Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence.

Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1-3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid-distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22-producing T cells to orchestrate immune protection in the intestine.

A phase II randomized double blinded trial evaluating the efficacy of curcumin with pre-operative chemoradiation for rectal cancer.

Background: In vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome. Methods: From 2008-2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m2 twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood samples taken pre- and 1-hour post-ingestion and tissue biopsies (both collected at CRT week 2) were analyzed for pharmacokinetics. The primary outcome was surgical pCR rate. Results: Of 22 enrolled patients, 15 received curcumin. Median age was 61 years and the majority were male (n=13; 59%). The median serum curcumin concentrations before (3.04 ng/mL; range, 1.24-18.88 ng/mL) and 1 hour after (3.32 ng/mL; range, 0.84-5.36 ng/mL) curcumin intake did not differ significantly (P=0.33). Serum curcumin concentrations both increased and decreased 1-hour post-administration (range as percentage of baseline: 8.8-258.1%). Twelve curcumin patient tissue biopsies had median curcumin concentration of 33.7 ng/mg tissue (range, 0.1-4,765.7 ng/mg). Two placebo and 1 curcumin patient achieved pCRs (P=0.18). One grade 3 toxicity (infection) was experienced. Conclusions: The addition of curcumin to CRT did not increase pCR rates for LARC patients. The unpredictable bioavailability of curcumin contributes to continued uncertainties regarding curcumin efficacy. Trial Registration: ClinicalTrials.gov identifier: NCT00745134.

Pilot study of neurologic toxicity in mice after proton minibeam therapy.

Proton minibeams (MBs) comprised of parallel planar beamlets were evaluated for their ability to spare healthy brain compared to proton broad beams (BBs). Juvenile mice were given partial brain irradiation of 10 or 30 Gy integral dose using 100 MeV protons configured either as BBs or arrays of 0.3-mm planar MBs spaced 1.0 mm apart on center. Neurologic toxicity was evaluated during an 8-month surveillance: no overt constitutional or neurologic dysfunction was noted for any study animals. Less acute epilation was observed in MB than BB mice. Persistent chronic inflammation was noted along the entire BB path in BB mice whereas inflammation was confined to just within the MB peak regions in MB mice. The potential neurologic sparing, possibly via reduced volume of chronic inflammation, offers a compelling rationale for clinical advancement of this proton technique.

Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma.

BACKGROUND AND PURPOSE: This study documents the utilization and efficacy of proton beam therapy (PBT) in western patients with localized unresectable hepatocellular carcinoma (HCC). METHODS AND METHODS: Forty-six patients with HCC, Child-Pugh class of A or B, no prior radiotherapy history, and ECOG performance status 0-2 received PBT at our institution from 2007 to 2016. Radiographic control within the PBT field (local control, LC) and overall survival (OS) were calculated from the start of PBT. RESULTS: Most (83%) patients had Child-Pugh class A. Median tumor size was 6 cm (range, 1.5-21.0 cm); 22% of patients had multiple tumors and 28% had tumor vascular thrombosis. Twenty-five (54%) patients received prior treatment. Median biologically effective dose (BED) was 97.7 GyE (range, 33.6-144 GyE) administered in 15 fractions. Actuarial 2-year LC and OS rates were 81% and 62% respectively; median OS was 30.7 months. Out-of-field intrahepatic failure was the most common site of disease progression. Patients receiving BED ≥90 GyE had a significantly better OS than those receiving BED <90 GyE (49.9 vs. 15.8 months, p = 0.037). A trend toward 2-year LC improvement was observed in patients receiving BED ≥90 GyE compared with those receiving BED <90 GyE (92% vs. 63%, p = 0.096). On multivariate analysis, higher BED (p = 0.023; hazard ratio = 0.308) significantly predicted improved OS. Six (13%) patients experienced acute grade 3 toxicity. CONCLUSIONS: High-dose PBT is associated with high rates of LC and OS for unresectable HCC. Dose escalation may further improve outcomes.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis.

PURPOSE: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. METHODS AND MATERIALS: From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. RESULTS: The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. CONCLUSIONS: CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.

Does Unintentional Splenic Radiation Predict Outcomes After Pancreatic Cancer Radiation Therapy?

