The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (<svg     style="vertical-align:-0.30096pt;width:58.712502px;" id="M1" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><path id="x35" d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8&#xA;l-26 -65h-233z" /></g>

		
	
</svg>), whereas frequency and onset of peripheral neuropathy were highly significant (<svg     style="vertical-align:-0.30096pt;width:58.712502px;" id="M2" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3C"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g>

		
	
</svg>) in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85&#x2009;mg/m<sup  >2</sup>), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130&#x2009;mg/m<sup  >2</sup>) after few treatment cycles.

Nusrat Bano

Rahila Najam

Ahmed Mateen

Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX

<i>Purpose</i>. The purpose of this study was to evaluate medications that cancer survivors with oxaliplatin-induced peripheral neuropathy take to control neuropathic symptom, and to explore self-management techniques used at home to provide temporary relief of painful neuropathy. This was a mixed methods, descriptive, cross-sectional study using self-reported data from colorectal cancer survivors previously treated with oxaliplatin. We analyzed demographic and medication data obtained from participants, along with written comments from an open-ended question regarding methods participants had tried to self-manage symptoms of neuropathy. <i>Results</i>. Twenty-nine percent of the sample reported taking some type of nutritional supplement with potential neuroprotective qualities. Opioids were being taken by 10&#x25; of the sample, and nonsteroidal anti-inflammatory and over-the-counter medications were taken by 15&#x25; of participants. Twelve percent of participants were taking antidepressants and 10&#x25; were taking anticonvulsants, primarily gabapentin. Recurrent themes for nonpharmacologic treatment included avoiding the cold/keeping warm, keeping moving, massaging or rubbing the affected area, and living with it. <i>Conclusions</i>. Patients treated with oxaliplatin for colorectal cancer utilize a variety of traditional pharmacologic agents and nutritional supplements in an effort to self-manage neuropathic symptoms. Patients also employ a variety of home-based therapies to provide temporary relief of peripheral neuropathy symptoms.

Cindy Tofthagen

Laura Gonzalez

Constance Visovsky

Alex Akers

Self-Management of Oxaliplatin-Related Peripheral Neuropathy in Colorectal Cancer Survivors

Resistance to methicillin by <i  >Staphylococcus aureus</i> is a persistent clinical problem worldwide. A mechanism for resistance has been proposed in which methicillin resistant <i  >Staphylococcus aureus</i> (MRSA) isolates acquired a new protein called <i  >&#x3b2;</i>-lactam inducible penicillin binding protein (PBP-2&#x2032;). The PBP-2&#x2032; functions by substituting other penicillin binding proteins which have been inhibited by <i  >&#x3b2;</i>-lactam antibiotics. Presently, there is no structural and regulatory information on PBP-2&#x2032; protein. We conducted a complete structural and functional regulatory analysis of PBP-2&#x2032; protein. Our analysis revealed that the PBP-2&#x2032; is very stable with more hydrophilic amino acids expressing antigenic sites. PBP-2&#x2032; has three striking regulatory points constituted by first penicillin binding site at Ser25, second penicillin binding site at Ser405, and finally a single metallic ligand binding site at Glu657 which binds to <svg     style="vertical-align:-0.0pt;width:32.987499px;" id="M1" height="15.8375" version="1.1" viewBox="0 0 32.987499 15.8375" width="32.987499"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,15.775)"><path id="x5A" d="M561 176l29 -6q-25 -130 -36 -170h-517l-8 15l420 599h-173q-77 0 -102 -7t-39 -29q-19 -29 -35 -87l-29 1q9 111 12 183h24q9 -16 19 -20.5t34 -4.5h399l7 -14l-413 -594q48 -6 163 -6q94 0 131.5 7.5t58.5 29.5q28 29 55 103z" /></g><g transform="matrix(.017,-0,0,-.017,10.313,15.775)"><path id="x6E" d="M524 0h-209v26q44 5 55 18t11 65v167q0 114 -91 114q-50 0 -109 -51v-235q0 -50 10 -61.5t55 -16.5v-26h-217v26q51 5 62 17t11 61v206q0 47 -9.5 58.5t-50.5 19.5v23q82 15 139 40v-79l67 47q47 30 83 30q60 0 94.5 -40t34.5 -112v-193q0 -50 10 -61.5t54 -16.5v-26z&#xA;" /></g>

			<g transform="matrix(.012,-0,0,-.012,19.612,7.613)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" /></g><g transform="matrix(.012,-0,0,-.012,25.324,7.613)"><path id="x2B" d="M535 230h-212v-233h-58v233h-213v50h213v210h58v-210h212v-50z" /></g>

		
	
</svg> ions. This report highlights structural features of PBP-2&#x2032; that can serve as targets for developing new chemotherapeutic agents and conducting site direct mutagenesis experiments.

