Earthquake Nowcasting: Retrospective Testing in Greece.

Earthquake nowcasting (EN) is a modern method of estimating seismic risk by evaluating the progress of the earthquake (EQ) cycle in fault systems. EN evaluation is based on a new concept of time, termed 'natural time'. EN employs natural time, and uniquely estimates seismic risk by means of the earthquake potential score (EPS), which has been found to have useful applications both regionally and globally. Amongst these applications, here we focused on Greece since 2019, for the estimation of the EPS for the largest-magnitude events, MW(USGS) ≥ 6, that occurred during our study period: for example, the MW= 6.0 WNW-of-Kissamos EQ on 27 November 2019, the MW= 6.5 off-shore Southern Crete EQ on 2 May 2020, the MW= 7.0 Samos EQ on 30 October 2020, the MW= 6.3 Tyrnavos EQ on 3 March 2021, the MW= 6.0 Arkalohorion Crete EQ on 27 September 2021, and the MW= 6.4 Sitia Crete EQ on 12 October 2021. The results are promising, and reveal that the EPS provides useful information on impending seismicity.

Estimating the Epicenter of a Future Strong Earthquake in Southern California, Mexico, and Central America by Means of Natural Time Analysis and Earthquake Nowcasting.

It has recently been shown in the Eastern Mediterranean that by combining natural time analysis of seismicity with earthquake networks based on similar activity patterns and earthquake nowcasting, an estimate of the epicenter location of a future strong earthquake can be obtained. This is based on the construction of average earthquake potential score maps. Here, we propose a method of obtaining such estimates for a highly seismically active area that includes Southern California, Mexico and part of Central America, i.e., the area N1035W80120. The study includes 28 strong earthquakes of magnitude M ≥7.0 that occurred during the time period from 1989 to 2020. The results indicate that there is a strong correlation between the epicenter of a future strong earthquake and the average earthquake potential score maps. Moreover, the method is also applied to the very recent 7 September 2021 Guerrero, Mexico, M7 earthquake as well as to the 22 September 2021 Jiquilillo, Nicaragua, M6.5 earthquake with successful results. We also show that in 28 out of the 29 strong M ≥7.0 EQs studied, their epicenters lie close to an estimated zone covering only 8.5% of the total area.

Nowcasting Avalanches as Earthquakes and the Predictability of Strong Avalanches in the Olami-Feder-Christensen Model.

Nowcasting earthquakes, suggested recently as a method to estimate the state of a fault and hence the seismic risk, is based on the concept of natural time. Here, we generalize nowcasting to a prediction method the merits of which are evaluated by means of the receiver operating characteristics. This new prediction method is applied to a simple (toy) model for the waiting (natural) time of the stronger earthquakes, real seismicity, and the Olami-Feder-Christensen earthquake model with interesting results revealing acceptable to excellent or even outstanding performance.

Natural Time Analysis: The Area under the Receiver Operating Characteristic Curve of the Order Parameter Fluctuations Minima Preceding Major Earthquakes.

It has been reported that major earthquakes are preceded by Seismic Electric Signals (SES). Observations show that in the natural time analysis of an earthquake (EQ) catalog, an SES activity starts when the fluctuations of the order parameter of seismicity exhibit a minimum. Fifteen distinct minima-observed simultaneously at two different natural time scales and deeper than a certain threshold-are found on analyzing the seismicity of Japan from 1 January 1984 to 11 March 2011 (the time of the M9 Tohoku EQ occurrence) 1 to 3 months before large EQs. Six (out of 15) of these minima preceded all shallow EQs of magnitude 7.6 or larger, while nine are followed by smaller EQs. The latter false positives can be excluded by a proper procedure (J. Geophys. Res. Space Physics 2014, 119, 9192-9206) that considers aspects of EQ networks based on similar activity patterns. These results are studied here by means of the receiver operating characteristics (ROC) technique by focusing on the area under the ROC curve (AUC). If this area, which is currently considered an effective way to summarize the overall diagnostic accuracy of a test, has the value 1, it corresponds to a perfectly accurate test. Here, we find that the AUC is around 0.95 which is evaluated as outstanding.

Identifying the Occurrence Time of the Deadly Mexico M8.2 Earthquake on 7 September 2017.

