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The efficacy of transfusion with hyperimmune plasma (HIP) for preventing pneumonia caused by Rhodococcus equi remains ill-defined. Quarter Horse foals at 2 large breeding farms were randomly assigned to be transfused with 2 L of HIP from adult donors hyperimmunized either with R. equi (RE HIP) or a conjugate vaccine eliciting antibody to the surface polysaccharide β-1→6-poly-N-acetyl glucosamine (PNAG HIP) within 24 hours of birth. Antibody activities against PNAG and the rhodococcal virulence-associated protein A (VapA), and to deposition of complement component 1q (C՛1q) onto PNAG were determined by ELISA, and then associated with either clinical pneumonia at Farm A (n = 119) or subclinical pneumonia at Farm B (n = 114). Data were analyzed using multivariable logistic regression. Among RE HIP-transfused foals, the odds of pneumonia were approximately 6-fold higher (P = 0.0005) among foals with VapA antibody activity ≤ the population median. Among PNAG HIP-transfused foals, the odds of pneumonia were approximately 3-fold (P = 0.0347) and 11-fold (P = 0.0034) higher for foals with antibody activities ≤ the population median for PNAG or C՛1q deposition, respectively. Results indicated that levels of activity of antibodies against R. equi antigens are correlates of protection against both subclinical and clinical R. equi pneumonia in field settings. Among PNAG HIP-transfused foals, activity of antibodies with C՛1q deposition (an indicator of functional antibodies) were a stronger predictor of protection than was PNAG antibody activity alone. Collectively, these findings suggest that the amount and activity of antibodies in HIP (i.e., plasma volume and/or antibody activity) is positively associated with protection against R. equi pneumonia in foals., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Gerald B. Pier (GBP) is an inventor of intellectual properties [human monoclonal antibody to PNAG and PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Vaccine, LLC, an entity in which GBP also holds equity. As an inventor of intellectual properties, GBP also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Vaccine, LLC. GBP’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners Health care in accordance with their conflict of interest policies. Colette Cywes-Bentley (CC-B) is an inventor of intellectual properties [use of human monoclonal antibody to PNAG and use of PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Vaccine, LLC. As an inventor of intellectual properties, CC-B also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Vaccine, LLC. Daniel R. Vlock is the Chief Executive Officer of ALOPEXX Vaccines and owns the rights to the PNAG vaccine. Dr. Vlock had no role in the design or analysis of the study. SC Meyer and PJ Sutter work for MG Biologics that produced the plasma and thus might have potential earnings; however, they had no part in the design or analysis of the study. Drs. Glenn Blodgett and Nathan Canaday are employees of the 6666 Ranch and Dr. Carly Turner-Garcia is employed by the Lazy E Ranch. Sarah Meyer and Patrick Sutter are employed by Mg Biologics, Inc. and Dr. Daniel Vlock is employed by ALOPEXX Vaccines. The 6666 Ranch, Lazy E Ranch, Mg Biologics, and ALOPEXX provided support in the form of salaries, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Immune correlates of protection against intracellular bacterial pathogens are largely thought to be cell-mediated, although a reasonable amount of data supports a role for antibody-mediated protection. To define a role for antibody-mediated immunity against an intracellular pathogen, Rhodococcus equi, that causes granulomatous pneumonia in horse foals, we devised and tested an experimental system relying solely on antibody-mediated protection against this host-specific etiologic agent. Immunity was induced by vaccinating pregnant mares 6 and 3 weeks prior to predicted parturition with a conjugate vaccine targeting the highly conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG). We ascertained antibody was transferred to foals via colostrum, the only means for foals to acquire maternal antibody. Horses lack transplacental antibody transfer. Next, a randomized, controlled, blinded challenge was conducted by inoculating at ~4 weeks of age ~10(6) cfu of R. equi via intrabronchial challenge. Eleven of 12 (91%) foals born to immune mares did not develop clinical R. equi pneumonia, whereas 6 of 7 (86%) foals born to unvaccinated controls developed pneumonia (P = 0.0017). In a confirmatory passive immunization study, infusion of PNAG-hyperimmune plasma protected 100% of 5 foals against R. equi pneumonia whereas all 4 recipients of normal horse plasma developed clinical disease (P = 0.0079). Antibodies to PNAG mediated killing of extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms depended on antibody recognition of surface expression of PNAG on infected cells, along with complement deposition and PMN-assisted lysis of infected macrophages. Peripheral blood mononuclear cells from immune and protected foals released higher levels of interferon-γ in response to PNAG compared to controls, indicating vaccination also induced an antibody-dependent cellular release of this critical immune cytokine. Overall, antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against diseases caused by intracellular bacterial pathogens., Competing Interests: Gerald B. Pier is an inventor of intellectual properties [human monoclonal antibody to PNAG and PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Vaccine, LLC, and Alopexx Pharmaceuticals, LLC, entities in which GBP also holds equity. As an inventor of intellectual properties, GBP also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC, and Alopexx Vaccine, LLC. GBP’s interests were reviewed and are managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies. Colette Cywes-Bentley is an inventor of intellectual properties [use of human monoclonal antibody to PNAG and use of PNAG vaccines] that are licensed by Brigham and Women’s Hospital to Alopexx Pharmaceuticals, LLC. As an inventor of intellectual properties, CC-B also has the right to receive a share of licensing-related income (royalties, fees) through Brigham and Women’s Hospital from Alopexx Pharmaceuticals, LLC. Noah D. Cohen has received an unrestricted gift to the EIDL from Alopexx Vaccines, LLC. Daniel Vlock, holds an equity share and potential royalty income from Alopexx Vaccines, LLC for vaccines to PNAG and monoclonal antibody to PNAG from Alopexx Pharmaceuticals, LLC. Mark Meyer holds minority equity shares of Mg Biologics, Inc. Sarah Anthony and McKenzie Lambert are employees of Mg Biologics, Inc.

Purpose: To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck., Patients and Methods: Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m(2) (24-hour infusion) + cisplatin 75mg/m(2) + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m(2) (24-hour infusion) + cisplatin 75 mg/m(2). Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival., Results: No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal., Conclusion: This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.

Background: Antitumor effects of antibodies against ganglioside antigens of melanoma have been reported, but neither optimal doses nor mechanisms have been established., Methods: This Phase IB trial of the murine immunoglobulin IgG(3) monoclonal antibody R(24) against disialoganglioside GD3 was conducted with 37 patients to define better the dose-response relation and mechanism of action of R(24) in patients with metastatic melanoma., Results: Dose-limiting toxicity consisted of a pulmonary capillary leak syndrome in 3 of 5 patients in the 80 mg/M(2)/day dosage tier. Serial blood and tumor biopsy samples were obtained prior to therapy and on Days 5, 9, and 22 following R(24) infusion. Tumor biopsy-infiltrating lymphocytes were enumerated in peritumoral, endotumoral, and perivascular compartments: endotumoral CD4(+) and CD8(+) T cells and HLA-DR(+) T cells increased over time on R(24) antibody. Endotumoral CD4 lymphoid infiltrate activation (DR expression) and antibody-dependent cytotoxicity were the greatest in the one patient who achieved a complete response., Conclusions: Clinical response was associated with depression in natural killer (CD56(+) and CD56(+)DR(+)) blood cells (P = 0.03) and was associated with R(24) dosage (P = 0.01). A complete response that lasted 2 years and a partial response that lasted 2 months occurred at a dose of 1 mg/M(2)/day. The limited number of clinical responses observed in this trial hampered the correlation of antitumor and immune parameters but provided a rational foundation for the future evaluation of antiganglioside antibodies., (Copyright 2000 American Cancer Society.)

