Pemphigoid Gestationis Refractive to Dual Systemic Therapy Treated With Dupilumab.

Dual biologic therapy for recalcitrant psoriasis and psoriatic arthritis

Intro. Most patients with stage II BC will receive surgery along with systemic therapy, but no consensus exists among experts on optimal use of neoadjuvant vs adjuvant therapy in many cases. Furthermore, treatment guidelines list multiple reasonable regimens for EBC, but lack patient-specific recommendations. We have shown previously that online decision support tools can affect treatment decisions of community practitioners. In this study, we sought to determine areas of consensus and disagreement among expert faculty providing treatment recommendations for a 2015 decision support tool on EBC as well as those using the online tool. Methods. An online decision support tool was developed with input from 5 experts on systemic therapy recommendations for 235 patient scenarios in EBC. Tool users were asked to enter specific patient criteria and their intended management for each case before displaying the 5 expert recommendations for the user-entered case. Users were asked to indicate if the expert recommendations changed their intended approach. Results. At interim analysis, 406 individuals used this tool, with 674 patient scenarios entered. Among users reporting on the tool's clinical impact, 88% indicated expert recommendations either confirmed or changed their intended therapy. Expert recommendations in the tool showed areas of consensus and disagreement in treating patients with EBC. For example, expert recommendations varied in the choice of systemic therapy prior to surgery and when to continue directly to surgery before systemic treatment. Expert recommendations for initiating systemic neoadjuvant therapy in HER2-, HR+ EBCcNcTExpert 1Expert 2Expert 3Expert 4Expert 5NCCN GuidelinesNegativecT1a cT1b cT1c Recommend cT2 RecommendConsider cT3ConsiderRecommendConsiderPositivecT1a RecommendConsider cT1b RecommendConsider cT1c RecommendConsider cT2ConsiderRecommendConsider cT3ConsiderRecommendConsider Experts did agree on starting with surgery in patients with node-negative, T1a disease; however, only 30% of tool users agreed. Both experts and users agreed in recommending systemic neoadjuvant therapy for patients with HER2+, node-positive T2 disease. In patients with HER2+ EBC, experts always chose to include dual HER2-targeted therapy in neoadjuvant systemic therapy but only included trastuzumab in adjuvant regimens. However, only 51% of tool users selected dual HER2-targeted therapy as part of neoadjuvant therapy and 13% use dual HER2-targeted therapy in the adjuvant setting. Expert opinion varied on when to use adjuvant chemotherapy in patients with HR+, HER2- EBC, particularly for those with intermediate or unknown recurrence scores and no lymph node involvement. Detailed comparison of expert consensus and disagreement, analysis of practice pattern information from user responses, and perceived impact of the expert recommendations will be presented. Conclusions. This EBC tool highlights specific clinical scenarios having either consensus or disagreement among experts and community practitioners. Education that includes online decision support tools may increase the number of clinicians making optimal treatment decisions for patients with EBC. Citation Format: Obholz KL, Rosenthal KM, O'Regan RM, Swain SM, Yardley DA, Brady ED. Consensus and disagreement between experts and community practitioners asked to make therapeutic recommendations for early breast cancer (EBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-09-04.

Impact of Targeted Systemic Therapy and Radiotherapy on Patients Undergoing Spine Surgery for Metastatic Renal Cell Carcinoma.

To report a case of Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae ventriculitis successfully treated with dual intraventricular plus systemic antibiotic therapy. A 43-year-old woman with a ventriculoperitoneal shunt was transferred from a nursing home with fever, altered mental status, and leukocytosis. She was found to have KPC-producing K pneumoniae ventriculitis. Combination intraventricular antibiotic therapy with colistin and gentamicin plus systemic colistin and amikacin led to the resolution of infection. Utilization of intraventricular or intrathecal antibiotics has been described in the literature for multidrug resistant (MDR) Gram-negative central nervous system (CNS) infections; however, none of the cases were caused by a KPC-producing organism. Given the pathogenicity and limited treatment options for this resistant organism, we utilized intraventricular colistin 10 mg and intraventricular gentamicin 10 mg in combination with systemic colistin and amikacin. An extensive literature search revealed several case reports and case series of documented MDR Acinetobacter baumanii CNS infections successfully treated with intraventricular colistin or aminoglycoside therapy with good tolerability. Additionally, recent pharmacokinetic analyses suggest improved cerebrospinal fluid (CSF) concentrations with direct CNS antimicrobial administration in combination with systemic therapy. Although our patient's cerebral spinal fluid cultures were cleared with dual intraventricular plus systemic therapy, she continued to deteriorate clinically because of her comorbid conditions and required hospice admission. This describes the first reported case of KPC-producing K pneumoniae ventriculitis microbiologically cured based on negative blood and CSF cultures with a combination of intraventricular and systemic therapy.