It has been shown that some dynamic features hidden in the time series of complex systems can be unveiled if we analyze them in a time domain termed natural time. In this analysis, we can identify when a system approaches a critical point (dynamic phase transition). Here, based on natural time analysis, which enables the introduction of an order parameter for seismicity, we discuss a procedure through which we could achieve the identification of the occurrence time of the M8.2 earthquake that occurred on 7 September 2017 in Mexico in Chiapas region, which is the largest magnitude event recorded in Mexico in more than a century. In particular, we first investigated the order parameter fluctuations of seismicity in the entire Mexico and found that, during an almost 30-year period, i.e., from 1 January 1988 until the M8.2 earthquake occurrence, they were minimized around 27 July 2017. From this date, we started computing the variance of seismicity in Chiapas region and found that it approached the critical value 0.070 on 6 September 2017, almost one day before this M8.2 earthquake occurrence.

Spatiotemporal variations of seismicity before major earthquakes in the Japanese area and their relation with the epicentral locations.

Using the Japan Meteorological Agency earthquake catalog, we investigate the seismicity variations before major earthquakes in the Japanese region. We apply natural time, the new time frame, for calculating the fluctuations, termed ß, of a certain parameter of seismicity, termed κ1. In an earlier study, we found that ß calculated for the entire Japanese region showed a minimum a few months before the shallow major earthquakes (magnitude larger than 7.6) that occurred in the region during the period from 1 January 1984 to 11 March 2011. In this study, by dividing the Japanese region into small areas, we carry out the ß calculation on them. It was found that some small areas show ß minimum almost simultaneously with the large area and such small areas clustered within a few hundred kilometers from the actual epicenter of the related main shocks. These results suggest that the present approach may help estimation of the epicentral location of forthcoming major earthquakes.

Statistical Significance of Earth's Electric and Magnetic Field Variations Preceding Earthquakes in Greece and Japan Revisited.

By analyzing the seismicity in a new time domain, termed natural time, we recently found that the change of the entropy under time reversal (Physica A2018, 506, 625-634) and the relevant complexity measures (Entropy2018, 20, 477) exhibit pronounced variations before the occurrence of the M8.2 earthquake in Mexico on 7 September 2017. Here, the statistical significance of precursory phenomena associated with other physical properties and in particular the anomalous variations observed in the Earth's electric and magnetic fields before earthquakes in different regions of the world and in particular in Greece since 1980s and Japan during 2001-2010 are revisited (the latter, i.e., the magnetic field variations are alternatively termed ultra low frequency (ULF) seismo-magnetic phenomena). Along these lines we employ modern statistical tools like the event coincidence analysis and the receiver operating characteristics technique. We find that these precursory variations are far beyond chance and in addition their lead times fully agree with the experimental findings in Greece since the 1980s.

Study in Natural Time of Geoelectric Field and Seismicity Changes Preceding the Mw6.8 Earthquake on 25 October 2018 in Greece.

A strong earthquake of magnitude M w 6.8 struck Western Greece on 25 October 2018 with an epicenter at 37.515 ∘ N 20.564 ∘ E. It was preceded by an anomalous geolectric signal that was recorded on 2 October 2018 at a measuring station 70 km away from the epicenter. Upon analyzing this signal in natural time, we find that it conforms to the conditions suggested for its identification as precursory Seismic Electric Signal (SES) activity. Notably, the observed lead time of 23 days lies within the range of values that has been very recently identified as being statistically significant for the precursory variations of the electric field of the Earth. Moreover, the analysis in natural time of the seismicity subsequent to the SES activity in the area candidate to suffer this strong earthquake reveals that the criticality conditions were obeyed early in the morning of 18 October 2018, i.e., almost a week before the strong earthquake occurrence, in agreement with earlier findings. Finally, when employing the recent method of nowcasting earthquakes, which is based on natural time, we find an earthquake potential score around 80%.

Tsallis Entropy Index q and the Complexity Measure of Seismicity in Natural Time under Time Reversal before the M9 Tohoku Earthquake in 2011.

The observed earthquake scaling laws indicate the existence of phenomena closely associated with the proximity of the system to a critical point. Taking this view that earthquakes are critical phenomena (dynamic phase transitions), here we investigate whether in this case the Lifshitz-Slyozov-Wagner (LSW) theory for phase transitions showing that the characteristic size of the minority phase droplets grows with time as t 1 / 3 is applicable. To achieve this goal, we analyzed the Japanese seismic data in a new time domain termed natural time and find that an LSW behavior is actually obeyed by a precursory change of seismicity and in particular by the fluctuations of the entropy change of seismicity under time reversal before the Tohoku earthquake of magnitude 9.0 that occurred on 11 March 2011 in Japan. Furthermore, the Tsallis entropic index q is found to exhibit a precursory increase.

The Complexity Measures Associated with the Fluctuations of the Entropy in Natural Time before the Deadly México M8.2 Earthquake on 7 September 2017.

