotecan-based second-line chemotherapy of metastatic colorectal cancer (CRC) is effective, it might, however, be contraindicated in cases of severe liver dysfunction due to advanced liver metastases. Case Report: A 57-year-old woman with diffuse CRC liver metastases showed progressive disease on first-line treatment with capecitabine and oxaliplatin (XELOX). Chronic cholestasis and hyperbilirubinemia caused by advanced liver involvement prohibited second-line treatment with irinotecan-based chemotherapy. We initiated combined antibody treatment with cetuximab and bevacizumab. Results: Clinical performance status as well as laboratory parameters improved rapidly. Staging investigations after 8 weeks revealed a partial remission. Since bilirubin levels had returned to the upper limit of normal, therapy could be changed to standard irinotecan, 5-fluorouracil, folinic acid, and bevacizumab. Conclusion: Combined treatment with cetuximab and bevacizumab may be considered as an effective treatment option in patients who cannot be treated with standard chemotherapy regimens due to impaired liver metabolism of cytotoxic substances

Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer

Objective: To date, no standard regimen for salvage chemotherapy after gemcitabine (Gem) failure has been defined for patients with advanced pancreatic cancer (PC). Oral capecitabine (Cap) has shown promising activity in first-line chemotherapy trials in PC patients. Methods: Within a prospective single-center study, Cap was offered to patients who had already received at least 1 previous treatment regimen containing full-dose Gem (as a single agent, as part of a combination chemotherapy regimen or sequentially within a chemoradiotherapy protocol). Cap was administered orally at a dose of 1,250 mg/m(2) twice daily for 14 days followed by 7 days of rest. Study endpoints were objective tumor response rate by imaging criteria (according to RECIST), carbohydrate antigen 19-9 (CA19-9) tumor marker response, time to progression, overall survival and toxicity. Results: A median of 3 treatment cycles (range 1-36) was given to 39 patients. After a median follow-up of 6.6 months, 27 patients were evaluable for response: no complete or partial responses were observed, but 15 patients (39%) had stable disease. A CA19-9 reduction of >20% after 2 cycles of Cap was documented in 6 patients (15%). Median time to progression was 2.3 months (range 0.5-45.1) and median overall survival (since start of Cap treatment) was 7.6 months (range 0.7-45.1). Predominant grade 2 and 3 toxicities (per patient analysis) were hand-foot syndrome 28% (13% grade 3); anemia 23%; leg edema 15%; diarrhea 13%; nausea/vomiting 10%, and leukocytopenia 10%. Conclusion: Single-agent Cap is a safe treatment option for Gem-pretreated patients with advanced PC. Further evaluation of Cap in controlled clinical trials of Gem-pretreated patients with advanced PC is recommended. Copyright (C) 2008 S. Karger AG, Basel

3D characterisation of hydrogen environmentally assisted cracking during static loading of AA7449-T7651

In this investigation, synchrotron X-ray microtomography was used to perform 3D in situ observations of crack initiation and growth during hydrogen environmentally assisted cracking (HEAC) in tensile samples of AA7449-T7651. Two smooth tensile samples with a 1 mm diameter gauge section were held at a fixed displacement (≈30% of yield stress) in warm, moist air (≈76∘C, 73% relative humidity). The samples were then imaged repeatedly using X-ray tomography until they fractured completely. The tomograms showing the nucleation and evolution of intergranular cracks were correlated with electron microscopy fractographs. This enabled the identification of crack initiation sites and the characterisation of the crack growth behaviour relative to the microstructure. The samples were found to fracture within an environmental exposure time of 240 min. Some cracks in both samples nucleated within an exposure time of 80 min (33–40% of the total lifetime). Many cracks were found to nucleate both internally and at the sample surface. However, only superficial cracks contributed to the final fracture surface as they grew faster owing to the direct environmental exposure and the larger crack opening. HEAC occurred prominently via brittle intergranular cracking, and cracks were found to slow down when approaching grain boundary triple junctions. Additionally, crack shielding from nearby cracks and the presence of coarse Al–Cu–Fe particles at the grain boundaries were also found to temporarily reduce the crack growth rates. After prolonged crack growth, the HEAC cracks displayed ductile striations and transgranular fracture, revealing a change in the crack growth mechanism at higher stress intensity factors