Title: Does definitive local therapy have a role in select HER2+de novo metastatic breast cancer patients treated with dual anti HER2 blockade? Background: The role of surgery with curative intent in HER2+de novo metastatic breast cancer (dnMBC) is uncertain in the era of dual antibody therapy. We sought to determine from existing retrospective data current practice patterns if an association exists between surgery to the primary tumor and improved survival in HER2+dnMBC patients treated with dual anti-HER2 blockade, accounting for selection bias. Methods: This study employed data from the National Cancer Database (NCDB) from the years 2013 to 2015. Study inclusion was limited to adult women with HER2+dnMBC, who received immunotherapy/biologic response modifier drugs (BRM) as a first line treatment. Patients who received both systemic therapy and surgery to the primary breast tumor and patients who received systemic therapy alone were analyzed in two groups. Chi-square test for discrete variables and Wilcox on RankSum test for numeric variables was used to compare the two groups based on patient, tumor, and treatment characteristics. The primary endpoint was overall survival from the time of diagnosis to the time of death. Results: 928 women with HER2+dnMBC treated with BRM were identified with 43.5% (n=404) receiving surgery and 56.5% (n=524) receiving systemic therapy alone. The 3-year overall survival was superior for the surgery group (74.1%, 95% CI 67.9–79.2%) compared to the no surgery group (53.3%; 95% CI 47.6–58.6%). The no surgery group had median overall survival of 39.8 months (95% CI 34.1–44.9), while the surgery group had not yet reached median overall survival. Conclusion: In a group of HER2+dnMBC patients receiving systemic treatment in the era of dual antibody therapy, patients who underwent surgery had a superior 3-year survival rate than those who did not. There may be a role for a prospective trial in HER2+dnMBC patients with an excellent response to dual HER2 blockade to investigate the contribution of curative intent local therapy to the primary tumor compared to systemic therapy alone.

The role of surgery with curative intent in HER2+ de novo metastatic breast cancer (dnMBC) is uncertain in the era of dual antibody therapy. We sought to determine from existing retrospective data current practice patterns and if an association exists between surgery to the primary tumor and improved survival in HER2+ dnMBC patients treated with dual anti-HER2 blockade, accounting for selection bias. This study employed data from the National Cancer Database (NCDB) from the years 2013 to 2015. Study inclusion was limited to adult women with HER2+ dnMBC, who received immunotherapy/biologic response modifier drugs (BRM) as a first line treatment. Patients who received both systemic therapy and surgery to the primary breast tumor and patients who received systemic therapy alone were analyzed in two groups. Chi-square test for discrete variables and Wilcox on Rank-Sum test for numeric variables was used to compare the two groups based on patient, tumor, and treatment characteristics. The primary endpoint was overall survival from the time of diagnosis to the time of death. 928 women with HER2+ dnMBC treated with BRM were identified with 43.5% (n = 404) receiving surgery and 56.5% (n = 524) receiving systemic therapy alone. The 3-year overall survival was superior for the surgery group (74.1%, 95% CI 67.9-79.2%) compared to the no surgery group (53.3%; 95% CI 47.6-58.6%). The no surgery group had median overall survival of 39.8months (95% CI 34.1-44.9), while the surgery group had not yet reached median overall survival. In a group of HER2+ dnMBC patients receiving systemic treatment in the era of dual antibody therapy, patients who underwent surgery had a superior 3-year survival rate than those who did not. There may be a role for a prospective trial in HER2+ dnMBC patients with an excellent response to dual HER2 blockade to investigate the contribution of curative intent local therapy to the primary tumor compared to systemic therapy alone.

