Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.

There is growing interest in the investigation of ketogenic diets as a potential therapy for bipolar disorder. The overlapping pharmacotherapies utilized for both bipolar disorder and seizures suggest that a mechanistic overlap may exist between these conditions, with fasting and the ketogenic diet representing the most time-proven therapies for seizure control. Recently, preliminary evidence has begun to emerge supporting a potential role for ketogenic diets in treating bipolar disorder. Notably, some patients may struggle to initiate a strict diet in the midst of a mood episode or significant life stressors. The key question addressed by this pilot clinical trial protocol is if benefits can be achieved with a less restrictive diet, as this would allow such an intervention to be accessible for more patients. Recent development of so-called ketone esters, that once ingested is converted to natural ketone bodies, combined with low glycemic index dietary changes has the potential to mimic two foundational components of therapeutic ketosis: high levels of ketones and minimal spiking of glucose/insulin. This pilot clinical trial protocol thus aims to investigate the effect of a 'ketogenic-mimicking diet' (combining supplementation of ketone esters with a low glycemic index dietary intervention) on neural network stability, mood, and biomarker outcomes in the setting of bipolar disorder. Positive findings obtained via this pilot clinical trial protocol may support future target engagement studies of ketogenic-mimicking diets or related ketogenic interventions. A lack of positive findings, in contrast, may justify a focus on more strict dietary interventions for future research.

Four Biomarkers Linked to Activation of Cluster of Differentiation 8-Positive Lymphocytes Predict Clinical Outcomes in Pediatric Acute Liver Failure.

BACKGROUND AND AIMS: Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. APPROACH AND RESULTS: Among 47 PALF study participants, 12 IAMs collected ≤6 days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8+ ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n = 10), medium (n = 15), and low IAM (n = 22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P < 0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8 mg/dL, P < 0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P = 0.002); no deaths were reported. In an independent validation cohort (n = 71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile. CONCLUSION: Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.

1kW fiber-coupled pump-module at 976nm with 50% efficiency.

We present a fiber-coupled pump-module emitting more than 1kW of mode-stripped power at 976nm from a detachable 225µm, 0.22NA fiber. The electrical-to-optical efficiency at 1kW is ~50%. Six of these pump modules attached to a (6 + 1):1 multimode combiner enable a 5-6kW, single-mode, Yb-doped fiber amplifier.

The Noncell Autonomous Requirement of Proboscipedia for Growth and Differentiation of the Distal Maxillary Palp during Metamorphosis of Drosophila melanogaster.

The Drosophila maxillary palpus that develops during metamorphosis is composed of two elements: the proximal maxillary socket and distal maxillary palp. The HOX protein, Proboscipedia (PB), was required for development of the proximal maxillary socket and distal maxillary palp. For growth and differentiation of the distal maxillary palp, PB was required in the cells of, or close to, the maxillary socket, as well as the cells of the distal maxillary palp. Therefore, PB is required in cells outside the distal maxillary palp for the expression, by some mechanism, of a growth factor or factors that promote the growth of the distal maxillary palp. Both wingless (wg) and hedgehog (hh) genes were expressed in cells outside the distal maxillary palp in the lancinia and maxillary socket, respectively. Both wg and hh were required for distal maxillary palp growth, and hh was required noncell autonomously for distal maxillary palp growth. However, expression of wg-GAL4 and hh-GAL4 during maxillary palp differentiation did not require PB, ruling out a direct role for PB in the regulation of transcription of these growth factors.

Inhibition of MT1-MMP proteolytic function and ERK1/2 signalling influences cell migration and invasion through changes in MMP-2 and MMP-9 levels.

Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14) is a unique protease that cleaves extracellular proteins, activates proMMPs, and initiates intracellular signalling. MCF-7 cells are non-invasive and deficient in MT1-MMP, MMP-2, and MMP-9 expression. We created an MCF-7 cell line (C2) that stably produces active MT1-MMP and demonstrated increased ERK1/2 phosphorylation. MAPK inhibition in this cell line showed an inverse relationship in MMP-2 and MMP-9 transcripts where levels of these genes increased and decreased, respectively. Using invasive MDA-MB 231 cells that endogenously produce MT1-MMP and have naturally high pERK levels, we demonstrated the identical inverse relationship between MMP-2 and -9 transcript and protein levels, suggesting that this novel relationship is conserved amongst MT1-MMP positive breast cancer cells. To further analyze the relationship between MMP-2 and -9 levels, we chemically inhibited activation and catalytic activity of MT1-MMP using a furin and MMP inhibitor, respectively, to show that interference with the functions of MT1-MMP induced changes in MMP-2 and 9 transcript levels that were always inverse of each other, and likely mediated by differential transcriptional activity of the NF-κB transcription factor. Furthermore, we analyzed the functional consequences of these expression changes to show MMP, and in particular ERK, inhibition decreased migration and invasion using 2D culture, and inhibits the formation of an invasive phenotype in Matrigel 3D culture. This study demonstrated a novel inverse transcriptional relationship between MMP-2 and -9 levels and MT1-MMP activity that have functional consequences, and also showed that increases in the levels of MMPs does not necessarily correlate with an invasive phenotype.

Less is more: low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells.

BACKGROUND: Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) is a multifunctional protease implicated in metastatic progression ostensibly due to its ability to degrade extracellular matrix (ECM) components and allow migration of cells through the basement membrane. Despite in vitro studies demonstrating this principle, this knowledge has not translated into the use of MMP inhibitors (MMPi) as effective cancer therapeutics, or been corroborated by evidence of in vivo ECM degradation mediated by MT1-MMP, suggesting that our understanding of the role of MT1-MMP in cancer progression is incomplete. METHODS: MCF-7 and MDA-MB 231 breast cancer cell lines were created that stably overexpress different levels of MT1-MMP. Using 2D culture, we analyzed proMMP-2 activation (gelatin zymography), ECM degradation (fluorescent gelatin), ERK signaling (immunoblot), cell migration (transwell/scratch closure/time-lapse imaging), and viability (colorimetric substrate) to assess how different MT1-MMP levels affect these cellular parameters. We also utilized Matrigel 3D cell culture and avian embryos to examine how different levels of MT1-MMP expression affect morphological changes in 3D culture, and tumourigenecity and extravasation efficiency in vivo. RESULTS: In 2D culture, breast cancer cells expressing high levels of MT1-MMP were capable of widespread ECM degradation and TIMP-2-mediated proMMP-2 activation, but were not the most migratory. Instead, cells expressing low levels of MT1-MMP were the most migratory, and demonstrated increased viability and ERK activation. In 3D culture, MCF-7 breast cancer cells expressing low levels of MT1-MMP demonstrated an invasive protrusive phenotype, whereas cells expressing high levels of MT1-MMP demonstrated loss of colony structure and cell fragment release. Similarly, in vivo analysis demonstrated increased tumourigenecity and metastatic capability for cells expressing low levels of MT1-MMP, whereas cells expressing high levels were devoid of these qualities despite the production of functional MT1-MMP protein. CONCLUSIONS: This study demonstrates that excessive ECM degradation mediated by high levels of MT1-MMP is not associated with cell migration and tumourigenesis, while low levels of MT1-MMP promote invasion and vascularization in vivo.

Developmental competence and the induction of ectopic proboscises in Drosophila melanogaster.

Developmental competence is the response of a cell(s) to information. Determination of adult labial identity in Drosophila requires Proboscipedia (PB) and Sex combs reduced (SCR); however, co-ectopic expression of PB and SCR is not sufficient for induction of ectopic adult labial identity, because the developmental information supplied by PB and SCR is suppressed. The evolutionarily conserved LASCY, DYTQL, NANGE motifs, and the C-terminal domain of SCR are sequence elements that mediate some, or all, of the suppression of ectopic proboscis determination. Therefore, the developmentally competent primordial proboscis cells provide an environment devoid of suppression, allowing PB and SCR to determine proboscis identity. SCR derivatives lacking suppression sequences weakly induce ectopic proboscis transformations independently of PB, suggesting that SCR may be the activity required for induction of adult labial identity, as is the case for larval labial identity. A possible explanation for PB independence of SCR in determination of adult and embryonic labial identity is PB operates as a competence factor that switches SCR from determining T1 identity to labial identity during metamorphosis. Lastly, labial determination is not conserved between SCR and murine HOXA5, suggesting that SCR has acquired this activity during evolution.