PURPOSE: To determine whether severity of lymphopenia is dependent on radiation dose and fractional volume of spleen irradiated unintentionally during definitive chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC). METHODS: 177 patients with LAPC received induction chemotherapy (mainly gemcitabine-based regimens) followed by CRT (median 50.4 Gy with concurrent capecitabine) from January 2006 to December 2012. Absolute lymphocyte count (ALC) was recorded at baseline, before CRT, and 2 to 10 weeks after CRT. Splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and percentage of splenic volume receiving at least 5- (V5), 10- (V10), 15- (V15), and 20-Gy (V20) dose. Overall survival (OS) was analyzed with use of the Cox model, and development of post-CRT severe lymphopenia (ALC <0.5 K/UL) was assessed by multivariate logistic regression with use of baseline and treatment factors. RESULTS: The median post-CRT ALC (0.68 K/UL; range, 0.13-2.72) was significantly lower than both baseline ALC (1.42 K/UL; range, 0.34-3.97; P<.0001) and pre-CRT ALC (1.32 K/UL, range 0.36-4.82; P<.0001). Post-CRT ALC <0.5 K/UL was associated with inferior OS on univariate analysis (median, 11.1 vs 15.3 months; P=.01) and multivariate analysis (hazard ratio = 1.66, P=.01). MSD (9.8 vs 6 Gy, P=.03), median V10 (32.6 vs 16%, P=.04), V15 (23.2 vs 9.5%, P=.03), and V20 (15.4 vs 4.6%, P=.02) were significantly higher in patients with severe lymphopenia than in those without. On multivariate analysis, postinduction lymphopenia (P<.001; odds ratio [OR] = 5.25) and MSD (P=.002; OR= 3.42) were independent predictors for the development of severe post-CRT lymphopenia. CONCLUSION: Severe post-CRT lymphopenia is an independent predictor of poor OS in LAPC patients receiving CRT. Higher splenic doses increase the risk for the development of severe post-CRT lymphopenia. When clinically indicated, assessment of splenic DVHs before the acceptance of treatment plans may minimize the risk of severe post-CRT lymphopenia.

Recent Advances and Prospects for Multimodality Therapy in Pancreatic Cancer.

The outcomes for treatment of pancreatic cancer have not improved dramatically in many decades. However, the recent promising results with combination chemotherapy regimens for metastatic disease increase optimism for future treatments. With greater control of overt or occult metastatic disease, there will likely be an expanding role for local treatment modalities, especially given that nearly a third of pancreatic cancer patients have locally destructive disease without distant metastatic disease at the time of death. Technical advances have allowed for the safe delivery of dose-escalated radiation therapy, which can then be combined with chemotherapy, targeted agents, immunotherapy, and nanoparticulate drug delivery techniques to produce novel and improved synergistic effects. Here we discuss recent advances and future directions for multimodality therapy in pancreatic cancer.

Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer.

PURPOSE: To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. METHODS: Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. RESULTS: Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. CONCLUSIONS: This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.

Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation.

PURPOSE: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. METHODS AND MATERIALS: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume was treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. RESULTS: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. CONCLUSION: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.

Hyperthermia using nanoparticles--Promises and pitfalls.

An ever-increasing body of literature affirms the physical and biological basis for sensitisation of tumours to conventional therapies such as chemotherapy and radiation therapy by mild temperature hyperthermia. This knowledge has fuelled the efforts to attain, maintain, measure and monitor temperature via technological advances. A relatively new entrant in the field of hyperthermia is nanotechnology which capitalises on locally injected or systemically administered nanoparticles that are activated by extrinsic energy sources to generate heat. This review describes the kinds of nanoparticles available for hyperthermia generation, their activation sources, their characteristics, and the unique opportunities and challenges with nanoparticle-mediated hyperthermia.

Paraneoplastic thrombocytosis independently predicts poor prognosis in patients with locally advanced pancreatic cancer.

BACKGROUND AND AIMS: Platelets are believed to promote tumor growth and metastasis but their prognostic role in locally advanced pancreatic cancer (LAPC) remains largely unknown. We assessed whether pretreatment platelet counts independently predict survival outcomes in patients with LAPC treated with chemoradiation (CRT). METHODS: We retrospectively reviewed the MD Anderson pancreatic cancer database and identified 199 patients with LAPC treated with CRT between 2006 and 2012. Induction chemotherapy was used prior to consolidative CRT in 177 (89%) patients. Median radiation dose was 50.4 Gy. Concurrent radiosensitizers were gemcitabine-based (13%) or capecitabine-based (84%) regimens. Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for overall survival (OS) and progression-free survival (PFS) calculated from the start of treatment. RESULTS: Median follow-up was 9.9 months. Median OS and PFS durations were 17.7 and 10.7 months, respectively. On univariate analysis, platelet count > 300 K/µl, KPS ≤ 80, ≥ 5% weight loss and pretreatment CA19-9 above the median were associated with inferior OS or PFS. Median OS was lower in patients with platelet count > 300 K/µl compared to patients with platelet count ≤ 300 K/µl (10.2 vs. 19 months; p = 0.0002). Corresponding median PFS times were 7.8 months and 11.1 months (p = 0.004), respectively. On multivariate analysis, platelet count > 300 K/µl (p = 0.012), ≥ 5% weight loss (p = 0.002) and elevated pretreatment CA19-9 (p = 0.005) were independent prognostic factors for OS. Platelet count > 300 K/µl (p = 0.03) and KPS ≤ 80 (p = 0.05) independently predicted PFS. CONCLUSIONS: Our analysis suggests that pretreatment thrombocytosis independently predicts inferior OS and PFS in LAPC.