A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: The AIO KRK 0110 Trial/ML22011 Trial

<p>Abstract</p> <p>Background</p> <p>Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies.</p> <p>Methods/Design</p> <p>The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m²bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m²BID for 14d (d1-14), irinotecan 200 mg/m²(d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life.</p> <p>Conclusion</p> <p>The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01249638">NCT01249638</a></p> <p>EudraCT-No.: 2009-013099-38</p

KRAB–Zinc Finger Proteins and KAP1 Can Mediate Long-Range Transcriptional Repression through Heterochromatin Spreading

Krüppel-associated box domain-zinc finger proteins (KRAB–ZFPs) are tetrapod-specific transcriptional repressors encoded in the hundreds by the human genome. In order to explore their as yet ill-defined impact on gene expression, we developed an ectopic repressor assay, allowing the study of KRAB–mediated transcriptional regulation at hundreds of different transcriptional units. By targeting a drug-controllable KRAB–containing repressor to gene-trapping lentiviral vectors, we demonstrate that KRAB and its corepressor KAP1 can silence promoters located several tens of kilobases (kb) away from their DNA binding sites, with an efficiency which is generally higher for promoters located within 15 kb or less. Silenced promoters exhibit a loss of histone H3-acetylation, an increase in H3 lysine 9 trimethylation (H3K9me3), and a drop in RNA Pol II recruitment, consistent with a block of transcriptional initiation following the establishment of silencing marks. Furthermore, we reveal that KRAB–mediated repression is established by the long-range spreading of H3K9me3 and heterochromatin protein 1 β (HP1β) between the repressor binding site and the promoter. We confirm the biological relevance of this phenomenon by documenting KAP1–dependent transcriptional repression at an endogenous KRAB–ZFP gene cluster, where KAP1 binds to the 3′ end of genes and mediates propagation of H3K9me3 and HP1β towards their 5′ end. Together, our data support a model in which KRAB/KAP1 recruitment induces long-range repression through the spread of heterochromatin. This finding not only suggests auto-regulatory mechanisms in the control of KRAB–ZFP gene clusters, but also provides important cues for interpreting future genome-wide DNA binding data of KRAB–ZFPs and KAP1

“En bloc” caudate lobe and inferior vena cava resection following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal and liver metastasis of colorectal cancer

There are diverse protocols to manage patients with recurrent disease after primary cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. We describe a case of metachronous liver metastasis after CRS and HIPEC for colorectal cancer, successfully treated with a selective metastectomy and partial graft of the inferior vena cava. A 35-year-old female presented with a large tumour in the cecum and consequent colonic stenosis. After an emergency right colectomy, the patient received adjuvant chemotherapy. One year later she was diagnosed with peritoneal carcinomatosis, and it was decided to carry out a CRS/HIPEC. After 2 years of total remission, an isolated metachronous liver metastasis was detected by magnetic resonance imaging surveillance. The patient underwent a third procedure including a caudate lobe and partial inferior vena cava resection with a prosthetic graft interposition, achieving an R0 situation. The postoperative course was uneventful and the patient was discharged on postoperative day 17 after the liver resection. At 18-mo follow-up after the liver resection the patient remained free of recurrence. In selected patients, the option of re-operation due to recurrent disease should be discussed. Even liver resection of a metachronous metastasis and an extended vascular resection are acceptable after CRS/HIPEC and can be considered as a potential treatment option to remove all macroscopic lesions

3D characterisation of hydrogen environmentally assisted cracking during static loading of AA7449-T7651