We analyse seismicity during the 6-year period 2012-2017 in the new time domain termed natural time in the Chiapas region where the M8.2 earthquake occurred, Mexico's largest earthquake in more than a century, in order to study the complexity measures associated with fluctuations of entropy as well as with entropy change under time reversal. We find that almost three months before the M8.2 earthquake, i.e., on 14 June 2017, the complexity measure associated with the fluctuations of entropy change under time reversal shows an abrupt increase, which, however, does not hold for the complexity measure associated with the fluctuations of entropy in forward time. On the same date, the entropy change under time reversal has been previously found to exhibit a minimum [Physica A 506, 625-634 (2018)]; we thus find here that this minimum is also accompanied by increased fluctuations of the entropy change under time reversal. In addition, we find a simultaneous increase of the Tsallis entropic index q.

Estimating the Compressibility of Osmium from Recent Measurements of Ir-Os Alloys under High Pressure.

Several fcc- and hcp-structured Ir-Os alloys have been recently studied up to 30 GPa at room temperature by means of synchrotron-based X-ray powder diffraction in diamond anvil cells. Using their bulk moduli, which increase with increasing osmium content, showing a deviation from linearity, and after employing a thermodynamical model, it was concluded that the bulk modulus for osmium is slightly smaller than that for diamond. Here, a similar conclusion is obtained upon employing an alternative model, thus strengthening the conclusion that osmium is the densest but not the most incompressible element. This is particularly interesting for Earth Sciences because it may be of key importance toward clarifying the anomalous elastic properties of the Earth's core.

Minimum of the order parameter fluctuations of seismicity before major earthquakes in Japan.

It has been shown that some dynamic features hidden in the time series of complex systems can be uncovered if we analyze them in a time domain called natural time χ. The order parameter of seismicity introduced in this time domain is the variance of χ weighted for normalized energy of each earthquake. Here, we analyze the Japan seismic catalog in natural time from January 1, 1984 to March 11, 2011, the day of the M9 Tohoku earthquake, by considering a sliding natural time window of fixed length comprised of the number of events that would occur in a few months. We find that the fluctuations of the order parameter of seismicity exhibit distinct minima a few months before all of the shallow earthquakes of magnitude 7.6 or larger that occurred during this 27-y period in the Japanese area. Among the minima, the minimum before the M9 Tohoku earthquake was the deepest. It appears that there are two kinds of minima, namely precursory and nonprecursory, to large earthquakes.

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

Natural time analysis of critical phenomena.

A quantity exists by which one can identify the approach of a dynamical system to the state of criticality, which is hard to identify otherwise. This quantity is the variance κ(1)(≡<χ(2)> - <χ>(2)) of natural time χ, where = Σp(k)f(χ(k)) and p(k) is the normalized energy released during the kth event of which the natural time is defined as χ(k) = k/N and N stands for the total number of events. Then we show that κ(1) becomes equal to 0.070 at the critical state for a variety of dynamical systems. This holds for criticality models such as 2D Ising and the Bak-Tang-Wiesenfeld sandpile, which is the standard example of self-organized criticality. This condition of κ(1) = 0.070 holds for experimental results of critical phenomena such as growth of rice piles, seismic electric signals, and the subsequent seismicity before the associated main shock.

Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial.

BACKGROUND: The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer. METHODS: Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov, number NCT00095875. FINDINGS: Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39-63), 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60-82) in the induction therapy followed by chemoradiotherapy group and 78% (66-86) in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI 0·59-2·03; p=0·77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient). INTERPRETATION: Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure. FUNDING: Sanofi-Aventis.

On the recent seismic activity in North-Eastern Aegean Sea including the M(w)5.8 earthquake on 8 January 2013.

In the last week of November 2012, we announced that a strong electrotelluric disturbance, which we judged to be a Seismic Electric Signal (SES) activity, was recorded at station Assiros located in Northern Greece. This disturbance was actually followed by an Mw5.8 earthquake on 8 January 2013 in North-Eastern Aegean Sea. Here we show that, by analyzing this SES activity and employing the natural time analysis of subsequent seismicity, we estimated the epicentral location, magnitude and occurrence time which are reasonably compatible with those of the Mw5.8 event.

Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Novel biomarker panel predicts prognosis in human papillomavirus-negative oropharyngeal cancer: an analysis of the TAX 324 trial.

