Real-world ramucirumab and immune checkpoint inhibitor sequences in US patients with advanced gastroesophageal cancer.

Aim: To describe real-world treatment sequences of ramucirumab relative to immune checkpoint inhibitors (ICIs) in patients with advanced gastroesophageal cancer. Methods: Retrospective, observational study including adult patients treated with ramucirumab (April 2014-June 2020) from a nationwide health-record database. Results: In 1117 eligible patients, ramucirumab + paclitaxel was the most common ramucirumab-containing regimen (72.0%). A total of 217 patients also received an ICI. For ramucirumab then ICI (n = 148) and ICI then ramucirumab (n = 50), ramucirumab + taxane and ICI monotherapy were the most frequent approaches, most commonly observed as second- and third-line (2L and 3L). Median time on ramucirumab in 2L and 3L was similar regardless of sequence with ICI. Conclusion: Most patients with advanced gastroesophageal cancer received ramucirumab before ICI, with ramucirumab + paclitaxel as the most common ramucirumab-based regimen.

What is the Order of New Treatments for Gastroesophageal Cancers in the Real World? What is this summary about? Gastroesophageal cancers (cancers of the stomach or food pipe) which cannot be cured are first treated using traditional chemotherapy. Newer anti-cancer therapies with fewer side effects, such as ramucirumab (RAM) and immune checkpoint inhibitors (ICI), are now available either alone or in combination with chemotherapy. We designed this study to describe the order of use for RAM and ICI. What were the results? The patients in this study were from Flatiron Health database, which includes electronic medical record data of US patients with gastroesophageal cancers. The included patients had been treated with RAM and were grouped based on the treatments received and in the order in which they received RAM and ICI. Of the patients who received both RAM and ICI, RAM then ICI was the most common order, followed by ICI then RAM and then RAM plus ICI at the same time. RAM in combination with paclitaxel (a chemotherapy) was the most common RAM-containing treatment. The duration of RAM therapy was the same whether patients received the treatment before or after ICI. What do results of the study mean? These findings can be used by patients with gastroesophageal cancers and oncologists when making treatment decisions, specifically if RAM might be an option when it is time to change treatments. Real-world studies like this help answer questions that were not addressed in clinical trials.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.

Real-World Molecular Biomarker Testing Patterns and Results for Advanced Gastroesophageal Cancers in the United States.

The decision to treat advanced gastroesophageal cancers (GECs) with targeted therapy and immunotherapy is based on key biomarker expression (human epidermal growth factor receptor 2 (HER2), programmed cell death-ligand 1 (PD-L1), microsatellite instability (MSI), and/or mismatch repair (MMR)). Real-world data on testing, results, and treatment patterns are limited. This retrospective observational study used a nationwide electronic health record-derived de-identified database of patients from the United States. The analysis included adult patients with advanced GECs who initiated systemic treatment between 2017 and 2020. Biomarker testing patterns, timing, assays, tissue collection site, results, and treatment sequences were assessed. Of 1142 eligible patients, adenocarcinoma was the most prevalent histology (83% of patients). Overall, 571 (50%) patients were tested for PD-L1, 582 (51%) were tested for MMR/MSI, and 857 (75%) were tested for HER2. Between 2017 and 2020, the PD-L1 testing rate increased from 39% to 58%, and the MMR/MSI testing rate increased from 41% to 58%; the median time from initial diagnosis to first test decreased for both biomarkers. Programmed cell death receptor-1 inhibitor use was observed among patients with positive PD-L1 or MMR-deficient/MSI-High results. These results supplement data reported in key clinical trials and may inform decision-making as treatment options for advanced GECs evolve.

Risk thresholds for patients to switch between daily tablets and biweekly infusions in second-line treatment for advanced hepatocellular carcinoma: a patient preference study.