During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 10(6) U/mg protein, < 5.0 endotoxin units/mg protein) was given over 2 h intravenously on days 1, 8-12, 29-33, 50-54, and 71-75 at doses of 40, 80, 160, 200, and 240 micrograms/m2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-gamma and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-gamma or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose-related diminished production of IFN-gamma by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.

The objective of this study was to study the antitumor, host toxicity, and immunomodulatory effects of recombinant interferon-alpha 2b (IFN) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Seventy-one patients with recurrent or metastatic SCCHN were entered into a phase II noncomparative randomized trial of IFN at two dosage schedules. Eligible patients with histologically proven SCCHN were randomized to receive low-dose IFN, 6 x 10(6) U/m2 daily x 3 every 4 weeks or high-dose IFN, 12 x 10(6) U/m2, 3 x/week. Pretreatment levels of natural killer (NK) activity, CD3, CD4, CD5, CD8, CD16, CD19, CD56, DR, and the CD4/CD8 ratio were evaluated for any relationship with survival. The toxicity encountered in patients receiving low-dose IFN was for the most part mild to moderate. With high-dose IFN, toxicity was greater with significantly more episodes of grade 3 and 4 toxicity encountered. Dosage reduction was required in the majority of patients receiving high-dose IFN. Of the four lethal complications, only one was thought to be possibly associated with therapy. Of the 32 evaluable patients receiving low-dose IFN, there were 1 complete response, 1 stable disease, 24 patients with progressive disease, and 6 unevaluable. Of the 29 evaluable patients taking high-dose IFN, there were 2 complete responses, 7 with stable disease, 16 with progressive disease, and 4 patients were unevaluable. Median survival in the two arms was similar (6.2 months). Because it was postulated that a more prolonged exposure to IFN might be needed for it to be effective, patients receiving > or = 6 weeks of therapy were evaluated. Median survival in that subset was 10 and 12 months for patients receiving low- and high-dose IFN, respectively. None of the immune parameters tested was a significant predictor of survival when evaluated in all cases entered into study regardless of therapy duration. No difference in baseline NK activity was noted between patients who received < 6 or > or = 6 weeks of IFN (p = 0.90). However, among the 35 patients who received > or = 6 weeks of therapy, a high baseline NK activity was a significant predictor of the duration of survival (p = 0.04). IFN was well tolerated in patients with recurrent or metastatic SCCHN. The higher incidence of toxicity encountered in the high-dose arm could be ameliorated by reducing the dose 50%. In patients receiving 6 or more weeks of therapy, elevated baseline NK activity was associated with increases in survival, suggesting that IFN may play an immunomodulatory role. Although the overall response rates were low, disease stabilization was noted, suggesting an antiproliferative, noncytotoxic role of IFN in this group of heavily pretreated patients.

We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) significantly potentiates the antitumor activity of a variety of chemotherapeutic agents, including cisplatin (cDDP). In studies described here, we examined the potential of combining IL-1 alpha and the platinum analogue carboplatin (CBDCA) and compared the schedule-dependent and pharmacokinetic effects for IL-1 alpha combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.p. injections of varying doses of CBDCA, alone or concurrently with IL-1 alpha (48 or 480 micrograms/kg). Clonogenic cell kill and tumor regrowth delay were significantly increased when CBDCA was combined with IL-1 alpha, at both doses, compared to either CBDCA or IL-1 alpha alone (P < 0.001 and P < 0.01, respectively). Although pretreatment with IL-1 receptor antagonist blocked the acute tumor hemorrhagic response induced by IL-1 alpha alone, IL-1 receptor antagonist only partially blocked IL-1 alpha enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 alpha enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 alpha was administered 4-12 h before CBDCA. In contrast, administration of IL-1 alpha from 24 h before or as late as 6 h after cDDP resulted in the same antitumor activity as simultaneous administration of cDDP and IL-1 alpha. Tumor and normal tissue platinum content were significantly increased by IL-1 alpha in animals treated with CBDCA (P < 0.01) but not in those treated with cDDP. The observed differences between cDDP and CBDCA may be explained by their known differential rates of clearance and protein binding affinities and are compatible with an induced alteration in CBDCA pharmacokinetics.

Thirty-six patients with unresectable squamous cell carcinoma of the head and neck were entered into a phase Ib trial evaluating the toxicity, maximally tolerated dose (MTD), and immunomodulating effects of locally administered interleukin-2 (IL-2). Patients received daily IL-2 injected perilesionally in divided doses in each of four quadrants and bilaterally into the superior jugular lymph nodes. The dose of IL-2 began at 200 U/day and was escalated to 4 x 10(6) U/day in groups of six patients. Overall, regionally administered IL-2 was well tolerated. The most frequently encountered toxicities were fever, hepatotoxicity, and hypotension. Dose-limiting toxicity was encountered at 4 x 10(6) U. Of the 36 patients treated, 2 partial responses were noted at 2,000 and 4 x 10(6) U. We conclude that regionally administered IL-2 is well tolerated in patients with head and neck cancer and that the MTD is 2 x 10(6) U/day, similar to what has been reported with systemically administered IL-2. Although the overall response rate was low, it may be improved with prolonged administration of IL-2 or by combining it with other biologic or cytotoxic agents.

Purpose: To evaluate the correlation between the presence and titer of host-derived antibody reactivity, circulating immune complexes, and clinical course and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN)., Materials and Methods: Serum samples, obtained from untreated patients with squamous cell carcinoma of the larynx entered onto a multiinstitutional trial, were evaluated for the presence of elevated circulating immune complexes (221 patients) and host-derived antibody directed against two SCCHN cell lines (107 patients)., Results: Patients had significantly elevated levels of circulating immune complexes as measured by C1q binding compared with normal controls. Patients with higher levels of circulating immune complexes were less likely to respond to chemotherapy. No correlations were noted between immune complex levels and stage of disease, nodal status, site of disease, recurrence, or survival. Evaluation of native antibody titers for their relationship to clinical correlates showed no statistically significant associations. In sera subjected to immune complex dissociation, patients with moderately or poorly differentiated tumors had significantly higher antibody titers when compared with patients with well-differentiated tumors. Because marked variation in the increase of antibody titers following immune complex dissociation was noted, the ratio of immune complex-dissociated to native antibody titer was examined. Patients with a high ratio had a lower proportion of complete and partial responses to chemotherapy., Conclusion: Our results support the conclusion that the formation of tumor-associated immune complexes in patients with SCCHN is associated with a decreased response to chemotherapy.

