Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

Softening of a flat phonon mode in the kagome ScV6Sn6.

Geometrically frustrated kagome lattices are raising as novel platforms to engineer correlated topological electron flat bands that are prominent to electronic instabilities. Here, we demonstrate a phonon softening at the kz = π plane in ScV6Sn6. The low energy longitudinal phonon collapses at ~98 K and q = [Formula: see text] due to the electron-phonon interaction, without the emergence of long-range charge order which sets in at a different propagation vector qCDW = [Formula: see text]. Theoretical calculations corroborate the experimental finding to indicate that the leading instability is located at [Formula: see text] of a rather flat mode. We relate the phonon renormalization to the orbital-resolved susceptibility of the trigonal Sn atoms and explain the approximately flat phonon dispersion. Our data report the first example of the collapse of a kagome bosonic mode and promote the 166 compounds of kagomes as primary candidates to explore correlated flat phonon-topological flat electron physics.

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations.

BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape. PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA). RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations. CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

Lipid metabolism in Giardia: a post-genomic perspective.

Giardia lamblia, a protozoan parasite, infects a wide variety of vertebrates, including humans. Studies indicate that this anaerobic protist possesses a limited ability to synthesize lipid molecules de novo and depends on supplies from its environment for growth and differentiation. It has been suggested that most lipids and fatty acids are taken up by endocytic and non-endocytic pathways and are used by Giardia for energy production and membrane/organelle biosynthesis. The purpose of this article is to provide an update on recent progress in the field of lipid research of this parasite and the validation of lipid metabolic pathways through recent genomic information. Based on current cellular, biochemical and genomic data, a comprehensive pathway has been proposed to facilitate our understanding of lipid and fatty acid metabolism/syntheses in this waterborne pathogen. We envision that the current review will be helpful in identifying targets from the pathways that could be used to design novel therapies to control giardiasis and related diseases.

Novel T9 loop conformation of filamenting temperature-sensitive mutant Z from Mycobacterium tuberculosis.

As of 2017, tuberculosis had infected 1.7 billion people (23% of the population of the world) and caused ten million deaths. Mycobacterium tuberculosis (Mtb) is quickly evolving, and new strains are classified as multidrug resistant. Thus, the identification of novel druggable targets is essential to combat the proliferation of these drug-resistant strains. Filamenting temperature-sensitive mutant Z (FtsZ) is a key protein involved in cytokinesis, an important process for Mtb proliferation and viability. FtsZ is required for bacterial cell division because it polymerizes into a structure called the Z-ring, which recruits accessory division proteins to the septum. Here, the crystal structure of the MtbFtsZ protein has been determined to 3.46 Šresolution and is described as a dimer of trimers, with an inter-subunit interface between protomers AB and DE. In this work, a novel conformation of MtbFtsZ is revealed involving the T9 loop and the nucleotide-binding pocket of protomers BC and EF.

GM-CSF and IL-2 induce specific cellular immunity and provide protection against Epstein-Barr virus lymphoproliferative disorder.

Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a potentially life-threatening complication in immune-deficient patients. We have used the severe combined immune deficient (SCID) mouse engrafted with human leukocytes (hu-PBL-SCID) to evaluate the use of human cytokines in the prevention of EBV-LPD in vivo. Daily low-dose IL-2 therapy can prevent EBV-LPD in the hu-PBL-SCID mouse, but protection is lost if murine natural killer (NK) cells are depleted. Here we demonstrate that combined therapy with human GM-CSF and low-dose IL-2 is capable of preventing EBV-LPD in the hu-PBL-SCID mouse in the absence of murine NK cells. Lymphocyte depletion experiments showed that human NK cells, CD8(+) T cells, and monocytes were each required for the protective effects of GM-CSF and IL-2 combination therapy. This treatment resulted in a marked expansion of human CD3(+)CD8(+) lymphocytes in vivo. Using HLA tetramers complexed with EBV immunodominant peptides, a subset of these lymphocytes was found to be EBV-specific. These data establish that combined GM-CSF and low-dose IL-2 therapy can prevent the immune deficiencies that lead to fatal EBV-LPD in the hu-PBL-SCID mouse depleted of murine NK cells, and they point to a critical role for several human cellular subsets in mediating this protective effect.