BACKGROUND: New treatment strategies for locally advanced head and neck squamous cell carcinoma combine induction chemotherapy and chemoradiation. Identifying the predictors of outcome in sequentially treated patients is critical for focusing therapeutic research. In this analysis, the authors evaluated human papillomavirus type 16 (HPV-16) status and the expression levels of a defined set of biomarkers to identify predictors of response to this treatment modality. METHODS: In total, 114 patients with oropharyngeal cancer (OPC) who were treated on the TAX 324 trial (cisplatin and fluorouracil with or without docetaxel in patients with locally advanced head and neck squamous cell carcinoma) had pretreatment biopsy specimens that were evaluable for HPV-16 DNA and immunohistochemical expression of the following biomarkers: beta-tubulin II (ßT-II), glutathione S-transferase (GST-π), p53, and B-cell lymphoma 2 (Bcl-2). Patients were categorized into risk groups based on their HPV status and biomarker expression levels. RESULTS: Patients with high-risk OPC were defined by HPV-negative status and either elevated expression of ßT-II or levels of at least 2 of the other 3 adverse markers (elevated GST-π, elevated p53, or low Bcl-2). All other HPV-negative patients were categorized as moderate risk. In total, 55 patients were HPV-positive, and 59 patients were HPV-negative, with 34 were categorized as high risk and 25 categorized as moderate risk. The median survival for HPV-positive patients was not reached. The median survival was 44.2 months for moderate-risk patients (95% confidence interval, 20.9 months to not reached) and 12.1 months for high-risk patients (95% confidence interval, 7.5-19.7 months). The 24-month survival rate was 89% for HPV-positive patients, 67% for moderate-risk patients, and 29% for high-risk patients (P < .0001). CONCLUSIONS: The molecular data set in this study readily differentiated between 2 distinct groups of patients with locally advanced, HPV-negative OPC. This risk-stratification strategy may serve as a guide for treatment selection.

Functional polymorphisms in the insulin-like binding protein-3 gene may modulate susceptibility to differentiated thyroid carcinoma in Caucasian Americans.

The insulin-like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF-1 and IGF binding protein-3 (IGFBP-3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking. In a case-control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF-1 and IGFBP-3 and DTC risk. IGFBP-3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted OR = 0.6, 95% CI: 0.4-0.9), particularly multifocal DTC (adjusted OR = 0.3, 95% CI: 0.1-0.7). The association with DTC was more evident in subjects with a first-degree family history of cancer (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) = 0.013) and non-drinkers (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) = 0.028). A four single nucleotide polymorphism haplotype of IGFBP-3 was associated with a decreased risk of DTC (adjusted OR = 0.7, 95% CI: 0.5-1.0, P = 0.030). Our study suggests that polymorphic IGFBP-3 may be involved in susceptibility to DTC.

Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial.

BACKGROUND: At a minimum follow-up of 2 years, the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) versus cisplatin and fluorouracil (PF) in locally advanced head and neck cancer. We report the long-term results at 5 years' minimum follow-up. METHODS: TAX 324 was a randomised, open-label phase 3 trial comparing three cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2), followed by intravenous cisplatin 100 mg/m(2) and fluorouracil 1000 mg/m(2) per day, administered as a continuous 24-h infusion for 4 days) with three cycles of PF (intravenous cisplatin 100 mg/m(2), followed by fluorouracil 1000 mg/m(2) per day as a continuous 24-h infusion for 5 days) in patients with stage III or IV squamous-cell carcinoma of the head or neck. Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin. Randomisation was done centrally with the use of a biased-coin minimisation technique. At study entry, patients were stratified according to the site of the primary tumour, nodal status (N0 or N1 vs N2 or N3), and institution. For this long-term analysis, data as of Dec 1, 2008, were gathered retrospectively from patients' medical records. Overall and progression-free survival were the primary endpoints. Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity. The intention-to-treat analysis included data from all 501 patients (255 TPF, 246 PF); data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up. TAX 324 was registered at ClinicalTrials.gov, NCT00273546. FINDINGS: Median follow-up was 72·2 months (95% CI 68·8-75·5). Overall survival was significantly better after treatment with TPF versus PF (hazard ratio [HR] 0·74, 95% CI 0·58-0·94), with an estimated 5-year survival of 52% in patients treated with TPF and 42% in those receiving PF. Median survival was 70·6 months (95% CI 49·0-89·0) in the TPF group versus 34·8 months (22·6-48·0) in the PF group (p=0·014). Progression-free survival was also significantly better in patients treated with TPF (median 38·1 months, 95% CI 19·3-66·1, vs 13·2 months, 10·6-20·7; HR 0·75, 95% CI 0·60-0·94). We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups. In the TPF group, three (3%) of 91 patients remained feeding-tube dependent, compared with eight (11%) of 71 patients in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, versus eight (11%) of 71 in the PF group. INTERPRETATION: Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer. Patients who are candidates for induction chemotherapy should be treated with TPF. FUNDING: Sanofi-Aventis.