We have previously reported the purification and partial characterization of a human melanoma-associated antigen (M-66) recognized by autologous antibody. This antigen was found to be an unusually acidic 66 kDa glycoprotein. In studies of murine melanoma, a 67-kDa albumin-like melanoma-associated antigen (MAA) isolated from B16 melanoma cells has also been reported by our laboratories. Because the murine MAA, B700, has a molecular weight that is nearly the same as M-66, we sought to determine what similarities and differences existed between these two antigens. Human sera S150, which is known to recognize M-66, was found to bind to murine melanoma cell line B16. The addition of purified M-66 inhibited binding of S150 to B16 cells. Binding by S150 was not noted against murine melanoma cell line S91, which is known not to express cell surface B700. Conversely, reactivity of S150 against Y-Mel 84:420, known to express M-66, could be inhibited by preincubation with B16 cells. Four monoclonal antibodies known to recognize B700 were evaluated for-binding against murine B16 and human melanoma cell line Y-Mel 84:420. Binding was noted against both B16 and Y-Mel 84:420 which could be inhibited by the addition of M-66. Binding of S150 was also noted against purified B700 as tested by ELISA. While a comparison of the amino acid composition of the two antigens revealed similarities, M-66 contained 2.8 times as much serine and 0.4 times as much proline as B700. B700 has been reported to be related to serum albumin, which is not the case for M-66.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously shown that detection of autologous antibody activity to squamous cell carcinoma of the head and neck may be augmented by dissociation of immune complexes. Western blot analysis with autologous antibody has identified a 60 kDa squamous cell carcinoma of the head and neck-associated antigen in spent media and immune complex-dissociated serum ultrafiltrate not recognized by normal human sera. Antigen-containing fractions of spent media were eluted from anion exchange columns immediately after serum albumin indicating that the antigen has an acidic pI < 4. Preparative purification of the squamous cell carcinoma antigen was accomplished by anion exchange of concentrated spent media (protein concentration 300 mg/ml) followed by lectin affinity chromatography with a Triticum vulgaris column. A single 60 kDa band was detected by silver stain and Western blot in antigen-containing fractions eluted following lectin affinity chromatography and SDS-PAGE. Final concentration of the antigen was determined to be 1 microgram/ml of protein with relative activity increased 1600 x over unfractionated spent media. We conclude that a squamous cell carcinoma of the head and neck-associated antigen, detected by autologous antibody, is an acidic 60 kDa glycoprotein.

XOMAZYME-Mel (XMMME-001-RTA) is an immunoconjugate comprised of ricin A chain conjugated to a murine monoclonal antibody directed against high molecular weight melanoma antigens. Although not necessarily related to increased toxicity or decreased efficacy, the development of anti-immunoconjugate antibodies may limit repetitive dosing with an immunoconjugate. We evaluated the role of cyclosporine A in blocking the antibody response in patients with melanoma treated with XMMME-001-RTA. Patients received cyclosporine in divided daily doses to achieve serum levels by HPLC of 150-200 ng/ml on days 1-22. On day 3, XMMME-001-RTA was begun at dosages 0.2-0.6 mg/kg daily for 5 days. Treatment was repeated every 35 days. Three patients were treated in each dosage tier (0.2, 0.4, 0.6 mg/kg). Nine patients were entered and all nine were evaluable. Patients had histologically confirmed melanoma. Metastatic sites included skin, soft tissue, and lymph nodes (seven), lung (two), liver (one), and spleen (one). There were four men and five women aged 46-75 years. Toxicities included myalgia, arthralgia, hypoalbuminemia, fatigue, elevations in liver function tests, and increased peripheral edema. Four patients received two to five repeated dosages of XMMME-001-RTA. One wheal-and-flare reaction from an immunotoxin test dose of XMMME-001-RTA was noted after five cycles. After a test dose subsequent to one cycle, two patients experienced chest tightness without ECG changes and were removed from the study. All toxicities resolved without sequelae. One patient experienced partial lymph node remission for 9 months. A second patient had stable mediastinal disease for 20 months. XMMME-001-RTA is safe when given repeatedly with cyclosporine.

Administration of interleukin-1 alpha (IL-1 alpha) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 alpha itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 alpha's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 alpha on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 alpha and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 alpha and cDDP being analyzed through median dose-effect. In vitro, IL-1 alpha had no enhancing effect on the cDDP-mediated tumor-cell kill. For examination of the in vivo efficacy of this regimen, RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 alpha and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 alpha/cDDP was dose-dependent, with significant enhancement by IL-1 alpha being observed (P < 0.001), even at the lowest doses tested (2 mg/kg and 6 micrograms/kg for cDDP and IL-1 alpha, respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 alpha significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P < 0.001). These results demonstrate that IL-1 alpha synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 alpha and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.

Genetic studies have implicated the early involvement of a gene on chromosome arm 9p in the development of cutaneous melanoma. We have performed loss-of-heterozygosity studies to confirm these original findings and identify the most frequently rearranged or deleted region of 9p. Eight markers were analyzed, including (from 9pter to proximal 9q) D9S33, the beta-interferon (IFNB1) locus, the alpha-interferon (IFNA) gene cluster, D9S126, D9S3, D9S19, the glycoprotein 4 beta-galactosyltransferase (GGTB2) gene, and the argininosuccinate synthetase pseudogene 3 (ASSP3). Two or more of these loci were found to be hemizygously reduced in 12 of 14 (86%) informative metastatic melanoma tumor and cell line DNAs, and homozygous deletions of the marker D9S126 were observed in 2 of 20 (10%) melanoma cell lines. These findings have resulted in the identification of a small critical region of 2-3 megabases on 9p21 in which a putative melanoma tumor-suppressor gene appears likely to reside. Several 9p candidate genes, including IFNB1, the IFNA gene cluster, GGTB2, and the tyrosinase-related protein (TYRP) locus, have all been eliminated as potential targets because they are located outside of the homozygously deleted regions.

Interferons (IFN) are known to alter the expression of histocompatibility and tumour-associated antigens. We have reported the isolation and purification of a 66-kD melanoma-associated antigen (MAA) that is recognized by the host. Competitive binding with MAA reduced autologous antibody binding to five melanoma cell lines, suggesting that a similar antigen is detected by other patients with melanoma. Nine melanoma cell lines were incubated for 3 days with 0.01-100 units/ml of interferon alpha (IFN-alpha) or interferon gamma (IFN-gamma) and the maximum titre of autologous antibody reactivity was determined by protein A haemadsorption. Incubation with IFN-alpha or IFN-gamma resulted in a decrease in maximum titre of autologous antibody reactivity directed against all melanoma cell lines. A 3-day incubation of three melanoma cell lines with IFN-gamma augmented the expression of HLA-DR, as has been reported by others. Incubation with spent media from autologous melanoma cells exposed to IFN-alpha inhibited autologous antibody binding less than control media from melanoma cells to which no IFN was added, indicative of decreased production or internalization of MAA. Conversely, incubation with spent media obtained after exposure to IFN-gamma inhibited autologous antibody binding to a greater degree than control spent media, consistent with increased shedding of antigen. These results suggest that IFN-alpha and IFN-gamma down-regulate the expression of MAA detected by autologous antibody by different mechanisms of action.

