Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Liver resection for colorectal cancer metastases.

QUESTIONS: Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy ("conversion")?What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy? PERSPECTIVES: Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%-10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required. METHODOLOGY: Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline. PRACTICE GUIDELINE: These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent. 1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-in cases with limited nodal involvement and with metastases that can be completely resected.1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-for metastases that can be completely resected.2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence.

Insulin-like growth factor-II uptake into choroid plexus and brain of young and old sheep.

Insulin-like growth factor II (IGF-II) is a major growth factor in brain and is involved in neuroprotection in later life. However, synthesis and delivery of IGF-II to brain by the choroid plexus (CP) in later life is not well understood. This study investigated these issues in old sheep (7-10 years) in comparison to young adult sheep (1-2 years). IGF-II messenger RNA expression at the CP did not change with age although cerebrospinal fluid (CSF) levels fell. 125I-IGF-II uptake in the CP was saturated from either side of the CP, whereas age-related decrease of the uptake was seen at the CSF side but not at the blood side of the CP. The insulin-like growth factor binding protein-2 (IGFBP-2) at 0.01 or 0.1 microg/mL tended to enhance IGF-II uptake at the young CP but not the old CP or other brain tissues, whereas bovine serum albumin generally inhibited the uptake. These age-related changes suggest that the normal autocrine/paracine role of IGF-II at the CP is attenuated with age.

Decrease of transthyretin synthesis at the blood-cerebrospinal fluid barrier of old sheep.

Transthyretin (TTR), synthesized by the choroid plexus (CP) and secreted into cerebrospinal fluid (CSF), is involved in thyroxine (T4) transport and chelation of beta-amyloid peptide, attenuating neurotoxicity. To characterize age-related changes in TTR synthesis, CSF and CPs were collected from young adult (1-2 years) and old (>8 years) sheep anesthetized with thiopentone sodium. TTR in old sheep CSF was low compared to young (n = 4 each); however, CP messenger RNA (mRNA) for TTR did not change. CPs were perfused with Ringer containing 14C-leucine to assess de novo protein synthesis, or with 125I-T4 to assess T4 transport. Protein synthesis, including TTR, was reduced in old sheep CP and in newly secreted CSF. 125I-T4 Vmax and Kd (but not Km) were reduced in old sheep CP. These age-related changes suggest reduced capacity of CP to maintain CSF T4 homeostasis and could also reduce chelation of beta-amyloid and be an added risk for Alzheimer's disease.

Stretch-induced regional mechanoelectric dispersion and arrhythmia in the right ventricle of anesthetized lambs.

Regional mechanical and electrophysiological changes accompany most ventricular arrhythmias and, it has been suggested, by mechanoelectric feedback. We hypothesized that an intervention producing regional mechanical dispersion was associated with regional, proarrhythmic electrical dispersion and studied the regional mechanoelectric feedback in the right ventricle (RV) of anesthetized lambs. Ten lambs were deeply anesthetized, and their hearts were exposed. Three tripodal devices, each incorporating three monophasic action potential electrodes and an integrated strain-gauge system, were placed on the RV apex outflow and inflow regions. Measurements were made before, during, and after 10-s pulmonary arterial occlusion. Pulmonary arterial occlusion increased RV pressure and overall regional segment length. Length excursion became out of phase with RV pressure beats immediately after occlusion, and the strain patterns were different in the three regions at the peak of occlusion. The occlusion resulted in different alterations in regional monophasic action potential morphology, including reduction in monophasic action potential amplitude and duration by different amounts and early afterdepolarizations that were unevenly distributed in the monophasic action potential recordings. This was associated with dispersion of repolarization and recovery time. The combination of electromechanical events precipitated a variety of arrhythmias. Acute RV distension is proarrhythmic, possibly through a causal relationship among mechanically induced afterdepolarizations, dispersion (heterogeneity) of mechanical strain, and dispersion of electrical recovery. The relationship among the different wall motions, the dispersion of repolarization, and arrhythmia underscored mechanoelectric feedback as an important part of arrhythmogenesis in pulmonary embolism and commotio cordis.

Results after rectal cancer resection with in-continuity partial vaginectomy and total mesorectal excision.

BACKGROUND: Although sharp mesorectal excision reduces circumferential margin involvement and local recurrence, a concomitant partial vaginectomy may be required in women with locally advanced rectal cancer. METHODS: Sixty-four patients requiring a partial vaginectomy during resection of primary rectal cancer were identified. Survival was determined by the Kaplan-Meier method, and distributions were compared by the log-rank test. RESULTS: Locally advanced disease was reflected by presentation with malignant rectovaginal fistulae (n = 6) or cancers described as bulky or adherent/tethered to the rectovaginal septum (n = 32). Thirty-five patients received adjuvant radiation with or without chemotherapy. At a median follow-up of 22 months, 27 (42%) patients developed recurrent disease, with most of these occurring at distant sites. The 5-year overall survival was 46%, with a median survival of 44 months. The 2-year local recurrence-free survival was 84%. The crude local failure rate was 16% (10 of 64), and local recurrence was more common in patients with a positive as opposed to a negative microscopic margin (2 [50%] of 4 vs. 8 [13%] of 60, respectively). Positive nodal status had a significant effect on overall survival (P <.001). CONCLUSIONS: Partial vaginectomy is indicated for locally advanced rectal cancers involving the vagina. The results are most favorable in patients with negative surgical margins and node-negative disease.

Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers.

BACKGROUND AND AIMS: To evaluate the clinical outcome of selected patients with distal rectal cancer treated by preoperative radiation with or without chemotherapy and full-thickness local excision (FTLE). PATIENTS AND METHODS: Ten patients with invasive distal rectal cancer (six T2, four T3) were treated with preoperative radiotherapy (3600-5040 cGy) with or without 5-fluorouracil based chemotherapy. FTLE was performed 4-6 weeks after completion of radiotherapy, primarily because of comorbid diseases or patient refusal of a permanent colostomy. Median follow-up was 28.5 months. RESULTS: There were no prolonged wound complications, and only one positive microscopic margin was detected. Among three cases of complete pathological response, two remain without evidence of disease. All patients retained sphincter function and avoided creation of a stoma. Two patients developed recurrence, one with widespread disease including pelvic recurrence 26 months after surgery and the other with distant disease only at 23 months. There were four deaths: two unrelated to cancer, one of undetermined cause after 7 years, and one after widespread recurrence at 26 months, with death 4 months later. Two-year actuarial survival was 78%. CONCLUSIONS: This pilot study demonstrates that preoperative radiotherapy and FTLE avoids major abdominal surgery yet facilitates sphincter preservation, excision with negative margins, and short-term local control in selected patients with distal rectal cancer.

Impact of a surgeon-trained observer on accuracy of colorectal surgical site infection rates.

PURPOSE: The aims of this study were 1) to establish accurate and reproducible baseline surgical site infection rates for our department and 2) to identify risk factors associated with surgical site infection in patients undergoing surgery on a colorectal service. METHODS: Phase I--Surgical site infection grading between the surgeon-trainer and the observer-trainee was validated using a four-point scale for wound evaluation previously used by our institution. Phase II--Patients undergoing colorectal surgery were prospectively monitored. The observed surgical site infection rate was compared with morbidity and mortality reports. Patient and perioperative variables were analyzed for their effect on surgical site infection using the chi-squared test. Risk factors approaching significance on univariate analysis (P < 0.2) were entered into a multivariate stepwise logistic regression model. RESULTS: Concordance on surgical site infection grading between the surgeon-trainer and the observer-trainee improved from an initial 79 percent to 96 percent during the validation period. The surgeon-trained observer reported a surgical site infection rate of 7.2 percent vs. a morbidity and mortality reported rate of 3.3 percent. Among the variables examined, obesity and surgical procedure category were significantly associated with surgical site infection rates. The effect of prophylactic antibiotics and prior chemotherapy, radiation, or steroid therapy on surgical site infection rates approached significance. A logistic regression analysis incorporating these risk factors for surgical site infection accurately predicted infection status 93 percent of the time. CONCLUSION: Use of a surgeon-trained observer doubles the detection rate of postoperative surgical site infection. Accurate, prospective assessment identifies risk factors significantly associated with increased surgical site infection rates in colorectal surgical patients.

Limitations of family cancer history assessment at initial surgical consultation.

PURPOSE: Although important for the diagnosis of familial clustering of colorectal cancer and hereditary nonpolyposis colorectal cancer, the accuracy of familial cancer history assessment in the office setting has been questioned. Furthermore, there are few publications describing the optimal method for accurately capturing a family cancer history. The purpose of this study was to determine how well family cancer history is assessed in patients with early age-of-onset colorectal cancer at initial surgical consultation compared with a telephone interview and mailed questionnaire. METHODS: Medical records of patients 40 years old or younger at the time of colorectal cancer surgery were reviewed for documentation of family cancer history at initial surgical consultation. In addition, family cancer history was solicited from surviving patients or their next of kin by telephone and a mailed questionnaire. The kappa coefficient was used to measure degree of correlation between family cancer history obtained at initial surgical consultation and subsequent telephone interview and questionnaire. RESULTS: One hundred twenty-five patients were available for analysis. Family cancer history was documented on the initial surgical consultation report in 78 percent of cases. Although 31.2 percent were identified as having no family cancer history at initial surgical consultation, this proportion decreased to 13.5 percent after telephone interviews and questionnaires. Family history assessment at initial surgical consultation also failed to identify 7 of 11 individuals meeting Amsterdam criteria for hereditary nonpolyposis colorectal cancer and 10 of 16 individuals meeting modified clinical criteria for hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Although family cancer history was commonly obtained during the initial surgical consultation of patients with colorectal cancer, there was a tendency to underestimate the extent of familial cancer. A telephone interview and questionnaire conducted at a later date may reveal a more comprehensive family cancer history. This is an important observation, because individuals identified as high-risk for hereditary nonpolyposis colorectal cancer or familial clustering of colorectal cancer require special consideration with respect to screening, surveillance, and surgical management.