5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells.

The mixed inhibitory and excitatory effects of 5-HT on hippocampal pyramidal cells were studied on hippocampal slices perfused with a low-Ca2+/high Mg2+ solution that blocked synaptic activity and induced spontaneous pyramidal cell discharge. Extracellular recordings of the spontaneous discharge revealed that, in 65% of the cells, 5-HT (0.5-10 microM) initially inhibited and then, upon washout, facilitated spontaneous discharge. Sometimes the off-stimulation persisted for the duration of the experiment. In 17% of the cells the response to 5-HT was only stimulatory, and in 15% the response was exclusively inhibitory. The 5-HT1 agonists, 8-hydroxy-dipropylamino-tetraline, and 5-carboxamidotryptamine produced inhibition with no excitatory responses upon washout. The inhibition was blocked by spiroxatrine indicating it was mediated by 5-HT1A receptors. The 5-HT3 agonist, 2-methyl 5-HT, had no effect, and the 5-HT2 antagonist, ketanserin, did not alter the excitatory responses to 5-HT. This indicates the excitatory response is not mediated by 5-HT2 or 3 receptors. Cisapride, a 5-HT4 agonist increased pyramidal cell discharge. The 5-HT3 & 4 antagonist, ICS 205-930 antagonized the excitatory responses to 5-HT, alpha-methyl 5-HT, and cisapride, indicating the excitatory response is mediated, in part, by 5-HT4 receptors. The phosphodiesterase inhibitor, isobutyl-methyl-xanthine, stimulated pyramidal cell discharge and potentiated the response to cisapride. This further suggests 5-HT4 receptor involvement since these receptors are positively coupled to adenylyl cyclase.

Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla requires excitatory amino acid transmission.

Although the importance of the rostral ventromedial medulla in pain modulation is generally accepted, the recognition that it can exert both pain facilitating and pain inhibiting influences, and that its constituent neuronal population is physiologically and pharmacologically heterogeneous, is relatively recent. A class of neuron which may be a source of facilitating influences from the rostral ventromedial medulla has been identified in electrophysiological experiments. These neurons, termed "on-cells," are characterized by a sudden burst of activity beginning just before nocifensive reflexes. This burst of firing is thought to be a significant factor in brainstem control of nociceptive transmission under physiological conditions. The aim of the present study was to determine whether an excitatory amino acid is involved in generation of the reflex-related burst that defines on-cells, and more generally, to examine the role of excitatory amino acid neurotransmitters within the rostral ventromedial medulla of the rat. Iontophoretic application of the broad-spectrum excitatory amino acid receptor antagonist kynurenate significantly reduced the reflex-related on-cell burst, whereas ongoing firing was unaffected. Spontaneous activity of other medullary neurons was unchanged. These data demonstrate that release of an endogenous excitatory amino acid neurotransmitter is necessary for the activation of on-cells that is associated with nocifensive reflexes. In contrast, these receptors evidently play a much less significant role in maintaining the ongoing activity of any cell class in the rostral ventromedial medulla in lightly anaesthetized rats.

Endogenous opioids acting at a medullary mu-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray.