In previous studies we evaluated the incidence and specificity of autologous antibody reactivity against squamous cell carcinoma of the head and neck (SCCHN). We were able to demonstrate that autologous antibody reactivity is present in native sera but was usually of too low a titer to allow further analysis. Dissociation of immune complexes by acidification and ultrafiltration of serum augmented autologous antibody reactivity in nine out of nine autologous systems tested. Native antibody and antibody derived from immune complexes produced by the host and reactive with autologous tumor cells may be directed against physiologically relevant antigens. Therefore, correlations of antibody titers with clinical course may provide insight into the nature of the host response to cancer. In the present analysis, serological studies of six patients with SCCHN were performed with serum samples obtained over many months. Results of serial serological assays were correlated to tumor progression and clinical course. Fluctuations in autologous antibody reactivity were noted over time. In four cases, rises in autologous antibody titers preceded the clinical diagnosis of recurrence by several months. Drops in autologous antibody reactivity were noted in two cases following surgery or radiation therapy. In two cases of long-term survivors, no correlation between antibody reactivity and clinical course was noted. Specificity analysis of the six autologous systems demonstrated reactivity against autologous and allogeneic SCCHN as well as melanoma cell lines. These sera did not react with glioma, neuroblastoma, renal cell, breast, bladder and colon carcinoma cell lines nor with fetal calf serum, pooled lymphocytes, red blood cells and platelets. Autologous serial serological studies may provide a means by which to evaluate the host/tumor relationship in patients with SCCHN.

We have previously reported the isolation of a 66 kDa melanoma-associated antigen, identified by autologous antibody, in serum and unfractionated spent tissue culture media by Western blot analysis. The antigen, detected by autologous serum S150, was found to be broadly represented on melanoma, glioma, renal cell carcinoma, neuroblastoma and head and neck carcinoma cell lines. S150 did not react with bladder or colon carcinoma, fetal fibroblasts, pooled platelets, lymphocytes and red blood cells, autologous cultured lymphocytes or fetal calf serum. To further characterize the antigen, spent tissue culture media, obtained from autologous melanoma cell line, Y-Mel 84:420, was separated by an isoelectric focusing column. Unabsorbed control serum S150 was noted to have a maximum titer of 1:2040 against autologous melanoma cells as measured by protein A hemadsorption. Following isoelectric focusing the greatest decrease in autologous antibody titer (30-fold) occurred with fractions having a pI between 2 and 3. Further resolution of the antigen was accomplished with high-pressure ion-exchange chromatography. One of these fractions showed a significantly higher concentration of antigen and was distinctly resolved from bulk serum albumin. Subsequent Western blot analysis, with autologous antibody, of the isolated antigen-containing fraction, confirmed the presence of a single 66 kDa band. Exposure of the antigen, purified by high-pressure ion-exchange chromatography, to neuraminidase ablated recognition by autologous antibody and suggests that sialic acid is present on the protein and may be part of the antigenic epitope. Binding of antigen, obtained following DEAE anion exchange chromatography, was noted to lectins derived from Triticum vulgaris, Dolichos biflorus and Lycopersicon esculentum. Preparative purification of the antigen was accomplished by anion exchange followed by lectin affinity chromatography with a Dolichos biflorus column. Antigen obtained following lectin affinity chromatography subjected to SDS-PAGE and silver stain revealed a single band at 66 kDa. We conclude that a melanoma-associated antigen detected by autologous antibody in spent tissue culture media is an unusually acidic glycoprotein (pI 2-3).

The role of the immune system in the pathogenesis and treatment of cancer remains to be determined. Impairment of humoral and cellular immunity has been associated with various factors implicated in head and neck cancer--tobacco, alcohol, and malnutrition. Whether these immune dysfunctions are causative or a secondary effect is not known. Patients with head and neck cancer have well-documented defects in immune function. In general, depression in cellular immunity has been noted, which can be correlated with stage of disease and prognosis. Conversely, increased humoral immune responses are seen, especially salivary IgA and circulating immune complexes. It may be that IgA or immune complexes are capable of suppressing the cellular immune response. Clinical trials utilizing biologic response modifiers in head and neck cancer have begun. Preliminary studies with heavily pretreated patients have demonstrated antitumor activity, suggesting that immunotherapy may provide a treatment alternative. In conclusion, the weight of evidence suggests that the immune response to head and neck cancer does play a role in the pathogenesis of the disease. A better understanding of the host-tumor interaction will allow for improved utilization of biologic response modifiers in the treatment of head and neck cancer.

Fourteen patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with 10 x 10(6) U of nonrecombinant interferon alpha (IFN) intramuscularly (IM) daily for 3 days every 28 days. There were 11 men and 3 women, with ages ranging from 48 to 74 years. Patients had previously been treated with surgery (9 patients), radiotherapy (13 patients), or chemotherapy (8 patients). All patients had measurable disease by physical exam and radiologic evaluation and a performance status of less than or equal to 2 (ECOG). Patients were treated for a minimum of 3 months and continued on therapy until disease progression. The dose and treatment schedule of IFN was well-tolerated. Toxicities included low-grade fever, mild anorexia, and malaise. Treatment was stopped in 1 patient due to the development of atrial fibrillation. One death occurred as a complication of aspiration pneumonia 2 weeks following the onset of therapy and was not felt to be related to IFN therapy. Of the 14 patients treated, there was 1 complete response (30+ months) of a base of tongue primary. Two patients had stabilization of disease (SD, 8 and 12 months). One patient had a mixed response with resolution of subcutaneous nodules. The remaining 10 patients died of progressive disease. Immunological assessment was performed on 8 patients. The 1 patient who had a complete response was noted to have markedly low pretreatment natural killer (NK) cell activity and a subsequent sharp rise in activity after initial treatment. We conclude that low-dose cyclic IFN is well-tolerated in patients with recurrent SCCHN and has potential antitumor activity.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLNexpressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. [ABSTRACT FROM AUTHOR]

Copyright of JBES: Brazilian Journal of Health Economics / Jornal Brasileiro de Economia da Saúde is the property of JBES: Brazilian Journal of Health Economics and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Conventional gallium scans are not useful to evaluate patients with metastatic melanoma. We evaluated a new method of tomographic gallium imaging. One hundred fourteen tomographic scans were obtained in a prospective surveillance study of 67 patients over a 3-year period. Scans were evaluated and compared to findings of independent clinical evaluations. Sensitivity of gallium identification of tumor involving peripheral lymph nodes and soft tissues, abdomen, mediastinum, and osseous sites was 68% to 100%; overall sensitivity of this technique is 82% with specificity of 99% in 570 organ system assessments. Analysis of discordant findings when a site was clinically occult but gallium-positive showed gallium uptake to be true-positive in six of seven lymphatic sites, three of three lung and mediastinal sites, six of six abdominal sites, but in no brain or bone sites. Gallium lesions identified by computed tomographic scans proved to be false-positive at one lymphatic and one bone site, and false-negative at four otherwise clinically evident lymph node and soft tissue sites, seven pulmonary sites, and four brain sites. Gallium tomographic scanning provides a composite assessment of melanoma and may eliminate the need for other studies.