BACKGROUND: Historically, high hepatocellular carcinoma (HCC)-related mortality has been, in part, due to lack of effective therapies; however, several systemic therapies have been recently approved for HCC treatment, including regorafenib and ramucirumab. These two treatments utilize different routes of administration (four daily tablets and biweekly intravenous infusions, respectively) and have different risks of adverse events (AEs). However, we lack data on patient preferences in balancing the route of administration and risk of AEs in patients with HCC. We aimed to determine patient preferences and trade-offs for second-line treatment in patients with HCC.  METHODS: Patients with advanced or metastatic HCC were recruited through their physicians for this study. Patient preferences were assessed by using a modified threshold technique (TT) design in which respondents were asked two direct-elicitation questions before (assuming same safety and efficacy and only varying mode of administration) and after (incorporating the safety profiles of ramucirumab and regorafenib) the TT series on seven risks of clinically relevant AEs. RESULTS: In total, of the 157 patients recruited by their physicians, 150 were eligible and consented to participate. In the first elicitation question (assuming risk and efficacy were equivalent), 61.3% of patients preferred daily tablets. However, 76.7% of patients preferred the biweekly infusion when the safety profiles of the two available second-line therapies were included. The TT analysis confirmed that preferences for oral administration were not strong enough to balance out the risk of AEs that differentiate the two therapies. DISCUSSION: We found that when patients were asked to choose between a daily, oral medication and a biweekly IV medication for HCC, they were more likely to choose a daily, oral medication if efficacy and safety profiles were the same. However, when risks of AEs representing the safety profiles of two currently available second-line treatments were introduced in a second direct-elicitation question, respondents often selected an IV administration with a safety profile similar to ramucirumab, rather than oral tablets with a safety profile similar to regorafenib. Our findings indicate that the risk profile of a second-line treatment for HCC may be more important than the mode of administration to patients.

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. MATERIALS AND METHODS: We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. RESULTS: In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. CONCLUSION: For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. IMPLICATIONS FOR PRACTICE: The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.

Early Weight Loss as a Prognostic Factor in Patients with Advanced Gastric Cancer: Analyses from REGARD, RAINBOW, and RAINFALL Phase III Studies.

BACKGROUND: Weight loss is common in advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA); however, the prognostic implications of weight loss during the first cycle (C1) of chemotherapy remain poorly characterized. In this study, we investigated the impact of early weight loss during systemic treatment as a potential prognostic factor for overall survival (OS) in patients with advanced G/GEA. MATERIALS AND METHODS: We performed a post hoc analysis of three phase III studies of ramucirumab. Patients were categorized into two groups: weight loss of ≥3% and <3% based on weight change during C1 (3-4 weeks) of treatment. OS by weight groups was assessed for each study and as a pooled meta-analysis. The effect of C1 weight change on patient survival was evaluated using univariate and multivariate Cox models. RESULTS: A total of 1,464 patients with weight data at the end of C1 were analyzed: REGARD (n = 311), RAINBOW (n = 591), and RAINFALL (n = 562). For all three studies, there were fewer patients in the weight loss ≥3% than <3% group. OS was numerically shorter for patients with weight loss of ≥3% than for patients with weight loss of <3% during C1 irrespective of treatment arm. Similar treatment independent effects of early weight loss on OS were observed in the meta-analysis. Overall, early weight loss ≥3% was associated with shorter survival in patients receiving active drug as well as placebo/best supportive care. CONCLUSION: This large post hoc analysis demonstrated that weight loss of ≥3% during C1 was a negative prognostic factor for OS in patients with advanced G/GEA. IMPLICATIONS FOR PRACTICE: This comprehensive analysis examining early weight loss during systemic treatment as a predictor of survival outcomes in patients with advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA) includes a large sample size, reliable on-treatment data reported in well-conducted phase III clinical trials, and global representation of cancer patients with advanced G/GEA. Understanding the impact of on-treatment weight loss is clinically relevant and may represent an opportunity for targeted interventions.

Data suggest COVID-19 affected numbers greatly exceeded detected numbers, in four European countries, as per a delayed SEIQR model.

People in many countries are now infected with COVID-19. By now, it is clear that the number of people infected is much greater than the number of reported cases. To estimate the infected but undetected/unreported cases using a mathematical model, we can use a parameter called the probability of quarantining an infected individual. This parameter exists in the time-delayed SEIQR model (Scientific Reports, article number: 3505). Here, two limiting cases of a network of such models are used to estimate the undetected population. The first limit corresponds to the network collapsing onto a single node and is referred to as the mean-[Formula: see text] model. In the second case, the number of nodes in the network is infinite and results in a continuum model wherein the infectivity is statistically distributed. We use a generalized Pareto distribution to model the infectivity. This distribution has a fat tail and models the presence of super-spreaders that contribute to the disease progression. While both models capture the detected numbers well, the predictions of affected numbers from the continuum model are more realistic. Our results suggest that affected people outnumber detected people by one to two orders of magnitude in Spain, the UK, Italy, and Germany. Our results are consistent with corresponding trends obtained from published serological studies in Spain, the UK and Italy. The match with limited studies in Germany is poor, possibly because Germany's partial lockdown approach requires different modeling.

Optimizing treatment duration with ramucirumab and paclitaxel by managing chemotherapy-associated toxicity: Review of four cases.

Gastric and gastroesophageal junction adenocarcinomas have poor prognoses. Ramucirumab is considered a second-line standard of care for patients with these cancers. Patients may develop chemotherapy-induced adverse events, and physicians may benefit from greater familiarity with treatment management in the setting of common adverse events. We report four cases of metastatic gastric or gastric and gastroesophageal junction adenocarcinoma treated with second-line ramucirumab plus paclitaxel. All patients developed chemotherapy-associated grade ⩾2 neutropenia and/or neuropathy, and one experienced recurrence of neurotoxicity, during second-line therapy. These adverse events were successfully managed by withholding or reducing the paclitaxel dose, without modifying the ramucirumab dosage schedule, and allowed administration of additional therapy cycles. In all patients, second-line therapy was associated with a best overall response of complete or partial response ranging from 2.2 to 12.4 months. These four cases demonstrate that paclitaxel-associated adverse events can be managed with dose modifications, thereby allowing continued therapy and potential survival benefits.

New approximations, and policy implications, from a delayed dynamic model of a fast pandemic.

We study an SEIQR (Susceptible-Exposed-Infectious-Quarantined-Recovered) model due to Young et al. (2019) for an infectious disease, with time delays for latency and an asymptomatic phase. For fast pandemics where nobody has prior immunity and everyone has immunity after recovery, the SEIQR model decouples into two nonlinear delay differential equations (DDEs) with five parameters. One parameter is set to unity by scaling time. The simple subcase of perfect quarantining and zero self-recovery before quarantine, with two free parameters, is examined first. The method of multiple scales yields a hyperbolic tangent solution; and a long-wave (short delay) approximation yields a first order ordinary differential equation (ODE). With imperfect quarantining and nonzero self-recovery, the long-wave approximation is a second order ODE. These three approximations each capture the full outbreak, from infinitesimal initiation to final saturation. Low-dimensional dynamics in the DDEs is demonstrated using a six state non-delayed reduced order model obtained by Galerkin projection. Numerical solutions from the reduced order model match the DDE over a range of parameter choices and initial conditions. Finally, stability analysis and numerics show how a well executed temporary phase of social distancing can reduce the total number of people affected. The reduction can be by as much as half for a weak pandemic, and is smaller but still substantial for stronger pandemics. An explicit formula for the greatest possible reduction is given.

Complete dimensional collapse in the continuum limit of a delayed SEIQR network model with separable distributed infectivity.

We take up a recently proposed compartmental SEIQR model with delays, ignore loss of immunity in the context of a fast pandemic, extend the model to a network structured on infectivity and consider the continuum limit of the same with a simple separable interaction model for the infectivities ß . Numerical simulations show that the evolving dynamics of the network is effectively captured by a single scalar function of time, regardless of the distribution of ß in the population. The continuum limit of the network model allows a simple derivation of the simpler model, which is a single scalar delay differential equation (DDE), wherein the variation in ß appears through an integral closely related to the moment generating function of u = ß . If the first few moments of u exist, the governing DDE can be expanded in a series that shows a direct correspondence with the original compartmental DDE with a single ß . Even otherwise, the new scalar DDE can be solved using either numerical integration over u at each time step, or with the analytical integral if available in some useful form. Our work provides a new academic example of complete dimensional collapse, ties up an underlying continuum model for a pandemic with a simpler-seeming compartmental model and will hopefully lead to new analysis of continuum models for epidemics.

Acoustics of Idakka: An Indian snare drum with definite pitch.

The vibration of a homogeneous circular membrane backed by two taut strings is shown to yield several harmonic overtones for a wide range of physical and geometric parameters. Such a membrane is present at each end of the barrel of an idakka, an Indian snare drum well known for its rich musicality. The audio recordings of the musical drum are analyzed and a case is made for the strong sense of pitch associated with the drum. A computationally inexpensive model of the string-membrane interaction is proposed assuming the strings to be without inertia. The interaction essentially entails wrapping/unwrapping of the string around a curve on the deforming membrane unlike the colliding strings in Western snare drums. The range of parameters for which harmonicity is achieved is examined and is found to be conforming with what is used in actual drum playing and construction.