This study examined the contribution of endogenous opioids to the antinociception produced by microinjection of the GABAA receptor antagonist, bicuculline, into the rat midbrain ventrolateral periaqueductal gray region. Microinjection of bicuculline (40 ng/0.4 microliter) into the periaqueductal gray produced robust antinociception as measured by the tail-flick latency to noxious heat. This antinociception was partially reversed by intravenous administration of the non-selective opioid antagonist naloxone hydrochloride (1 and 5 mg/kg), indicating that endogenous opioid release is necessary for this effect. To determine whether opioid release in the rostral ventromedial medulla, a major projection target of the periaqueductal gray, contributes to this effect, we microinjected another opioid antagonist, naltrexone, into the rostral ventromedial medulla. Naltrexone in the rostral ventromedial medulla (5 and 10 micrograms/microliter) significantly attenuated bicuculline antinociception elicited from the periaqueductal gray. Cys2, tyr3, orn5, pen7-amide (26.5 nmol), a selective mu-opioid receptor antagonist, also reversed the antinociception when microinjected into the rostral ventromedial medulla. Microinjections of naltrexone (10 micrograms/microliter) or cys2, tyr3, orn5, pen7-amide at sites in the medulla dorsal to the rostral ventromedial medulla were ineffective. None of the antagonists altered baseline tail-flick latencies. These results support the hypothesis that a population of periaqueductal gray neurons produces antinociception through a mu-opioid receptor-mediated action of endogenous opioids in the rostral ventromedial medulla. Thus, two opioid-sensitive pain-modulating brainstem sites are linked by an endogenous opioid synapse in the rostral ventromedial medulla.

Rapid tranquilization with olanzapine in acute psychosis: a case series.

Acute, high-dose loading strategies (rapid neuroleptization) with the first-generation antipsychotics administered orally or parenterally, alone or combined with benzodiazepines, have been a commonly used treatment paradigm for controlling acutely agitated psychotic patients. The rationale was to achieve high plasma levels of drug within a shorter time period, resulting in rapid symptom mitigation. However, studies have shown that rapid neuroleptization with first-generation antipsychotics is associated with a greater incidence of side effects. To our knowledge, loading strategies with second-generation antipsychotics have not been investigated, primarily owing to a need for dose titration. Olanzapine, a second-generation antipsychotic, is well tolerated in doses ranging from 5 to 20 mg. The objective of this report was to determine experience with the use of up to 20 mg of an oral loading dose of olanzapine administered within 4 hours in the treatment of patients early in an acute psychotic phase of their illness. In the reported case series of 57 patients, olanzapine initiated at 15 to 20 mg/day was a safe and effective medication for rapidly calming the agitation of acutely agitated psychotic patients (rapid tranquilization). Furthermore, dose reduction over 2 to 3 weeks was achieved in a number of patients without appreciable loss of efficacy.

Effective resolution with olanzapine of acute presentation of behavioral agitation and positive psychotic symptoms in schizophrenia.

Behavioral agitation and prominent positive psychotic symptoms often characterize the acute presentation of schizophrenia. The clinical treatment goal is a rapid control of these symptoms. The relative efficacy of olanzapine, a novel antipsychotic drug, was compared with that of the conventional antipsychotic drug haloperidol. A post hoc analysis conducted on a large multicenter, double-blind, 6-week study of acute-phase patients with DSM-III-R schizophrenia or schizophreniform or schizoaffective disorders treated with olanzapine (5-20 mg/day) or haloperidol (5-20 mg/day) assessed the treatment effects on agitation (Brief Psychiatric Rating Scale [BPRS] agitation score) and positive symptoms (BPRS positive symptom score). Overall, olanzapine-treated patients experienced significantly greater improvement in behavioral agitation than did haloperidol-treated patients (last observation carried forward [LOCF]; p < .0002). Both groups showed similar reductions in agitation scores during the first 3 weeks of therapy; olanzapine was associated with significantly greater improvements at weeks 4, 5, and 6 (observed cases [OC]). Similarly, patients with predominantly positive psychotic symptoms experienced significantly greater improvement in BPRS positive symptom scores with olanzapine compared with haloperidol (LOCF; p = .013). In olanzapine-treated patients, improvement in BPRS agitation and positive symptom scores was significantly greater at weeks 4, 5, and 6 (agitation scores, p < or = .01; positive symptom scores, p < .05) (OC). These data suggest that olanzapine may be considered a first-line treatment for the patient in an acute episode of schizophrenia.