Malignant melanoma is considered unresponsive to conventional radiation therapy when it is delivered at a daily dose rate of 130--300 rad/fraction. Previous studies have suggested that this is in part due to a large shoulder on the radiation survival curve and that higher dose fractions might be beneficial. High-dose fraction therapy is effective for local control of cutaneous, lymph node, and soft-tissue metastases. Results in 46 patients treated with high- or low-dose fractions for intracranial metastases over the last decade in the Melanoma Unit and Department of Radiotherapy at Yale have been examined. Twenty-six patients received high-dose fraction therapy, generally 600 rad/fraction/week to 2400--3600 rad; 20 patients received low-dose fraction radiotherapy with 125--400 rad/fraction daily. All patients were given steroids, and most received chemotherapy. Results in both groups were similar. Comparison of high- and low-dose fraction patients revealed: improvement in 38 and 35%, respectively, stability in 23 and 25%, and deterioration in 38 and 40%. Median survival was three months in the high-dose fraction group and 2 1/2 months in the low-dose fraction group. Presence of hepatic metastases had no significant influence upon median survival in patients who received high-dose fraction radiotherapy. In patients receiving low-dose fraction, survival was 2 1/4 months with and three months without hepatic metastases. Death in most patients resulted from progression of central nervous system disease. Side effects, especially headache, were more prominent in the high-dose fraction group. However, in no instance did side effects require discontinuation of therapy. The greater ease of delivery for weekly high-dose fraction radiotherapy outweighed any other difference between the regimens.

The low titer and incidence of autologous antibody to melanoma has hampered its evaluation. Through acid dissociation and ultrafiltration of serum, we have been able to augment the autologous immune response in 9 of 10 patients studied. This result suggests that autologous antibody is present in most patients with melanoma, but is obscured by circulating antigen and the formation of immune complexes. Because native antibody and antibody derived from circulating immune complexes are produced by the host against physiologically relevant antigens, correlations can be made to clinical course. Serological studies of three patients with melanoma were performed with serum samples obtained over many months; these studies demonstrated correlations with tumor progression and clinical course. Serial serologic studies may yet provide one of the better ways to evaluate these relationships. They have the advantage of detecting transient events that may occur with the inception of metastatic disease or autoimmune phenomena, and of avoiding the difficulties encountered in comparing antibody responses between different individuals.

Sera of 22 individuals were examined for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody to autologous cultured tumor cells. Reactive native IgM was detected by immune adherence in four, and IgG by Protein A hemadsorption in five, sera. Direct and absorption testing of these reactive sera against a range of normal and neoplastic cells revealed one each with specificity for a highly restricted melanoma cell surface antigen and common tumor-associated antigen of melanoma. Given this low prevalence of antibody, we then tested whether IgG antibody might be retrieved from circulating immune complexes in melanoma patients' sera. Acidification and ultrafiltration of sera from seven patients have enhanced detectable IgG binding to autologous cultured melanoma in six. Characterization of one reactive autologous antibody has detected a common antigen in eight of nine melanoma lines tested. This antibody also detected two neuroblastomas, one of two glioblastomas, one of two sarcomas, and one of two breast carcinomas. The common melanoma antigen detected in these tests may be related to the neuroectodermal, oncofetal differentiation antigens described by others with autologous or allogeneic IgM. Autologous antitumor antibody in circulating immune complexes may provide a source of antibody for serodiagnostic and therapeutic applications relevant to treatment modalities, such as plasmapheresis and plasma perfusion over Protein A in melanoma and other cancers.

Antibody reactivity against cultured allogeneic melanoma Y-Mel 81:180 was studied in 43 patients who participated in an adjuvant trial for stage I and II melanoma. Serum samples were obtained at trial entry within 2 mo of definitive surgery. At the time of serum acquisition, all patients were free of disease by physical examination and routine radiologic and laboratory parameters. Serum antibody reactivity was tested for by protein A hemadsorption before and after acid dissociation and ultrafiltration of serum. We have previously shown that this technique for immune complex dissociation augments autologous antibody reactivity. Results of serum antibody reactivity were scored by an investigator blinded to the patient's clinical status. Of the 43 patients studied, 15 relapsed and 28 remained disease-free. At study entry, there were 25 stage I patients and 18 stage II patients. Breslow depth was 3.25 +/- 2.5 mm in relapse patients and 1.67 +/- 1.1 mm in disease-free patients. The presence and titer of antibody directed against melanoma in either native serum or serum dissociated from immune complexes was found to be associated with eventual relapse (P = 0.0001). When results were subgrouped by stage of disease, Breslow depth, and hypopigmentation, antibody reactivity was still correlated with eventual relapse. The incidence and titer of antibody reactivity against melanoma appears to be a new prognostic factor in predicting eventual disease recurrence.

The study of the autologous immune response to cancer avoids the difficulties encountered in the use of xenoantisera and may identify antigens of physiological relevance. However, the low titer and incidence of autologous antibody to melanoma have hampered further evaluation. By utilizing acid dissociation and ultrafiltration of serum, we have been able to augment the detectable autologous immune response to melanoma in the majority of patients studied. In autologous system Y-Mel 84:420, serum S150 demonstrated a rise in titer from 1:32 in native sera to 1:262,044 after dissociation. The antigen detected by S150 was found to be broadly represented on melanoma, glioma, renal cell carcinoma, neuroblastoma, and head and neck carcinoma cell lines. It did not react with bladder or colon carcinoma, fetal fibroblasts, pooled platelets, lymphocytes and red blood cells, or autologous cultured lymphocytes. Using polyacrylamide gel electrophoresis, S150 detects a 66,000-mol wt antigen in spent tissue culture media and serum ultrafiltrate. In cell lysate two bands between 20,000 and 30,000 mol wt are detected by S150. The 66,000-mol wt antigen is sensitive to trypsin digestion and but is resistant to pepsin and heat inactivation. Exposure of spent media to trypsin results in the development of a 24,000-mol wt band that appears to correspond to the antigen detected in the cell lysate. The difference between the antigens detected in the cell lysate as compared with spent media and serum ultrafiltrate may be due to degradation during cell lysis. We conclude that melanoma-associated antigens are present in the serum of patients with melanoma and are shed or secreted by their tumor cells.