Recommended first-line management of brain metastases from melanoma: A multicenter survey of clinical practice

Despite advances in the treatment of head and neck cancer, squamous cell carcinoma of the oral cavity remains primarily a surgical disease with few effective systemic therapies. Oral cavity tumors harbor both innate and acquired resistance mechanisms to cytotoxic chemotherapy. Additionally, the tumor microenvironment (TME) has limited immune cell infiltration, resulting in low response rates to immune checkpoint inhibitors. Given the need for novel systemic therapies for oral cavity squamous cell carcinoma, we investigated the role of liposomal doxorubicin (Doxil®) as both a cytotoxic agent and an immunomodulatory agent. We utilized the MOC2 syngeneic murine model of oral cavity squamous cell carcinoma, an aggressive tumor model with resistance to immune checkpoint blockade. We demonstrated that Doxil has moderate activity as a single agent in vivo for C57BL/6J mice harboring MOC2 flank tumors. We next performed flow cytometric analysis to characterize the changes in immune cell populations in the TME after treatment with Doxil. We found significantly increased numbers of innate immune cells including NK cells and myeloid cells. Multiplex immunofluorescence was also used to confirm the increase in myeloid cell tumor infiltration upon Doxil treatment. Given the changes seen in the tumor immune microenvironment, we hypothesized Doxil may improve response to immune checkpoint blockade. Therefore, we treated C57BL/6J mice inoculated with MOC2 flank tumors with Doxil alone or in combination with radiation therapy (RT) and/or anti-CTLA-4 therapy. While RT or anti-CTLA-4 alone had modest anti-tumor activity, combining either RT or anti-CTLA-4 with Doxil significantly reduced tumor growth. Moreover, the triple combination therapy of Doxil, RT, and anti-CTLA-4 had an increased effect compared to the dual therapy of Doxil and anti-CTLA-4. This included several complete responses, which resulted in a significant improvement in survival. Triple combination therapy also reduced both local and distant metastatic burden compared to single agent and dual combination therapy. Next, we selectively inhibited CD8+ T cells, myeloid cells, or NK cells to determine which immune cell populations contribute to the immunomodulatory activity of Doxil. We observed that inhibition of NK cells resulted in increased tumor growth as well as decreased survival, suggesting that Doxil-mediated infiltration of NK cells into the TME contributes to response to anti-CTLA-4 therapy. Taken together, these data provide a rationale for combining liposomal doxorubicin with anti-CTLA-4 therapy for the treatment of oral cavity squamous cell carcinoma. Citation Format: Jennifer L Anderson, Fabio H Brasil Da Costa, Allison Nipper, Laxman Devkota, Rohan Bhavane, Ratna Veeramachaneni, Sofia Cortes, Neeraja Dharmaraj, Sarah Latka, Andrew Badachhape, Renuka TR Menon, Prajwal Bhandari, Ketankumar Ghaghada, Simon Young, Ananth Annapragada, Andrew Sikora. Liposomal doxorubicin improves response to immune checkpoint blockade by enhancing innate immunity in a murine model of oral cavity squamous cell carcinoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A119.