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance.

Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that S6K1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of S6K1 also improved survival in mice transplanted with MLL-AF9-positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that S6K1 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.

A two-state hysteresis model from high-dimensional friction.

In prior work (Biswas & Chatterjee 2014 Proc. R. Soc. A 470, 20130817 (doi:10.1098/rspa.2013.0817)), we developed a six-state hysteresis model from a high-dimensional frictional system. Here, we use a more intuitively appealing frictional system that resembles one studied earlier by Iwan. The basis functions now have simple analytical description. The number of states required decreases further, from six to the theoretical minimum of two. The number of fitted parameters is reduced by an order of magnitude, to just six. An explicit and faster numerical solution method is developed. Parameter fitting to match different specified hysteresis loops is demonstrated. In summary, a new two-state model of hysteresis is presented that is ready for practical implementation. Essential Matlab code is provided.

Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder.

Although more than 90% systemic mastocytosis (SM) patients express gain of function mutations in the KIT receptor, recent next generation sequencing has revealed the presence of several additional genetic and epigenetic mutations in a subset of these patients, which confer poor prognosis and inferior overall survival. A clear understanding of how genetic and epigenetic mutations cooperate in regulating the tremendous heterogeneity observed in these patients will be essential for designing effective treatment strategies for this complex disease. In this review, we describe the clinical heterogeneity observed in patients with mastocytosis, the nature of relatively novel mutations identified in these patients, therapeutic strategies to target molecules downstream from activating KIT receptor and finally we speculate on potential novel strategies to interfere with the function of not only the oncogenic KIT receptor but also epigenetic mutations seen in these patients.

Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis.

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

A reduced-order model from high-dimensional frictional hysteresis.

Hysteresis in material behaviour includes both signum nonlinearities as well as high dimensionality. Available models for component-level hysteretic behaviour are empirical. Here, we derive a low-order model for rate-independent hysteresis from a high-dimensional massless frictional system. The original system, being given in terms of signs of velocities, is first solved incrementally using a linear complementarity problem formulation. From this numerical solution, to develop a reduced-order model, basis vectors are chosen using the singular value decomposition. The slip direction in generalized coordinates is identified as the minimizer of a dissipation-related function. That function includes terms for frictional dissipation through signum nonlinearities at many friction sites. Luckily, it allows a convenient analytical approximation. Upon solution of the approximated minimization problem, the slip direction is found. A final evolution equation for a few states is then obtained that gives a good match with the full solution. The model obtained here may lead to new insights into hysteresis as well as better empirical modelling thereof.

Pak and Rac GTPases promote oncogenic KIT-induced neoplasms.

An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21-activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak. Although both Rac1 and Rac2 are constitutively activated via the guanine nucleotide exchange factor (GEF) Vav1, loss of Rac1 or Rac2 alone moderately corrected the growth of KIT-bearing leukemic cells, whereas the combined loss resulted in 75% growth repression. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of myeloproliferative neoplasms (MPNs) and corrected the associated pathology in mice. To assess the role of Rac GEFs in oncogene-induced transformation, we used an inhibitor of Rac, EHop-016, which specifically targets Vav1 and found that EHop-016 was a potent inhibitor of human and murine leukemic cell growth. These studies identify Pak and Rac GTPases, including Vav1, as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.

Substance dependence treatment interventions: why we continue to fail people who use drugs in Asia.

INTRODUCTION: Substance use disorders contribute to a large number of preventable deaths in Asia; a majority of the negative health consequences are associated with opioid use. User friendly and effective drug dependence treatment is limited. SCOPE: Factors mediating drug user treatment outcomes in Asia are explored, with a focus on opioid use. Individual, programmatic, and legal/political issues which reduce the impact of drug user treatment are noted. DISCUSSION: Criminalization of drug users, inadequate insurance, chronic underinvestment, and an overall lack of therapeutic options create structural barriers for treatment for users and providers. The practice of detention as drug treatment serves to fracture the treatment alliance. At the individual level, extreme poverty and the lack of a social protection network mediate against the achievement of treatment goals. CONCLUSIONS: A range of factors has a bearing on processes and outcomes of drug user treatment. Acknowledging and addressing them, at each level, is fundamental to delivering useful interventions for people who use drugs.

Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT.

Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.