Serum antibody reactivity to squamous cell carcinoma of the head and neck (SCCHN) was evaluated in 41 autologous serum-tumor cell line combinations using the protein A hemadsorption assay. Autologous antibody reactivity (median titer of 1:4) was detected in sera from 24 of the patients tested. In 10 cases autologous antibody reactivity could be detected only in undiluted serum precluding further analysis. Analysis of higher titer sera from one patient revealed antibodies that define an antigen expressed on autologous tumor cells cultured from both the primary tumor (UM-SCC-17A) and from a metastasis (UM-SCC-17B). Absorption analysis showed that this antigen was also expressed on 6 of 10 allogeneic SCCHN cell lines but not on autologous fibroblasts or on allogeneic melanoma cell lines. Due to the low titer of autologous antibody reactivity in most sera, we sought to determine if dissociation of immune complexes through acidification and ultrafiltration of serum might enhance detectable antibody reactivity as has been done in previous studies in melanoma. Twelve serum samples from eight patients were subjected to acid dissociation and ultrafiltration (AD-U). Only six of the untreated sera had detectable antibody reactivity against the autologous SCCHN cell line whereas following AD-U all 12 sera had enhanced IgG reactivity against autologous SCCHN. Specificity analysis of one serum sample after dissociation revealed that the antibody detected an antigen common to SCCHN cell lines as well as melanoma, glioma, renal, and colon carcinoma cell lines. Circulating immune complexes may provide a reservoir of antibody with potential diagnostic and therapeutic applications.

Conventional gallium scans are not useful to evaluate patients with metastatic melanoma. We evaluated a new method of tomographic gallium imaging. One hundred fourteen tomographic scans were obtained in a prospective surveillance study of 67 patients over a 3-year period. Scans were evaluated and compared to findings of independent clinical evaluations. Sensitivity of gallium identification of tumor involving peripheral lymph nodes and soft tissues, abdomen, mediastinum, and osseous sites was 68% to 100%; overall sensitivity of this technique is 82% with specificity of 99% in 570 organ system assessments. Analysis of discordant findings when a site was clinically occult but gallium-positive showed gallium uptake to be true-positive in six of seven lymphatic sites, three of three lung and mediastinal sites, six of six abdominal sites, but in no brain or bone sites. Gallium lesions identified by computed tomographic scans proved to be false-positive at one lymphatic and one bone site, and false-negative at four otherwise clinically evident lymph node and soft tissue sites, seven pulmonary sites, and four brain sites. Gallium tomographic scanning provides a composite assessment of melanoma and may eliminate the need for other studies.

Radiation therapy (RT) for melanoma brain metastases, delivered either as whole brain radiation therapy (WBRT) or as stereotactic radiosurgery (SRS), is an established component of treatment for this condition. However, evidence allowing comparison of the outcomes, advantages and disadvantages of the two RT modalities is scant, with very few randomised controlled trials having been conducted. This has led to considerable uncertainty and inconsistent guideline recommendations. The present systematic review identified 112 studies reporting outcomes for patients with melanoma brain metastases treated with RT. Three were randomised controlled trials but only one was of sufficient size to be considered informative. Most of the evidence was from non-randomised studies, either specific treatment series or disease cohorts. Criteria for determining treatment choice were reported in only 32 studies and the quality of these studies was variable. From the time of diagnosis of brain metastasis, the median survival after WBRT alone was 3.5 months (IQR 2.4–4.0 months) and for SRS alone it was 7.5 months (IQR 6.7–9.0 months). Overall patient survival increased over time (pre-1989 to 2015) but this was not apparent within specific treatment groups. These survival estimates provide a baseline for determining the incremental benefits of recently introduced systemic treatments using targeted therapy or immunotherapy for melanoma brain metastases. [ABSTRACT FROM AUTHOR]

Rhodococcus equi (R. equi) was identified among the most relevant antimicrobial‐resistant (AMR) bacteria in the EU for horses in a previous scientific opinion. Thus, it has been assessed according to the criteria of the Animal Health Law (AHL), in particular criteria of Article 7 on disease profile and impacts, Article 5 on its eligibility to be listed, Annex IV for its categorisation according to disease prevention and control rules as in Article 9 and Article 8 for listing animal species related to the bacterium. The assessment has been performed following a methodology previously published. The outcome is the median of the probability ranges provided by the experts, which indicates whether each criterion is fulfilled (lower bound ≥ 66%) or not (upper bound ≤ 33%), or whether there is uncertainty about fulfilment. Reasoning points are reported for criteria with uncertain outcome. According to the assessment here performed, it is uncertain whether AMR R. equi can be considered eligible to be listed for Union intervention according to Article 5 of the AHL (10–66% probability). According to the criteria in Annex IV, for the purpose of categorisation related to the level of prevention and control as in Article 9 of the AHL, the AHAW Panel concluded that the bacterium does not meet the criteria in Sections 1 and 2 (Categories A and B; 5–10% and 10–33% probability of meeting the criteria, respectively), and the AHAW Panel is uncertain whether it meets the criteria in Sections 3, 4 and 5 (Categories C, D and E; 10–66% probability of meeting the criteria in all three categories). The animal species to be listed for AMR R. equi according to Article 8 criteria are mainly horses and other species belonging to the Perissodactyla and Artiodactyla orders. [ABSTRACT FROM AUTHOR]

Purpose: Recurrent nasopharyngeal carcinoma (NPC) after previous radiation therapy is a significant problem. This study was to determine the potential benefits from re-irradiation by fractionated stereotactic body radiotherapy (FSRT) on survival benefits and effects of severe late toxicities.Materials and Methods: Between 2009 and 2018, treatment outcomes were evaluated retrospectively in 26 patients with locally recurrent NPC treated using FSRT with CyberKnife. Five patients who had metastatic disease and one who had second recurrence were excluded from the study, and the remaining 20 patients were analyzed. The median age was 52 years (range, 28-80 years); re-treatment T stage was as follows: 6 (30%) - T2, 5 (25%) - T3, and 9 (45%) - T4. The median time from initial RT to recurrence was 22 months (range, 8-159 months). The median re-irradiation FSRT dose was 30 Gy in 5 fractions.Results: The median follow-up was 44 months; the overall survival (OS), local failure-free survival, and disease progression-free survival rates at 3 years were 89%, 73%, and 53%, respectively. All patients were evaluated for response after treatment: 9 (45%) had complete, 3 (15%) had partial, and 6 (30%) had no response. Univariate analysis demonstrated that higher cumulative total radiotherapy dose, gross tumor volume, and recurrent time interval were prognostic factors for local failure-free survival. The recurrent time interval was also an independent factor for progression-free survival and OS. The incidence of temporal lobe necrosis and trismus was 10% and 20%, respectively. One patient had Grade 5 toxicity to treatment-related bleeding.Conclusion: Tumor dose coverage is important for treating recurrent NPC, and treatment-related mortality was vascular in nature. FSRT is a promising treatment modality for recurrent NPC. [ABSTRACT FROM AUTHOR]