To the Editors: Elizabethkingia meningoseptica causes life-threatening infections in humans, especially in immunocompromised patients and infants with low birth weights. It is one of the main causes of meningitis in pediatric and immunocompromised patients in the context of nosocomial diseases associated with devices and is also related to low-birth-weight infants and prematurity1 Due to their resistance to many commonly used antibiotics (beta-lactams, carbapenemics, aminoglycosides, etc.), clinicians face treatment challenges.2 There are currently few publications on pediatric cases regarding E. meningoseptica device-associated meningitis with breakthrough resistance to trimethoprim-sulfamethoxazole (TMP/SMX) while treatment with dual intravenous (IV) therapy with TMP/SMX and high-dose ciprofloxacin requiring intraventricular ciprofloxacin for eradication. This letter is written to describe a case that posed a diagnostic challenge in our center. A 1-month-old female patient with hydrocephalus secondary to a history of myelomeningocele that required correction at birth with a ventriculoperitoneal (VP) shunt system presented during her prolonged hospitalization with device-associated meningitis due to E. meningoseptica initially susceptible to TMP/SMX MIC <16 µg/L, follow-up cerebrospinal fluid (CSF) cultures remained positive for the same pathogen with TMP/SMX breakthrough resistance acquired (MIC > 64 µg/L) (Table 1). Different antibiotics were tested in vitro and showed resistance to vancomycin, minocycline, and rifampicin, maintaining only susceptibility to ciprofloxacin without achieving eradication with systemic dual high-dose IV therapy. TABLE 1. - Cerebrospinal Fluid Culture Analyzed in Vitek2 System (Biomérieux) Initial Control Antibiotic Value/Interpretation Value/Interpretation Amikacin ≥64 µg/mL (R) ≥64 µg/mL (R) Aztreonam ≥64 µg/mL (R)) Cefazolin ≥64 µg/mL (R) Cefepime ≥64 µg/mL (R) ≥64 µg/mL (R) Ceftazidime ≥64 µg/mL (R) ≥64 µg/mL (R) Ceftriaxone ≥64 µg/mL (R) Ciprofloxacin ≥1 µg/mL (Susceptible) ≥1 µg/mL (S) Gentamicin ≥16 µg/mL (Resistant) ≥16 µg/mL (R) Meropenem ≥64 µg/mL (Resistant) ≥64 µg/mL (R) Piperacillin/tazobactam 32 µg/mL (Susceptible) ≥128 µg/mL (R) Tigecycline 1 µg/mL (S) ≥8 µg/mL (R) Trimethoprim/sulfamethoxazole (TMP/SMX) 40 µg/mL (S) ≥320 µg/mL (R) Colistin ≥16 µg/mL (R) Doripenem ≥8 µg/mL (R) Imipenem ≥16 µg/mL (R) (R), resistant; (S), susceptible. Intraventricular antimicrobial therapy with ciprofloxacin was proposed based on a case report in the literature: 21 days of systemic treatment combined with Intrathecal therapy, and another 21 days of systemic therapy alone. Negative CSF cultures were obtained after 6 days of dual therapy plus intraventricular ciprofloxacin with clinical improvement in the patient and replacement of the VP shunt. Although recent literature suggests that antibiotics such as fluoroquinolones can achieve good concentrations in the CSF fluid after IV administration and do not suggest their use in intraventricular or intrathecal routes,3 and that the FDA has not approved any antimicrobial agent for intraventricular use,3,4 when therapeutic options are limited due to multidrug-resistant pathogens in central nervous system infections, intraventricular/intrathecal antibiotic therapy with fluoroquinolones appears to be a viable option in the absence of other available treatments. More studies are required, particularly in cases, such as the one presented for antibiotics that theoretically achieve adequate CSF concentrations when only IV route is used.

4057 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival. Dual therapy OXAL+CAPE has demonstrated activity in advanced CRC. We report final results of an analysis of SYS OXAL+CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS), with 36 of 45 patients surviving 2 yrs as evidence of promising efficacy. Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. Prior adjuvant chemotherapy for completely resected primary was allowed. HAI+SYS therapy was initiated 21–56 days post-metastasectomy. Four alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 wks 1&amp;2. SYS included 130 mg/m2 OXAL d1, with CAPE at 1,000 mg/m2 po BID, d1–14, wks 4&amp;5. Two additional 3-wk courses of SYS were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity. Results: 54 of 73 eligible patients initiated HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Patients completed median of 6 cycles (range 1–6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No HAI+SYS related deaths occurred. Median follow-up on the 42 survivors is 28 months (range 7–51). 6 deaths occurred within 2 yrs. 48% (26/54) have recurred; 42% (11/26) with liver involvement. Median time-to-progression is 30 months. The estimated 2YS rate is 88% (95% CI 80–98%) and median overall survival is 46 months (95% CI 41.3-NA). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. A 2YS of 88% exceeds our preplanned level of success, supporting the use of this combination in the ongoing NSABP trial C-09. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. No significant financial relationships to disclose.