Studies on the genesis of Vibrio cholerae O139: identification of probable progenitor strains.

Four lines of evidence suggest that the recent outbreak strains of Vibrio cholerae O139 could have emerged from serogroup O1 strains typified by isolates M01 and M0477 described in this paper, which are neither truly classical nor truly E1 Tor in their biotype attributes. Firstly, like all O139 isolates, these O1 strains, isolated in Madras during and before the O139 outbreak, were resistant not only to polymyxin B but also to all biotype-specific choleraphages, i.e. classical phage phi 149 and E1 Tor phages e4 and e5. Secondly, the restriction fragment pattern (RFP) polymorphism displayed by these strains for the cholera toxin (ctx) gene, were identical with those produced by O139 isolates but were different from those of O1 type strains, namely V. cholerae 569B (classical) and V. cholerae MAK757 (E1 Tor). Thirdly, all the O139 isolates and the two O1 isolates carried an identical large number of copies of cholera toxin gene in their chromosomes. Finally, the outer-membrane protein profiles of strains M01 and M0477 were identical to those of O139 isolates but were different from those displayed by strains 569B and MAK757.

Effects of iontophoretically applied serotonin on three classes of physiologically characterized putative pain modulating neurons in the rostral ventromedial medulla of lightly anesthetized rats.

The importance of the rostral ventromedial medulla (RVM) in nociceptive modulation is well documented, and several lines of evidence point to a role for serotonin (5HT) in regulating the activity of pain modulating neurons in this region. The aim of the present study was to examine the effect of iontophoretically applied 5HT upon the firing of three physiologically defined classes of RVM neurons with distinct roles in pain modulation. The predominant effect across all classes was a facilitation of ongoing or evoked activity. A minority of cells within each class were inhibited by 5HT itself, but agonists at 5HT1 receptor types inhibited the majority of cells tested. The results thus indicate that the behavioral effects of manipulating 5HT within the RVM cannot be attributed to a selective influence on a particular cell class.

Multiple sclerosis: comparison of trace apparent diffusion coefficients with MR enhancement pattern of lesions.

BACKGROUND AND PURPOSE: Diffusion-weighted MR imaging and the trace apparent diffusion coefficient (ADC) provide important structural information about tissues. The purpose of this study was to investigate the relationship between trace ADC values and the enhancement pattern of multiple sclerosis (MS) lesions. METHODS: Ninety-six lesions, identified in 24 patients with MS, were characterized by their enhancement pattern on contrast-enhanced T1-weighted MR images. There were 57 nonenhancing lesions (NELs), 28 homogeneously enhancing lesions (HELs), and 11 ring-enhancing lesions (RELs). The trace ADC means for each type of lesion and for normal-appearing white matter (NAWM) were calculated and compared using Student's t-test. RESULTS: The mean trace ADC values for HELs (mean, 7.7 x 1(-10) m2s(-1); SD, 1.4 x 10(-10) m2s(-1)) were less than those for RELs (mean, 1.2 x 10(-9) m2s(-1); SD, 3.5 x 10(-10)m2s(-1)) and NELs (mean, 1.3 x 10(-9) m2(s-1); SD, 2.6 x 10(-10) m2(s-1)). There was a significant difference between the mean trace ADC values of HELs and RELs as well as between those for HELs and NELs. There was also a significant difference in the mean trace ADC values between all lesion types and NAWM (mean, 6.9 x 10(-10) m2s(-1); SD, 5.0 x 10(-11) m2s(-1)). CONCLUSION: We found a predictable relationship between mean trace ADC and the pattern of enhancement in MS lesions, corresponding to reported histopathologic differences in myelination between lesion types and magnetization transfer ratios.

MR imaging for predicting neoplastic invasion of the cervical esophagus.