In this investigation, synchrotron X-ray microtomography was used to perform 3D in situ observations of crack initiation and growth during hydrogen environmentally assisted cracking (HEAC) in tensile samples of AA7449-T7651. Two smooth tensile samples with a 1 mm diameter gauge section were held at a fixed displacement (≈30% of yield stress) in warm, moist air (≈76∘C, 73% relative humidity). The samples were then imaged repeatedly using X-ray tomography until they fractured completely. The tomograms showing the nucleation and evolution of intergranular cracks were correlated with electron microscopy fractographs. This enabled the identification of crack initiation sites and the characterisation of the crack growth behaviour relative to the microstructure. The samples were found to fracture within an environmental exposure time of 240 min. Some cracks in both samples nucleated within an exposure time of 80 min (33–40% of the total lifetime). Many cracks were found to nucleate both internally and at the sample surface. However, only superficial cracks contributed to the final fracture surface as they grew faster owing to the direct environmental exposure and the larger crack opening. HEAC occurred prominently via brittle intergranular cracking, and cracks were found to slow down when approaching grain boundary triple junctions. Additionally, crack shielding from nearby cracks and the presence of coarse Al–Cu–Fe particles at the grain boundaries were also found to temporarily reduce the crack growth rates. After prolonged crack growth, the HEAC cracks displayed ductile striations and transgranular fracture, revealing a change in the crack growth mechanism at higher stress intensity factors

Retrotilt of the Pelvis During Periacetabular Osteotomy: How to Avoid a Systematic Error Resulting in Acetabular Retroversion and Possible Femoroacetabular Impingement.

BACKGROUND Pelvic tilt directly influences acetabular version on radiographs. Changes of pelvic tilt potentially affect acetabular reorientation after periacetabular osteotomy (PAO). PURPOSE (1) To compare the ratio of the pubic symphysis height to the sacroiliac width (PS-SI) between hips with dysplasia and acetabular retroversion, uni- and bilateral PAO, and male and female patients. (2) To evaluate pelvic tilt (quantified using the PS-SI ratio) in patients after PAO by tracking it from preoperative to intra- and postoperative and short- and middle-term follow-up. STUDY DESIGN Case series; Level of evidence, 4. METHODS A retrospective and radiographic study was conducted evaluating pelvic tilt in 124 patients (139 hips) with dysplasia and 46 patients (57 hips) with acetabular retroversion who were undergoing PAO (January 2005-December 2019). Patients were excluded if they had insufficient radiographic data, previous or concomitant hip surgery, posttraumatic or pediatric deformities, or combined dysplasia and retroversion (90 patients, 95 hips). Dysplasia was defined as a lateral center-edge angle <23°; retroversion was defined by simultaneous appearance of a retroversion index 30% and positive ischial spine and posterior wall signs. Anteroposterior pelvic radiographs were taken in the supine position preoperatively, during PAO, postoperatively, and at short- and middle-term follow-up (mean ± SD [range]; 9 ± 3 weeks [5-23 weeks] and 21 ± 21 weeks [6-125 months]). The PS-SI ratio was calculated at 5 observation periods (preoperatively to middle-term follow-up) for different subgroups (dysplasia vs retroversion, uni- vs bilateral surgery, male vs female) and validated with intra- and interobserver agreement (intraclass correlation coefficients, 0.984 (95%CI, 0.976-0.989) and 0.991 (95% CI, 0.987-0.994), respectively). RESULTS The PS-SI ratio differed between dysplasia and retroversion at all observation periods (P = .041 to P < .001). Male dysplastic hips had a lower PS-SI ratio when compared with female dysplastic hips at all observation periods (P < .001 to P = .005). In hips with acetabular retroversion, the PS-SI ratio was lower in men than women at short- and middle-term follow-up (P = .024 and .003). No difference was found between uni- and bilateral surgery (P = .306 to P = .905) except for short-term follow-up in dysplasia (P = .040). The PS-SI ratio decreased in all subgroups preoperatively to intra- or postoperatively (P < .001 to P = .031). At short- and middle-term follow-up, the PS-SI ratio increased as compared with intraoperatively (P < .001 to P = .044) and did not differ from preoperatively in all subgroups (P = .370 to P = .795). CONCLUSION A lower PS-SI ratio was found for male or dysplastic hips. In all subgroups, the PS-SI ratio decreased during surgery, indicating retrotilt of the pelvis. Correct pelvic orientation during surgery is crucial for accurate acetabular reorientation. Retrotilt during surgery results in underestimation of acetabular version and iatrogenic retroversion of the acetabulum at follow-up, with the pelvis in the correct and more forward-tilted orientation. Not taking into account retrotilt during PAO potentially results in femoroacetabular impingement. Therefore, we changed our intraoperative setting with adjustment of the central beam to compensate for retrotilt of the pelvis