Exact factorization of correlation functions in two-dimensional critical percolation.

By use of conformal field theory, we discover several exact factorizations of higher-order density correlation functions in critical two-dimensional percolation. Our formulas are valid in the upper half-plane, or any conformally equivalent region. We find excellent agreement of our results with high-precision computer simulations. There are indications that our formulas hold more generally.

A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5 FU2 + irinotecan or LV5 FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer.

BACKGROUND: To assess activity and safety of an experimental combination of irinotecan and oxaliplatin (IRINOX) as first-line treatment in advanced colorectal cancer. PATIENTS AND METHODS: In this randomized phase II trial, 80 patients were treated: arm A (IRINOX) in 40 patients received at day 1 oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) biweekly, standard arm B received a biweekly simplified folinic acid (FA) and fluorouracil (FU), FA 200 mg/m(2) in a 2-h infusion and bolus injection of 5FU 400 mg/m(2) on day 1, then a two 400 mg/m(2) continuous infusion of FU on days 1 and 2 with either oxaliplatin 85 mg/m(2) (20 patients) or irinotecan 180 mg/m(2) (20 patients). RESULTS: Twenty-one partial responses (52.5%, median duration 7.2 months) were observed with the IRINOX arm and two complete and 20 partial responses (55%, median duration 6.4 months) with arm B. Median progression-free and overall survival times were 8.4 and 19 months, respectively, in the IRINOX arm and 8.1 and 20.4 months in arm B. Main grade 3/4 toxic effects were, respectively, neutropenia 42.5% and 32.5%; febrile neutropenia 10% and 5%; diarrhea 32.5% and 7.5%; vomiting 10.0% and 5%; neurosensory toxicity 17.5% and 7.5%. CONCLUSION: The IRINOX arm has a manageable toxicity and is active.

Blue light improves cognitive performance.

A newly discovered system of photoreceptors for circadian rhythms works non-visual and responds to blue light (460 nm). We report a longitudinal study in 44 adults, showing that a significant increase in alertness and speed of information processing could be achieved by blue light as compared to normal light.

Anchored critical percolation clusters and 2D electrostatics.

We consider the densities of clusters, at the percolation point of a two-dimensional system, which are anchored in various ways to an edge. These quantities are calculated by use of conformal field theory and computer simulations. We find that they are given by simple functions of the potentials of 2D electrostatic dipoles and that a kind of superposition cum factorization applies. Our results broaden this connection, already known from previous studies, and we present evidence that it is more generally valid. An exact result similar to the Kirkwood superposition approximation emerges.

Induction cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial.

A recent phase I study showed that weekly cisplatin, irinotecan and concurrent radiotherapy can be administered with moderate toxicity in patients with oesophageal cancer. Patients with no prior treatment and oesophageal cancer stage I to III, performance status <3, caloric intake >1,500 kcal day(-1) were included. Chemotherapy, with cisplatin 30 mg m(-2) and irinotecan 60 mg m(-2), was administered at days 1, 8, 22, 29, and concurrently with radiotherapy at days 43, 50, 64 and 71. Radiotherapy was delivered with 50 or 50.4 Gy in 25 fractions/5 weeks. Forty-three patients were included, 10 stage I, 19 stage II and 14 stage III. Mean age was 59.2 years (range 44-79). A total of 30 out of 43 (69.8%) patients underwent all planned treatment. During induction chemotherapy, 14 severe toxicities of grade 3 or 4 in 10 patients (23.3%) were reported with 57.1% due to haematoxicity. During chemoradiotherapy, 31 severe toxicities of grade 3 or 4 with 64.5% due to haematotoxicity were reported in 18 patients. One toxic death occurred (diarrhoea grade 4). The complete clinical response rate was 58.1% (95% CI: 43.4-72.8%). Overall survival rate at 1 and 2 years was 62.8%, (95% CI, 58.3-77.3%) and 27.9% (95% CI, 13.4-41.3%), respectively. In conclusion, cisplatin-irinotecan-radiotherapy is an active and well-tolerated regimen feasible in out-patients.

Clinical impact of fluorine-18 fluorodeoxyglucose positron emission tomography in cancer patients. A comparative study between dedicated camera and dual-head coincidence gamma camera.