Sir, Pemphigoid gestationis (PG) is a rare autoimmune blistering disease specific to pregnancy that usually presents in the second or third trimester or during the immediate postpartum period (1, 2). PG may develop in association with other autoimmune diseases, as well as with trophoblastic tumours, hydatiform mole and choriocarcinoma (3). The pathogenesis of PG is not fully established. However, most patients develop antibodies against 2 hemidesmosomal proteins, BP180 (BPAG2, collagen XVII) and, less frequently, BP230. Historically known as the herpes gestationis factors, these circulating antibodies belong to the heat-stable immunoglobulin G1 subclass. Sera from PG can recognize 5 distinct epitopes within BP180 NC16A, 4 of which have been reported as major antigenic sites targeted by bullous pemphigoid antibodies (4). The PG has a strong association with human leukocyte antigens HLA-DR3 and HLA-DR4 or both, and virtually all patients with a history of PG have demonstrable anti-HLA antibodies (5). During pregnancy PG is often treated with topical corticosteroids and systemic antihistamines. However, in some patients with severe disease, systemic steroid therapy is needed. If the disease continues, treatment options are limited. Although plasmapheresis, cyclophosphamide, azathioprine, cyclosporine and dapsone, as monotherapy or in combined regimens all have been reported to be beneficial, they have potential side-effects that can be harmful to both the mother and the foetus (6, 7). There are only 2 case reports in the literature describing the use of intravenous immunoglobulin (IVIg) therapy in PG (6, 8). We report here a persistent case of PG, refractory to the conventional treatment with steroid plus azathioprine or dapsone, which responded positively to IVIg.

Axillary Nodal Response to Neoadjuvant T-DM1 Combined with Pertuzumab in a Prospective Phase II Multi-Institution Clinical Trial.

Dual HER2 blockade with transtuzumab and pertuzumab is known to be associated with improved oncologic outcome, however, its evidence on the impact of surgical decision remains limited. This study aims to evaluate the efficacy of dual HER2 blockade, when compared to single blockade, in improving breast conservation rate in an Asian cohort. Retrospective study was performed on a prospectively-maintained database in our tertiary academic-based hospital, including patients with non-metastatic, HER2-positive breast cancer receiving neoadjuvant systemic therapy (NST) between January 2014 and December 2018. 142 patients were analyzed: 75 received Herceptin (H)-based NST and 67 received H + Pertuzumab (P)-based NST. Before NST, 65 patients (45.8%) were eligible for breast conserving therapy (BCT); and this increased to 103 (72.5%) after NST. Thirty-seven out of 75 patients (49.3%) who were deemed not BCT candidate converted to BCT-eligible after NST. More than half of the patients who were BCT-eligible opted for mastectomy. PH-based comparing to H-based NST did not differ significantly in BCT rate (35.5% vs 32.0%, P = 0.72); but there was a trend of increase in conversion to BCT-eligible rate (43.9-52.8%), reducing tumor diameter (40.2-53.1% reduction) and volume (69.5-80.0% reduction). The conversion rate from mastectomy to BCT-eligible was more than 50% after dual target therapy, which was slightly higher than single target agent. However the actual BCT rate was not significantly increased, and more than half of the BCT-eligible patients opted for mastectomy.

4557 Background: ICI-based regimens (ICI + ICI or ICI + VEGF targeted therapy [VEGF-TT]) represent current standard of care systemic therapies for the management of patients with mRCC. Robust biomarkers capable of predicting the therapeutic efficacy and safety of such regimens are still lacking. Eosinophils have been shown to play an important role in the response to immunotherapy. While recent investigations in RCC evaluated NER as a biomarker of poor response to immunotherapy, they did not fully account for the impact of different lines of therapy and the therapeutic classes of ICI-based regimens. We aimed to comprehensively evaluate the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI regimens. Methods: We retrospectively reviewed data from patients with mRCC treated with first line ICI-based regimens (dual ICI or ICI + VEGF-TT) at Dana-Farber Cancer Institute. Clinicodemographic information was collected, including tumor histology, ECOG performance status, IMDC risk score. We examined NER at baseline and at 6, 12, and 24 weeks while patients were still receiving treatment. The primary endpoint was overall survival (OS). Time to treatment failure (TTF) was a secondary endpoint. The association of NER with OS and TTF was evaluated using Cox regression models, adjusted for age, gender, BMI, histology, IMDC risk score and autoimmune disease. Results: Overall, 156 patients were included in the current analysis, with a median age of 61 years (IQR: 54-67). 60 patients received dual ICI therapy, while 96 were treated with ICI + VEGF-TT combinations. In the ICI+ICI group, a higher NER at baseline, 6 and 12 weeks was associated with worse OS. In the ICI + VEGF group, a higher NER only at 6 weeks appeared to be associated with worse OS. No association between NER and TTF was found. Conclusions: To our knowledge, this is the first study to investigate, across therapeutic classes, the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI-based regimens. Higher NER was linked to poor survival outcomes, especially in patients receiving dual ICI therapy. Future translational studies are needed to clarify these findings. [Table: see text]

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC