Generation time and fitness tradeoffs during the evolution of multicellularity.

The evolution of multicellular organisms from their unicellular ancestors is an example of an evolutionary transition in individuality (ETI), i.e. a change in the units of selection and adaptation. The theory of ETIs poses particular challenges because, by definition, key theoretical constructs such as fitness are shifting during an ETI. Past work emphasized the importance of life history tradeoffs during ETIs in which lower level units form groups and become individuals at a higher level. In particular, it has been hypothesized that the convexity of the lower-level tradeoff between viability and fecundity changes with group size and determines the optimality of lower-level specialization in the fitness components of the group. This is important because lower-level specialization is a key indicator of higher-level individuality. Here we show that increasing generation time can increase the convexity of the lower-level viability-fecundity tradeoff. This effect is a novel hypothesis for the positive association between cell-group size and cellular specialization in a major model system for ETIs, the volvocine algae. The pattern in this clade is thought to be an example of a more general size-complexity rule. Our hypothesis is that larger groups have longer generation times and longer generation times lead to more convex lower-level viability-fecundity tradeoffs, which could account for specialization being optimal only in larger cell groups (colonies). We discuss the robustness of this effect to various changes in the assumptions of our model. Our work is important for the study of ETIs in general because viability and fecundity are fundamental components of fitness in all systems and because generation time is expected to be changing during many ETIs.

Models of cell division initiation in Chlamydomonas: A challenge to the consensus view.

We develop and compare two models for division initiation in cells of the unicellular green alga Chlamydomonas reinhardtii, a topic that has remained controversial in spite of years of empirical work. Achieving a better understanding of C. reinhardtii cell cycle regulation is important because this species is used in studies of fundamental eukaryotic cell features and in studies of the evolution of multicellularity. C. reinhardtii proliferates asexually by multiple fission, interspersing rapid rounds of symmetric division with prolonged periods of growth. Our Model 1 reflects major elements of the current consensus view on C. reinhardtii division initiation, with cells first growing to a specific size, then waiting for a particular time prior to division initiation. In Model 2, our proposed alternative, growing cells divide when they have reached a growth-rate-dependent target size. The two models imply a number of different empirical patterns. We highlight these differences alongside published data, which currently fall short of unequivocally distinguishing these differences in predicted cell behavior. Nevertheless, several lines of evidence are suggestive of more Model 2-like behavior than Model 1-like behavior. Our specification of these models adds rigor to issues that have too often been worked out in relation to loose, verbal models and is directly relevant to future development of informative experiments.

Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.

BACKGROUND: Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. METHODS: In this 2 × 2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. FINDINGS: We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5.1 years (IQR 3.9-6.9). 391 of 432 (90.5%) patients in the mitomycin group versus 386 of 431 (89.6%) in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1; p=0.64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0.95, 95% CI 0.75-1.21; p=0.70). INTERPRETATION: The results of our trial--the largest in anal cancer to date--show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. FUNDING: Cancer Research UK.

EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer.

PURPOSE: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. METHODS AND MATERIALS: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m2) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m2 b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. RESULTS: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. CONCLUSIONS: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.

A multicenter phase II study of G17DT immunogen plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan.

BACKGROUND: The G17DT is a novel human immunogen that raises antibodies to the growth factor gastrin 17 (G17). The purpose of this study was to determine the safety and efficacy of G17DT in combination with irinotecan in patients refractory to irinotecan, and to correlate efficacy with anti-G17 immune response. METHODS: Patients received G17DT immunogen as a single intramuscular injection of 500 µg at weeks 1, 5, 9, and 26. Irinotecan was administered as an intravenous infusion of 125 mg/m(2) over 90 min starting at week 5. Each cycle of treatment consisted of irinotecan administered once weekly for 4 weeks, followed by a 2-week rest period. RESULTS: Of 161 patients who received G17DT, the best overall tumor response in the intent-to-treat population was complete response 0 (0 %), partial response 3 (3 %), stable disease 32 (32 %), and progressive disease 64 (65 %). Median survival was 217 days. About 94 (62 %) subjects evaluable for antibody titers were anti-G17 responders. Survival was significantly longer for anti-G17 responders compared with non-responders (9.0 vs. 5.6 months; P < 0.001). Toxicity was consistent with irinotecan (diarrhea, nausea, anemia, vomiting, fatigue, constipation, anorexia, and neutropenia) except for injection site reactions (pain 42 %, induration 13 %, edema 11 %, erythema 10 %, and three abscesses) attributed to G17DT in 52 % of the patients. CONCLUSION: Treatment with G17DT in combination with irinotecan results in an acceptable anti-G17 immune response, which correlated with promising survival activity in patients refractory to irinotecan-based chemotherapy.

Small cell carcinoma of the anus: a case report.

Small cell carcinoma of the anus is a very rare but aggressive tumour. We present a case of a 60-year old lady with small cell carcinoma of the anus. She had no metastatic disease on presentation. She had chemotherapy and radiotherapy but developed distant metastasis after completion of treatment. Immunohistochemistry is required to make a diagnosis. Chemotherapy remains the mainstay of treatment for small cell carcinoma of the anus with or without metastatic disease. Radiotherapy is for local control and relief of symptoms.

A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study.

BACKGROUND: In patients with advanced (stage IIIb/IV) NSCLC, the addition of cetuximab to chemotherapy has demonstrated increased activity compared with chemotherapy alone. Furthermore, the addition of cetuximab to RT in patients with locally advanced squamous cell head & neck carcinoma significantly prolongs the duration of locoregional control and median overall survival compared to radiotherapy alone. Therefore, the SCRATCH study was designed to assess the safety of synchronous cetuximab with radical RT in patients with Stage III NSCLC. The safety results of cohort 1 from this phase I study are presented below. METHODS: Twelve patients with inoperable stage III NSCLC were enrolled into cohort I. Inclusion criteria were performance status 0-1, adequate organ function, and disease encompassable within a radical RT volume. Exclusion criteria were previous malignancy, thoracic RT or treatment with EGFR (epidermal growth factor receptor) targeted therapy. Patients received platinum-based induction chemotherapy, followed by weekly intravenous cetuximab (initial dose 400mg/m2; maintenance dose 250 mg/m2) and concomitant Rt (64Gy/32 fractions/45 days). The primary end-point was toxicity. NCI Common Toxicity Criteria (CTC) V3.0 assessments were preformed weekly during radiotherapy, and at regular follow-up visits. RESULTS: 9 out of 12 patients completed the concomitant therapy as planned, with no dose reductions. 3 patients did not complete the full schedule. One died from bronchopneumonia mid-treatment; one experienced grade 3 lethargy following the first cetuximab dose and declined further cetuximab; one experienced a grade 2 skin reaction following the third dose of cetuximab and declined further treatment. On follow-up only one patient has developed a grade III reaction - pneumonitis - which settled on steroids with intermittent oxygen. Three patients have died on follow-up (2 from disease progression and one from thromboembolic disease). Of the 12 patients entered ito the study, 8 have survived at least 1 year, measured from the first day of induction chemotherapy. CONCLUSION: The results suggest that the early and late toxicities of synchronous cetuximab and radical RT are acceptable.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research.

PURPOSE: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. PATIENTS AND METHODS: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status