Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. Findings We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15–33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Background Standardized future liver remnant (sFLR) volume and degree of hypertrophy after portal vein embolization (PVE) have been recognized as significant predictors of surgical outcomes after major liver resection. However, regeneration rate of the FLR after PVE varies among individuals and its clinical significance is unknown. Study Design Degree of hypertrophy at initial volume assessment divided by number of weeks elapsed after PVE was defined as the kinetic growth rate (KGR). In 107 consecutive patients who underwent liver resection for colorectal liver metastases with a sFLR volume of greater than 20%, the ability of the KGR to predict overall and liver-specific postoperative morbidity and mortality was compared with sFLR volume and degree of hypertrophy. Results Using receiver operating characteristic analysis, the best cut-off values for sFLR volume, degree of hypertrophy, and KGR for predicting postoperative hepatic insufficiency were estimated as, respectively, 29.6%, 7.5%, and 2.0% per week. Among these, KGR was the most accurate predictor (area under the curve, 0.830 [0.736-0.923]; asymptotic significance, 0.002). KGR of less than 2% per week vs. ≥2% per week correlate with rates of hepatic insufficiency (21.6% vs. 0%, p = 0.0001) and liver-related 90-day mortality (8.1% vs. 0%, P=0.04). The predictive value of KGR was not influenced by sFLR volume or the timing of initial volume assessment when evaluated within 8 weeks after PVE. Conclusions KGR is a better predictor of postoperative morbidity and mortality after liver resection for small FLR than conventional measured volume parameters (sFLR volume and degree of hypertrophy).

Background The primary reported indication for the Associating Liver Partition with Portal vein Ligation for Staged hepatectomy (ALPPS) technique is in patients with very low future liver remnant volumes. Given the elevated incidence of major morbidity (40%) and liver-related mortality (12%) with ALPPS, we sought to determine the safety and efficacy of percutaneous portal vein embolization (PVE) in a similar patient population. Patients and Methods Tumor resectability and morbidity/mortality rates were reviewed for 144 consecutive liver tumor patients with future liver remnant to body weight ratios (LR/BW) less than 0.5%. All patients were referred for preoperative percutaneous right plus segment IV PVE using embolic microspheres, with planned reassessment of the LR/BW 30 days after PVE. Post-PVE outcomes were compared to reported outcomes for ALPPS. Results Percutaneous PVE was successfully performed in 141 of the 144 study patients (97.9%). Adequate regeneration was observed in 139 patients (98.5%) with median post-PVE LR/BW rising from 0.33% to 0.52% (p<0.0001), representing a per-patient median regeneration of 62% (range: 0.3 – 379%). In total, 104 patients underwent extended right hepatectomy (n=102) or right hepatectomy (n=2). The remaining 40 patients (27.8%) were not resectable due to short-interval disease progression (27 patients, 18.5%), insufficient liver regeneration (5 patients, 3.5%), and medical comorbidities (8 patients, 5.6%). After resection, the following outcomes were observed: major morbidity: 33.0% (34/104), liver insufficiency: 12.5% (13/104), and 90-day liver-related mortality: 5.8% (6/104). These oncologic and technical results compare favorably to those of ALPPS. Conclusion Based on its ability to select oncologically resectable patients and superior safety and efficacy profiles, percutaneous right+segment IV PVE and interval surgery remains the standard of care for patients with very low future liver remnant volumes.

Purpose A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. Methods A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%–79%, no agreement ≤ 49%). Results Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100–120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). Conclusion Practitioners are encouraged to work towards adoption of these recommendations.

Background The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. Results Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Trial registration ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011. Electronic supplementary material The online version of this article (10.1186/s13058-019-1154-8) contains supplementary material, which is available to authorized users.

Background Patients with colorectal liver metastases (CLM) are increasingly treated with preoperative chemotherapy. Chemotherapy associated liver injury is associated with postoperative hepatic insufficiency (PHI) and mortality. The adequate minimum future liver remnant (FLR) volume in patients treated with extensive chemotherapy remains unknown. Methods All patients with standardized FLR >20 %, who underwent extended right hepatectomy for CLM from 1993–2011, were divided into three cohorts by chemotherapy duration: no chemotherapy (NC, n = 30), short duration (SD, ≤12 weeks, n = 78), long duration (LD, >12 weeks, n = 86). PHI and mortality were compared by using uni-/multivariate analyses. Optimal FLR for LD chemotherapy was determined using a minimum p-value approach. Results A total of 194 patients met inclusion criteria. LD chemotherapy was significantly associated with PHI (NC + SD 3.7 vs. LD 16.3%, p = 0.006). Ninety-day mortality rates were 0 % in NC, 1.3 % in SD, and 2.3% in LD patients, respectively (p = 0.95). In patients with FLR >30 %, PHI occurred in only two patients (both LD, 2/20, 10 %), but all patients with FLR >30 % survived. The best cutoff of FLR for preventing PHI after chemotherapy >12 weeks was estimated as>30 %. Both LD chemotherapy (odds ratio [OR] 5.4, p = 0.004) and FLR ≤ 30 % (OR 6.3, p = 0.019) were independent predictors of PHI. Conclusions Preoperative chemotherapy >12 weeks increases the risk of PHI after extended right hepatectomy. In patients treated with long-duration chemotherapy, FLR >30 % reduces the rate of PHI and may provide enough functional reserve for clinical rescue if PHI develops.

No abstract

BackgroundTo assess differences between four different voxel-based dosimetry methods (VBDM) for tumor, liver, and lung absorbed doses following 90Y microsphere selective internal radiation therapy (SIRT) based on 90Y bremsstrahlung SPECT/CT, a secondary objective was to estimate the sensitivity of liver and lung absorbed doses due to differences in organ segmentation near the liver-lung interface.MethodsInvestigated VBDM were Monte Carlo (MC), soft-tissue kernel with density correction (SKD), soft-tissue kernel (SK), and local deposition (LD). Seventeen SIRT cases were analyzed. Mean absorbed doses () were calculated for tumor, non-tumoral liver (NL), and right lung (RL). Simulations with various SPECT spatial resolutions (FHWMs) and multiple lung shunt fractions (LSs) estimated the accuracy of VBDM at the liver-lung interface. Sensitivity of patient RL and NL on segmentation near the interface was assessed by excluding portions near the interface.ResultsSKD, SK, and LD were within 5 % of MC for tumor and NL . LD and SKD overestimated RL compared to MC on average by 17 and 20 %, respectively; SK underestimated RL on average by −60 %. Simulations (20 mm FWHM, 20 % LS) showed that SKD, LD, and MC were within 10 % of the truth deep (>39 mm) in the lung; SK significantly underestimated the absorbed dose deep in the lung by approximately −70 %. All VBDM were within 10 % of truth deep (>12 mm) in the liver. Excluding 1, 2, and 3 cm of RL near the interface changed the resulting RL by −22, −38, and −48 %, respectively, for all VBDM. An average change of −7 % in the NL was realized when excluding 3 cm of NL from the interface. was realized when excluding 3 cm of NL from the interface.ConclusionsSKD, SK, and LD are equivalent to MC for tumor and NL . SK underestimates RL relative to MC whereas LD and SKD overestimate. RL is strongly influenced by the liver-lung interface.