AIM: Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) can be performed using a dedicated PET scanner (PET-I) or a dual-head coincidence gamma camera (CGC-I). The aim of this study was to comparatively assess the impact of PET-I and CGC-I on clinical management in cancer patients. METHODS: From November 2000 to November 2002, PET-I and CGC-I were performed at an interval of 2 days in 151 patients with colorectal cancer (n=40), breast cancer (n=28), thyroid cancer (n=23), lung tumors (n=22), germ cell tumors (n=14), unknown primary cancer (n=7) and other cancers (n=17). PET-I and CGC-I were interpreted independently with knowledge of conventional imaging (CI). In June 2003, theoretical management, e.g. treatment modality/ies and treatment intent (curative or palliative), after CI, PET-I and CGC-I were stated during multidisciplinary sessions and were a posteriori considered as appropriate or inappropriate using pathological and follow-up data. RESULTS: The theoretical management proposed after PET-I and after CGC-I was similar in 112/151 (74%; 95% CI: 66-81%) patients. In 125 assessable patients, theoretical management after PET-I was appropriate in 86% (95% CI: 79-92%), significantly higher (P=0.0033) than after CGC-I (70%; 95% CI: 62-78%). Both proportions were also higher than after CI (46%; 95% CI: 37-56%), (P<0.0001). A similar trend for higher proportions of appropriate management after PET-I than after CGC-I was observed for each tumor localization. CONCLUSIONS: The clinical impact of PET-I is superior to that of CGC-I in a large series of cancer patients. Although CGC-I could be considered as an acceptable alternative, PET-I remains the standard and should preferably equip nuclear medicine departments.

'A phase II study of oral uracil/ftorafur (UFT) plus leucovorin combined with oxaliplatin (TEGAFOX) as first-line treatment in patients with metastatic colorectal cancer'.

This phase II trial was performed to evaluate the efficacy and tolerability of a new combination of Uracil/Ftorafur (UFT)/leucovorin (LV) and oxaliplatin in patients (pts) with metastatic colorectal cancer (MCRC) who had not received prior chemotherapy for metastatic disease. Between February 2002 and October 2002, 64 patients received UFT 300 mg m(-2) day(-1) and LV 90 mg day(-1) from day 1 to day 14 combined with oxaliplatin 130 mg m(-2) on day 1, every 3 weeks. All patients were evaluable for safety analysis and 58 of 64 patients were eligible for efficacy. Responses were reviewed by an independent review committee. Of the 58 per-protocol defined assessable patients, 1 complete response and 20 partial responses were observed yielding a response rate of 34% (95% CI: 22-47). The median response duration was 8.74 months (range 1.6-14). The median time to progression and the median survival were 5.88 months (95% CI: 4.34-8.21) and 18.2 months (95% CI: 10-20.7), respectively. Diarrhoea and peripheral neuropathy were the most frequent and predictable toxicities. These events were reversible, noncumulative and manageable. Grade 3 diarrhoea occurred in only 11% of the patients. No grade 4 gastrointestinal toxicity was reported in the study. The incidence of grade 3/4 (National Cancer Institute Common Toxicity Criteria 2: NCI-CTC 2) peripheral neuropathy was 15%. Haematological toxicity was of mild to moderate intensity with 10% of the patients with Grade 3/4 neutropenia without any episode of complication. The TEGAFOX regimen, a new combination using UFT/LV and oxaliplatin every 3 weeks is feasible on an outpatient basis. The combination is safe and active and may offer a promising alternative to the intravenous route. Nevertheless this efficacy results should be confirmed by randomized phase III trials.

High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer.

PURPOSE: The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)). RESULTS: Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2). CONCLUSION: These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.

Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients.