Andreas N. Mbah

Raphael D. Isokpehi

Identification of Functional Regulatory Residues of the <b><i>&#x3b2;</i></b>-Lactam Inducible Penicillin Binding Protein in Methicillin-Resistant <i>Staphylococcus aureus</i>

A retrospective review was performed on patients with stable melanoma brain metastases treated with HD IL-2 therapy (720,000&#x2009;IU/kg per dose intravenously; 14 doses, 2 cycles per course, maximum 2 courses) from January 1999 to June 2011 at Saint Louis University. There were 5 men and 3 women; median age was 52.2 years (26.8&#x2013;61.1 years). One patient started treatment with lung lesions only (after resection of melanoma brain disease) and experienced partial response. Seven patients had brain metastases at treatment initiation. Median overall survival (mOS) for entire cohort (<svg     style="vertical-align:-0.1638pt;width:36.237499px;" id="M1" height="11.125" version="1.1" viewBox="0 0 36.237499 11.125" width="36.237499"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,10.862)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z" /></g><g transform="matrix(.017,-0,0,-.017,13.305,10.862)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" /></g><g transform="matrix(.017,-0,0,-.017,28.008,10.862)"><path id="x38" d="M249 635q70 0 116 -43t46 -105q0 -46 -28 -80q-22 -25 -80 -64q62 -35 97 -75t35 -99q0 -81 -63 -131t-135 -50q-83 0 -137.5 45.5t-54.5 123.5q0 52 45 95q29 28 89 64q-109 62 -109 155q0 66 50.5 115t128.5 49zM238 603q-42 0 -67.5 -31t-25.5 -72q0 -50 32.5 -79.5&#xA;t98.5 -62.5q61 48 61 124q0 59 -29.5 90t-69.5 31zM248 20q46 0 76.5 33.5t30.5 89.5q0 50 -39 85.5t-110 71.5q-81 -54 -81 -137q0 -67 35.5 -105t87.5 -38z" /></g>

		
	
</svg>) was 8.7 months (2.1 to 19.0 months). All patients with brain metastases at first dose (<svg     style="vertical-align:-0.1638pt;width:36.237499px;" id="M2" height="10.925" version="1.1" viewBox="0 0 36.237499 10.925" width="36.237499"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,10.65)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,-0,0,-.017,13.305,10.65)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,28.008,10.65)"><path id="x37" d="M447 623l8 -12l-283 -613l-74 -10l-7 11q174 283 297 551h-216q-48 0 -62.5 -12t-33.5 -63h-29q10 60 18 148h382z" /></g>

		
	
</svg>) showed progressive disease; mOS was 6.7 months (range 2.1&#x2013;18.2 months) for this group. Patients received radiosurgery and whole brain radiation before and after HD IL-2 therapy. One patient had symptoms suggestive of neurotoxicity. A history of alcohol abuse was revealed during admission. The patient's symptoms improved with initiation of an alcohol withdrawal protocol. In this analysis, patients with melanoma brain metastases received HD IL-2 without treatment-related mortality. We think that HD IL-2 should be considered as a treatment option in patients with melanoma brain metastases who are otherwise eligible for therapy.

Melinda B. Chu

Mark J. Fesler

Eric S. Armbrecht

Scott W. Fosko


							Eddy Hsueh

John M. Richart

High-Dose Interleukin-2 (HD IL-2) Therapy Should Be Considered for Treatment of Patients with Melanoma Brain Metastases

Lomustine is a nitrosourea anticancer agent shown to be effective for treatment of childhood medulloblastoma. In silico substructure searches produced 17 novel nitrosourea agents analogous to lumustine and retaining activity for DNA alkylation and cytotoxic activity. The mean values for Log <i>P</i>, polar surface area, formula weight, number of oxygens &#x26; nitrogens, and rotatable bonds were 2.524, 62.89 Anstroms<sup>2</sup>, 232.8, 5, and 2, respectively. All 17 agents have formula weight less than 450 and Log <i>P</i> less than 5, two criteria preferred for blood-brain barrier penetration. These agents have a polar surface area less than 90 Angstroms<sup>2</sup>. Each show zero violations of the Rule of five indicating favorable drug likeness and oral drug activity. Hierarchical cluster analysis indicated that 16 of the novel agents were highly similar to lomustine, save for agent 12 which bears a hydroxylated branched carbon substituent. A total of 17 novel anticancer agents were elucidated having molecular properties very effective for penetrating through the BBB and into the central nervous system. This study shows the effectiveness of in silico search and recognition of anticancer agents that are suitable for the clinical treatment of brain tumors.

Ronald Bartzatt

Lomustine Analogous Drug Structures for Intervention of Brain and Spinal Cord Tumors: The Benefit of In Silico Substructure Search and Analysis

High-risk prostate cancer represents a pretentious clinical problem since a significant number of its patients will relapse and progress after radical prostatectomy. Neoadjuvant chemotherapy may be valuable since its efficacy in hormone-resistant prostate cancer has been established. In this paper, we report studies of neoadjuvant chemotherapies that have been used in high-risk patients prior to radical prostatectomy. Even though the results regarding the prognostic surrogates are not significant, the effects on clinical and pathological outcomes are promising, while toxicity in most of the studies is in the expected field.

Stavros Sfoungaristos

Vasileios Kourmpetis

Eleftherios Fokaefs

Petros Perimenis

Neoadjuvant Chemotherapy prior to Radical Prostatectomy for Patients with High-Risk Prostate Cancer: A Systematic Review

Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF-<i>&#x3ba;</i>B is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF-<i>&#x3ba;</i>B inhibitor with antiproliferative properties in GBM.  In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O<sup>6</sup>-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches.

M. S. Brassesco

G. M. Roberto

A. G. Morales

J. C. Oliveira

L. E. A. Delsin

J. A. Pezuk

E. T. Valera

C. G. Carlotti

E. M. Rego

H. F. de Oliveira

C. A. Scrideli

K. Umezawa

L. G. Tone

Inhibition of NF-<i>&#x3ba;</i>B by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and <i>&#x3b3;</i>-Radiation Cytotoxicity in Glioblastoma Cells

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Chemotherapy Research and Practice