Background: Tumors originating from the craniofacial region usually present in a locally advanced stage with frequent involvement of adjacent sites and have a strong tendency for local recurrence in the absence of adjuvant therapy, even when the original surgical resection was presumed to be radical. In the past decades, several advances in the radiological diagnosis and treatment of craniofacial malignancies have been introduced. There are, however, no randomized trials that define the optimal multimodal treatment of these tumors because of their rarity as well as heterogeneity in both histology and site of origin. The aim of this study was to conduct a critical review of the role of adjuvant therapy in the treatment of craniofacial malignancy. Method: We conducted a critical review of the past and contemporary literature available, focusing on adjuvant oncological treatments of the most common craniofacial malignancies. Results: Preoperative radiotherapy can have a documented role in the treatment of olfactory neuroblastoma and soft tissue sarcoma, while preoperative chemotherapy can be advocated in the treatment of sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, olfactory neuroblastoma, and craniofacial sarcoma (both soft-tissue and high-grade osteosarcoma). Postoperative radiotherapy has a well-established role in the treatment of most craniofacial malignancies. The role of postoperative chemotherapy is unclear in most histologies, but is commonly used during the treatment of well-selected cases of paranasal sinus carcinoma, olfactory neuroblastoma, mucosal melanoma, soft tissue sarcoma and high-grade craniofacial osteosarcoma. Discussion: Alongside developments in surgery, there have also been improvements in diagnostics, radiotherapy, and chemotherapy. Implementation of novel radiation techniques allows delivery of higher radiation doses while minimizing irradiation-related morbidity. Better understanding of tumor biology allows the construction of more complex treatment strategies, incorporating adjuvant chemotherapy either pre- or postoperatively. In the era of personalized targeted therapy, rapid strides are being made to identify specific tumor-targets for use of novel biologic agents, with the potential to change current management paradigms. [ABSTRACT FROM AUTHOR]

RNA epigenetics, or epitranscriptome, is a growing group of RNA modifications historically classified into two categories: RNA editing and RNA modification. RNA editing is usually understood as post-transcriptional RNA processing (except capping, splicing and polyadenylation) that changes the RNA nucleotide sequence encoded by the genome. This processing can be achieved through the insertion or deletion of nucleotides or deamination of nucleobases, generating either standard nucleotides such as uridine (U) or the rare nucleotide inosine (I). Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent type of RNA modification in mammals and is catalyzed by adenosine deaminase acting on the RNA (ADAR) family of enzymes that recognize double-stranded RNAs (dsRNAs). Inosine mimics guanosine (G) in base pairing with cytidine (C), thereby A-to-I RNA editing alters dsRNA secondary structure. Inosine is also recognized as guanosine by the splicing and translation machineries, resulting in mRNA alternative splicing and protein recoding. Therefore, A-to-I RNA editing is an important mechanism that causes and regulates "RNA mutations" in both normal physiology and diseases including cancer. In this chapter, we reviewed current paradigms and developments in the field of A-to-I RNA editing in the context of cancer., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

While probably originating from Africa, the plant Ricinus communis is found nowadays around the world, grown for industrial use as a source of castor oil production, wildly sprouting in many regions, or used as ornamental plant. As regards its pharmacological utility, a variety of medical purposes of selected parts of the plant, e.g., as a laxative, an anti-infective, or an anti-inflammatory drug, have been described already in the sixteenth century bc in the famous Papyrus Ebers (treasured in the Library of the University of Leipzig). Quite in contrast, on the toxicological side, the native plant has become the "poisonous plant 2018" in Germany. As of today, a number of isolated components of the plant/seeds have been characterized, including, e.g., castor oil, ricin, Ricinus communis agglutinin, ricinin, nudiflorin, and several allergenic compounds. This review mainly focuses on the most toxic protein, ricin D, classified as a type 2 ribosome-inactivating protein (RIP2). Ricin is one of the most potent and lethal substances known. It has been considered as an important bioweapon (categorized as a Category B agent (second-highest priority)) and an attractive agent for bioterroristic activities. On the other hand, ricin presents great potential, e.g., as an anti-cancer agent or in cell-based research, and is even explored in the context of nanoparticle formulations in tumor therapy. This review provides a comprehensive overview of the pharmacology and toxicology-related body of knowledge on ricin. Toxicokinetic/toxicodynamic aspects of ricin poisoning and possibilities for analytical detection and therapeutic use are summarized as well. [ABSTRACT FROM AUTHOR]

Purpose: The goals of this study were to assess safety and efficacy of triplet chemoradiotherapy (CRT) with paclitaxel for squamous cell anal carcinoma (SCAC). Methods: Patients with stage I-IIIB SCAC were enrolled and received 52-58 Gy intensity-modulated radiotherapy (IMRT) (with dose based on the T stage) in consecutive daily 1.8-2.2 Gy fractions. The concurrent chemotherapy consisted of paclitaxel 45 mg/m days 3, 10, 17, 24, 31, capecitabine 625 mg/m bid on treatment days and mitomycin C 10 g/m on day 1. Primary endpoints were complete clinical response at 26 weeks and protocol compliance; secondary endpoints included toxicity, overall survival (OS) and progression-free survival (PFS). Results: Thirty-eight patients were enrolled. The percentage of patients with stage I, II, IIIA, and IIIB disease were 1 (2.6%), 5 (13.2%), 15 (39.5%), and 17 (44.7%), respectively. 32 patients (84.2%) completed CRT without significant alterations. Grade 3-4 toxicity occurred in 23 (60.5%) patients. 33 (86.8%) patients had complete clinical response at 26 weeks. Median follow-up was 25.6 months. Seven (18.4%) patients experienced disease progression: four patients had residual tumor after CRT, 2 patients developed distant metastases and 1 patient developed a local recurrence 12 months after CRT. Two-year OS was 93.6%, 2-year PFS was 83.9%. Conclusions: Investigated treatment scheme is feasible despite high toxicity profile, and may be beneficial for patients with advanced SCAC. Further research is warranted. [ABSTRACT FROM AUTHOR]

The clinical benefit of nab-paclitaxel monotherapy for recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) that progressed on other taxanes (cremophor-based paclitaxel or docetaxel) is unknown. A retrospective analysis of patients treated at a single institution with nab-paclitaxel for taxane-resistant RM-HNSCC. The exploratory hypothesis was that nab-paclitaxel would result in clinical benefit (tumor response) in patients with taxane-resistant RM-HNSCC. Twelve patients who were treated with nab-paclitaxel monotherapy for taxane-resistant RM-HNSCC and met all eligibility criteria were identified. The majority of patients ( n = 9; 75%) received three or more lines of therapy for RM-HNSCC. All patients had platin-resistant, and ten patients (83%) had cetuximab-resistant disease. Patients had RM-HNSCC that progressed on cremophor-based paclitaxel (8), docetaxel (1), or both (3). With prior taxane, the best tumor response was partial (PR) in 4 patients (33%), stable (SD) in 3 (25%), and progression in 5 (42%). The median time-to-progression (TTP) with prior taxane was 1.7 (range 0.7-9.0) months. The median interval from last dose of taxane to first dose of nab-paclitaxel was 3 (0.7-31.3) months. With nab-paclitaxel, tumor response occurred in two patients (17%; PR in both) and disease control (PR and SD) occurred in five (42%). Median TTP with nab-paclitaxel was 2.1 months (range 0.6-6.2), and median overall survival was 4.9 months (range 1.9-13.5). nab-Paclitaxel provided clinical benefit in some patients with taxane-resistant RM-HNSCC. The median TTP with nab-paclitaxel and with prior taxane were similar. This exploratory observation warrants further investigation in prospective studies. [ABSTRACT FROM AUTHOR]

This paper provides detailed insight into the mechanisms of repair of different types of DNA damage and the direct molecular players (enzymes repairing the damage or tagging the damaged site for further processing; damage sensor molecules; other signalling and effector molecules). The genetic bases of diseases and condions associated with defective DNA repair are comprehensively reviewed, from the 'classic' severe diseases such as xeroderma pigmentosum and Cockayne syndrome to the much more subtle UV sensitivity syndromes. The review analyses the basic molecular mechanisms underlying the relatively rare monogenic diseases of DNA repair and management of genome integrity as well as the common multifactorial diseases and conditions with late onset that are associated with increased levels of oxidative stress (metabolic syndrome, diabetes type 2, cardiovascular disease) and with accumulation of 'errors' in DNA (normal and pathological ageing phenotypes, various cancers). The role of cell cycle checkpoints in dividing cells and the mechanisms of decision-making for the fate of a damaged cell are discussed with regards to the cell homeostasis in normal and cancerous issues. The role of major DNA damage-associated signalling and effector molecules (p53, ATM, poly-(ADP-ribose)-polymerase, DNA-dependent protein kinase, BRCA proteins, retinoblastoma protein, and others) is discussed and illustrated with examples in the context of health and disease. DNA repair and programmed cell death are viewed together as a unified mechanism for limiting the presence of damaged cells and cells with potentially oncogenic transformation in multicellular organisms. Special attention is paid to ageing as a natural phenomenon and an adaptive evolutionary mechanism, with a brief outline of 'successful ageing'. The differential rates of repair of DNA in transcribed and nontranscribed regions of the genome and the specificities of DNA repair profile in some types of cells (terminally differentiated cells, pluripotent stem cells, etc.) and in certain taxonomic groups (e.g. 'the rodent repairadox') are discussed with regards to replicative ageing and the evolutionary processes on micro- and macroscale. The role of mutagenesis as a 'hit and miss' mechanism and the 'leakiness' of DNA repair for increasing genetic diversity in the course of individual life and on evolutionary scale and the phenomenology of ongoing molecular evolution are extensively reviewed. [ABSTRACT FROM AUTHOR]

Protein Preferentially Expressed Antigen in Melanoma (Prame), a tumor-associated antigen, has been found to frequently overexpress in various cancers, which indicates advanced cancer stages and poor clinical prognosis. Moreover, previous reports noted that Prame functions as a substrate recognizing receptor protein of Cullin RING E3 ligases (CRLs) to mediate potential substrates degradation through Ubiquitin Proteasome System (UPS). However, none of the Prame specific substrate has been identified so far. In this study, proteomic analysis of RBX1-interacting proteins revealed p14/ARF, a well-known tumor suppressor, as a novel ubiquitin target of RBX1. Subsequently, immunoprecipitation and in vivo ubiquitination assay determined Cullin2-RBX1-Transcription Elongation Factor B Subunit 2 (EloB) assembled CRL2 E3 ligase complex to regulate the ubiquitination and subsequent degradation of p14/ARF. Finally, through siRNA screening, Prame was identified as the specific receptor protein responsible for recognizing p14/ARF to be degraded. Additionally, via bioinformatics analysis of TCGA database and clinical samples, Prame was determined to overexpress in tumor tissues vs. paired adjacent tissues and associated with poor prognosis of cancer patients. As such, downregulation of Prame expression significantly restrained cancer cell growth by inducing G2/M phase cell cycle arrest, which could be rescued by simultaneously knocking down of p14/ARF. Altogether, targeting overexpressed Prame in cancer cells inactivated RBX1-Cullin2-EloB-Prame E3 ligase (CRL2 Prame ) and halted p14/ARF degradation to restrain tumor growth by inducing G2/M phase cell cycle arrest.

Background: This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC).Methods: Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining.Results: Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC.Conclusions: Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study.Trial Registrations: ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012. [ABSTRACT FROM AUTHOR]

The author discusses applications of salvage surgery in patients with head and neck squamous cell carcinoma (HNSCC). Topics include complications of salvage surgery such as pharyngocutaneous fistula (PCF), preoperative measures for correction of co-morbidities, hemoglobin levels and nutritional deficiencies, and salvage surgery in a palliative setting.

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Purpose: To assess the clinical activity and toxicity of a combination chemotherapy regimen of S-1 and cisplatin in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) in a retrospective study. Methods: A total of 49 patients were treated in an outpatient setting with S-1 80 mg/m on days 1-14 and with cisplatin 70 mg/m on day 1 every 3 weeks for a maximum of six cycles as a first-line palliative chemotherapy. Patients who achieved complete response (CR), partial response (PR) or stable disease (SD) after six cycles received S-1 monotherapy as a maintenance therapy. Results: The median patient age was 55 years (range 33-79), 89.8 % were male, and the Eastern Cooperative Oncology Group performance status distribution was 0/1/2 (20.4 %/73.5 %/6.1 %). Of the 43 evaluable patients, 2 (4.1 %) achieved CR and 20 (40.8 %) had a PR, for an overall response rate of 44.9 %. Thirteen patients (26.6 %) had SD. The median number of chemotherapy treatments was 4 (range 1-18). Nine patients received maintenance S-1 monotherapy after six cycles of combination chemotherapy. With a mean 10.5 months (range 1.3-25.1) of follow-up, the median progression-free and overall survival were 4.5 (95 % CI, 3.7-5.3 months) and 10.8 months (95 % CI, 5.9-15.6 months), respectively. The main grade 3-4 toxicities were neutropenia (37 %), anemia (16 %) and general weakness (8 %). Other toxicities, including nausea/vomiting, mucositis and neuropathy, were mostly grade 1-2 and easily manageable. Conclusions: The combination of S-1/cisplatin therapy had a favorable efficacy with manageable toxicity as a first-line chemotherapy regimen for advanced head and neck squamous cell carcinoma patients. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study has been to quantitatively estimate and compare the circulating immune complexes (CIC) in pre-malignant and malignant lesions of oral cavity and to serially monitor the CIC levels in oral squamous cell carcinoma (SCC) during / following radiotherapy as to assess the status of the disease and to understand the prognostic significance. Materials and Methods: The present study was carried out on 90 individuals divided into three groups and CIC was estimated by spectrophotometric method using polyethylene glycol (PEG) precipitation method. The mean CIC level was determined in each group and was correlated with the degree of differentiation and degree of dysplasia in malignant and pre-malignant group respectively. The effect of radiotherapy on the level of CIC was studied after 2400 rad and after one week of 4500 - 5000 rad. Results: It was observed that the mean CIC level in the control group was significantly lower (59.56 ± 8.11) when compared with the pre-malignant group (75.93 ± 12.89) and malignant group (92.66 ± 13.96). Among the pre-malignant group, leukoplakia had the highest mean CIC level followed by lichen planus and oral submucous fibrosis (OSMF), suggesting its greater malignant potential. No correlation could be established between degree of differentiation and degree of dysplasia with the CIC levels in malignant and premalignant groups respectively. There was a definite decrease in the mean CIC levels in patients undergoing radiotherapy. Conclusion: The pretreatment value of CIC can be used as a prognostic indicator. A high CIC level would probably indicate a poor prognosis. [ABSTRACT FROM AUTHOR]