BACKGROUND AND PURPOSE: Esophageal invasion (EI) by head and neck neoplasm has important prognostic and surgical management implications. Our purpose was to determine the accuracy of MR imaging for predicting neoplastic cervical esophageal invasion. METHODS: MR scans of the neck obtained from 22 patients with periesophageal masses were retrospectively reviewed independently and by consensus by two experienced head and neck radiologists who were unaware of surgical findings. The patients were selected from clinical, radiologic, or pathologic reports suggesting EI. The following imaging criteria for EI were evaluated: effacement of periesophageal fat planes, circumferential mass, paraesophageal lymph nodes, luminal size, wall thickening, increased T2 wall signal, and wall enhancement. There were eight patients with EI and 14 patients without EI, as confirmed by surgical findings or pathologic examination. RESULTS: The consensus criteria with the best sensitivities were any wall thickening (100%), effaced fat plane (100%), and any T2 wall signal abnormality (100%). The criteria with the best specificities were circumferential mass greater than 270 (100%) or 180 degrees (93%) and focal T2 wall signal abnormality (86%). The overall kappa value for the two readers for all criteria was 0.57 (moderate agreement). CONCLUSION: A circumferential mass or focal T2 signal abnormality on the esophageal wall suggests the presence of EI. An intact fat plane, absence of wall thickening, and no T2 wall signal abnormalities imply that the esophagus is not invaded.

Location of the central sulcus via cortical thickness of the precentral and postcentral gyri on MR.

PURPOSE: To determine whether relative cortical thickness measurements of the precentral and postcentral gyri can be used to differentiate the central sulcus from adjacent cortical sulci. METHODS: Turbo inversion-recovery MR imaging of the entire brain was done with scans parallel to the anterior commissure-posterior commissure line. Cortical thickness was measured in each hemisphere with a jeweler's eyepiece with 0.1-mm gradations. Three measurements were obtained perpendicular to the central, precentral, and superior frontal sulci, as determined by means of established anatomic methods. The ratios of cortical thickness on both sides of the central, precentral, and superior frontal sulci were calculated and compared. RESULTS: The mean ratio of precentral/postcentral gyri was 1.64 for the right hemisphere and 1.53 for the left hemisphere. The mean cortical thickness ratios were as follows: 1.01 for the right hemisphere and 3.01 for the left hemisphere across the precentral sulcus, and 1.03 for the right hemisphere and 0.99 for the left hemisphere across the superior frontal sulcus. CONCLUSION: Cortical thickness measurements across the central sulcus provide a method for locating the primary motor (precentral gyri) and primary somatosensory (postcentral gyri) cortices. The higher mean cortical thickness ratio across the central sulcus corresponds with known cytoarchitectonic relationships.

Spontaneous intracranial hypotension: spinal MR findings.

We report three patients with spontaneous intracranial hypotension in whom spinal MR imaging revealed ventral extradural fluid collections that were centered at the cervicothoracic junction in two patients and extended throughout the entire spine in the third patient. These spinal fluid collections most likely resulted from the accumulation of CSF at the site of dural leakage. Knowledge of this association can be helpful in the selection of imaging studies to facilitate diagnosis and treatment.

Mapping of the candidate tumor suppressor genes' loci on human chromosome 3 in head and neck squamous cell carcinoma of an Indian patient population.

The candidate tumor suppressor genes' (TSG) loci on human chromosome 3 (chr.3) were mapped in six dysplastic lesions and 51 primary squamous cell carcinoma from head and neck region of an Indian patient population by using 20 highly polymorphic microsatellite markers. The two chromosomal regions 3p12-13 and 3p21.2-22 have shown the highest losses of heterozygosity (LOHs) of 34.6-38% and 37-46%, respectively with statistically significant clinical correlation's with tobacco habit, positive lymph node and tumor stages. In addition, high frequencies of microsatellite size alterations (MAs) of 16.2-28.5% and 23.8-28.2% were observed in the chromosomal 3p11-13 and 3p21.2-22 regions, respectively, with significant above-mentioned clinical correlation only in the 3p11-13 region. In the dysplastic lesions, the prevalence of LOHs compared to the MAs had indicated that LOHs might be the early events. Five tumors at stage-III/IV seemed to have lost an entire normal copy of chr.3. It was of particular note that 17% (10/57) of the samples showed rare bi-allelic alterations mainly in and around the high LOHs regions. Thus, (1) the gradual increase of LOHs/MAs during progression of the tumor, (2) high frequencies of MAs, (3) rare bi-allelic alterations in and around high LOHs regions and (4) loss of wild type chr.3 in the later stages of tumor development have suggested that such alterations might provide selective growth advantage to the tumors. Also, we propose from our data that the high LOHs regions (3p12-13 and 3p21.2-22) could harbour putative TSG(s), responsible for the development of head and neck squamous cell carcinoma.

Association of deletion in the chromosomal 8p21.3-23 region with the development of invasive head & neck squamous cell carcinoma in Indian patients.

BACKGROUND & OBJECTIVES: Deletions in chromosome 8 (chr.8) have been shown to be necessary for the development of head and neck squamous cell carcinoma (HNSCC). Attempts have been made in this study to detect the minimal deleted region in chr.8 associated with the development of HNSCC in Indian patients and to study the association of clinicopathological features with the progression of the disease. METHODS: The deletion mapping of chr.8 was done in samples from 10 primary dysplastic lesions and 43 invasive squamous cell carcinomas from the head and neck region of Indian patients to detect allelic alterations (deletion or size alteration) using 12 highly polymorphic microsatellite markers. The association of the highly deleted region was correlated with the tumour node metastasis (TNM) stages, nodal involvement, tobacco habit and human papilloma virus (HPV) infection of the samples. RESULTS: High frequency (49%) of loss of heterozygosity (LOH) was seen within 13.12 megabase (Mb) region of chromosomal 8p21.3-23 region in the HNSCC samples, whereas the dysplastic samples did not show any allelic alterations in this region. The highest frequency (17%) of microsatellite size alterations (MA) was observed in the chr.8p22 region. The loss of short arm or normal copy of chr.8 and rare bi-allelic alterations were seen in the stage II-IV tumours (939, 5184, 2772, 1319 and 598) irrespective of their primary sites. The highly deleted region did not show any significant association with any of the clinical parameters. However, HPV infection was significantly associated (P < 0.05) with the differentiation grades and overall allelic alterations (LOH/MA) of the samples. INTERPRETATION & CONCLUSION: Our data indicate that the 13.12 Mb deleted region in the chromosomal 8p21.3-23 region could harbour candidate tumour suppressor gene(s) (TSGs) associated with the progression anti invasion of HNSCC tumours in Indian patients.

Sequential deletions in both arms of chromosome 9 are associated with the development of head and neck squamous cell carcinoma in Indian patients.

In the deletion mapping of chromosome (chr) 9 in head and neck lesions of the Indian patient population by microsatellite markers, we have identified four discrete areas (D1-D4) with high loss of heterozygosities (LOHs) viz. 9p24-p23 (D1), 9p22-p21 (D2), 9q11-q13 (D3) and 9q22.3 (D4) regions. The deletions in D2 and D4 regions were suggested to be essential for the development of dysplastic lesions of head and neck, whereas the deletions in D1 and D3 regions were responsible for progression of the dysplastic lesions to early invasive head and neck squamous cell carcinoma (HNSCC). The microsatellite size alterations (MAs) were observed in the chromosomal 9pter-p23, 9p22-p21(D2), 9q13 and 9q21.1-q21.2 regions with gradual increase during progression of the tumor. Additional chromosomal alterations like loss of normal copy of chr.9 and biallelic alterations were also seen in our samples. There is a correlation between HPV infection with TNM stages, histopathological grades and LOHs at D1 and D4 regions. Whereas tobacco habit is associated with the occurrence of LOHs at D1 and LOHs / MAs at D2 region.