PURPOSE: To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FA) combination in patients with metastatic or advanced gastric cancer (M/AGC). PATIENTS AND METHODS: Of the 54 eligible patients with measurable or assessable M/AGC, 53 received oxaliplatin 100 mg/m(2) and FA 400 mg/m(2) (2-hour intravenous infusion) followed by 5-FU bolus 400 mg/m(2) (10-minute infusion) and then 5-FU 3,000 mg/m(2) (46-hour continuous infusion) every 14 days. RESULTS: Patients (69% male, 31% female) had a median age of 61 years (range, 31 to 75 years), 89% had a performance status of 0 or 1, 70% had newly diagnosed disease, and 87% had metastatic disease. All had histologically confirmed adenocarcinoma. With a median of three involved organs, disease sites included the lymph nodes (67%), stomach (65%), and liver (61%). A median of 10 cycles per patient and 468 complete cycles were administered. Best responses in the 49 assessable patients were two complete responses and 20 partial responses, giving an overall best response rate of 44.9%. Eight patients underwent complementary treatment with curative intent (six with surgery and two with chemoradiotherapy). Median follow-up, time to progression, and overall survival were 18.6 months, 6.2 months, and 8.6 months, respectively. Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia occurred in 38%, 19%, 4%, and 11% of patients, respectively, and febrile neutropenia occurred in six patients (one episode each). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. CONCLUSION: This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable safety profile in M/AGC patients, and may prove to be a suitable alternative regimen in this indication.

Localized squamous-cell cancer of the esophagus: retrospective analysis of three treatment schedules.

BACKGROUND AND PURPOSE: A retrospective study comparing chemotherapy and radiation, esophagectomy alone versus preoperative radiochemotherapy and surgery in localized squamous-cell esophageal carcinoma. MATERIALS AND METHODS: Between 1989 and 1995, 139 patients (40 stage I, 77 stage IIA and 22 stage IIB according to the UICC 78 TNM classification) were treated in two different institutions. They were divided into three groups according to the treatment proposed: E group (treatment by esophagectomy; n = 30), RCT+E group (treatment by preoperative radiochemotherapy and esophagectomy; n = 46), RCT group (treatment by radiochemotherapy; n = 63). Factors like age, tumor localization and stage were similar in all groups. An intention to treat analysis was made. RESULTS: The E group showed no postoperative mortality, while in the RCT+E group, the surgery mortality was 12.8%. The mortality after RCT was 1.7%. After preoperative radiochemotherapy, a pathological complete response was observed in 25% of cases and the curative resection rate was higher (82% after RCT + E versus 60% after E). The 5-year survival difference between the three groups was not relevant (E group, 12.6%; RCT group, 25.8%; RCT + E group, 38.7%). The median survival was 29, 24 and 28.5 months, respectively. The event-free survival was identical for the E group and the RCT group. For patients treated by radiochemotherapy, local and/or distant relapses were significantly reduced by esophagectomy (relapses occurred in 51% of patients in the RCT + E group versus 75% in the RCT group, P = 0.017). Palliative care (dilatations, prosthesis, gastrostomy or jejunostomy) to improve dysphagia was necessary for 38% of patients treated by exclusive radiochemotherapy versus 11% of patients treated by surgery (P = 0.001). CONCLUSIONS: Treatments by esophagectomy or radiochemotherapy were not significantly different. Preoperative radiochemotherapy and surgery lead to a higher survival rate than exclusive radiochemotherapy, however, with a high postoperative mortality rate. This study suggests the relevance of a prospective randomized trial to compare RCT+E and RCT alone.

Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus.

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer.

Patients with measurable or evaluable locally advanced or metastatic squamous cell carcinoma of the oesophagus were treated with cisplatin (CDDP), 100 mg/m2, combined with 5-fluorouracil (5-FU) at a dose of 1000 mg/m2 as a continuous infusion from days 1-5 (Arm A) or with CDDP alone (Arm B). Cycles were repeated every 3 weeks. 92 patients were randomised centrally, 88 were eligible. The response rate was 35% (95% CI (confidence interval), 20-54%) in Arm A and 19% (95% CI, 8-35%) in Arm B. One complete response was observed in each arm. The median duration of survival was 33 weeks and 28 weeks for Arm A and Arm B, respectively. Haematological and non-haematological toxicities were more frequent and more severe in Arm A. The most prominent toxicities were grade 4 aplasia and septicaemia (2), meningeal haemorrhage (1), cerebrovascular accident (3) and ischaemia of the lower limbs (1) all occurring in Arm A. Overall, seven treatment-related deaths (16%) were observed in Arm A, none in Arm B. The severe side-effects induced by the combination suggest that, currently, no standard chemotherapy can be recommended for patients with advanced squamous cell oesophageal cancer.