The role of adjuvant therapy after liver resection for colorectal cancer metastases.

Intrahepatic recurrence is common after major resection for colorectal cancer (CRC) metastases to the liver. In this review, the available data on different adjuvant therapies from systemic chemotherapy to regional approaches by direct perfusion of chemotherapeutic agents via the hepatic artery and portal vein will be discussed. Intraperitoneal administration of chemotherapy is another form of regional therapy. Novel approaches with immunotherapy and trials of neoadjuvant therapy in association with resection of CRC hepatic metastases have also been reported. The purpose of this review is to outline these various strategies and their role in combination with resection of CRC liver metastases. Although improved hepatic disease-free survival has been demonstrated with some strategies, overall survival is minimally affected and recurrence of metastatic disease at distant sites is still a major problem. Therefore, future directions should incorporate the use of new systemic agents effective against CRC metastases. Identification of subgroups through clinical features, molecular markers, proteins, or specific tumor properties may also help to individualize treatment.

Prospective assessment of primary rectal cancer response to preoperative radiation and chemotherapy using 18-fluorodeoxyglucose positron emission tomography.

PURPOSE: The purpose of this prospective study was to determine the ability of fluorine-18 fluorodeoxyglucose positron emission tomography to assess extent of pathologically confirmed rectal cancer response to preoperative radiation and 5-fluorouracil-based chemotherapy. METHODS: Patients with primary rectal cancer deemed eligible for preoperative radiation and 5-fluorouracil-based chemotherapy because of a clinically bulky or tethered tumor or endorectal ultrasound evidence of T3 and/or N1 were prospectively enrolled. Positron emission tomography and CT scans were obtained before preoperative radiation and 5-fluorouracil-based chemotherapy (5,040 cGy to the pelvis and 2 cycles of bolus 5-fluorouracil with leucovorin) and repeated four to five weeks after completion of radiation and 5-fluorouracil-based chemotherapy. In addition to routine pathologic staging, detailed assessment of rectal cancer response to preoperative radiation and 5-fluorouracil-based chemotherapy was performed independently by two pathologists. Positron emission tomography parameters studied included conventional measures such as standardized uptake value (average and maximum), positron emission tomography-derived tumor volume (size), and two novel parameters: visual response score and change in total lesion glycolysis. RESULTS: Of 21 patients enrolled, prospective data (pretreatment and posttreatment positron emission tomography, and complete pathologic assessment) were available on 15 patients. All 15 demonstrated pathologic response to preoperative radiation and 5-fluorouracil-based chemotherapy. This was confirmed in 100 percent of the cases by positron emission tomography compared with 78 percent (7/9) by CT. In addition, one positron emission tomography parameter (visual response score) accurately estimated the extent of pathologic response in 60 percent (9/15) of cases compared with 22 percent (2/9) of cases with CT. CONCLUSIONS: This pilot study demonstrates that fluorine-18 fluorodeoxyglucose positron emission tomography imaging adds incremental information to the preoperative assessment of patients with rectal cancer. However, further studies in a larger series of patients are needed to verify these findings and to determine the value of fluorine-18 fluorodeoxyglucose positron emission tomography in a preoperative strategy aimed at identifying patients suitable for sphincter-preserving rectal cancer surgery.

Acute abdominal pain and urgency to defecate in the young and the old: a useful symptom-complex?

In the belief that "pattern recognition" is an important first step of the diagnostic process, we report our observation of an uncommon and heretofore poorly documented symptom-complex in 10 patients, and suggest that the constellation of abdominal pain and urgency to defecate in the acutely ill surgical patient should raise the diagnostic possibility of intra-abdominal bleeding. In our experience, this is statistically likely to be associated with a ruptured abdominal aortic aneurysm in the old and a ruptured ectopic pregnancy in the young.

Surgical management of primary colorectal cancer.

Surgery for potentially curable colorectal cancer most commonly involves resection of the primary tumor and regional lymph nodes. However, the site, extent and presentation of disease have an impact on surgical strategy and the use of combined modality therapy. For colon cancer, complex presentations such as obstructing or perforated colon cancer may influence surgical therapy, and issues pertaining to en bloc resection and oophorectomy remain unresolved. For rectal cancer, surgical management may range from local excision to radical resection. Extent of resection and relatively new operative techniques such as coloanal anastomosis with or without a colonic pouch reservoir are directed towards optimizing both oncologic and functional results.