Treatment of metastatic rectal squamous cell carcinoma in a pregnant patient.

Rectal squamous cell carcinoma is an exceedingly rare form of rectal cancer, with limited data available regarding its presentation and effective treatment. Rectal cancer occurring during pregnancy is uncommon as well. This is a case of metastatic rectal squamous cell carcinoma presenting in a 22-week pregnant, female patient in her early 30s. The patient was treated with 5-fluorouracil and cisplatin and delivered a healthy male child born via uncomplicated vaginal delivery at 35 weeks. This article demonstrates that despite the rare nature of this cancer, in the already rare context of pregnancy, effective and safe treatment is possible with a multidisciplinary team.

Circumferential Resection Margin as Predictor of Nonclinical Complete Response in Nonoperative Management of Rectal Cancer.

BACKGROUND: Short-course radiation therapy and consolidation chemotherapy with nonoperative intent has emerged as a novel treatment paradigm for patients with rectal cancer, but there are no data on the predictors of clinical complete response. OBJECTIVE: Evaluate the predictors of clinical complete response and survival. DESIGN: Retrospective cohort. SETTINGS: National Cancer Institute-designated cancer center. PATIENTS: Patients with stage I to III rectal adenocarcinoma treated between January 2018 and May 2019 (n = 86). INTERVENTIONS: Short-course radiation therapy followed by consolidation chemotherapy. MAIN OUTCOME MEASURES: Logistic regression was performed to assess for predictors of clinical complete response. The end points included local regrowth-free survival, regional control, distant metastasis-free survival, and overall survival. RESULTS: A positive (+) circumferential resection margin by MRI at diagnosis was a significant predictor of nonclinical complete response (OR: 4.1, p = 0.009) when adjusting for CEA level and primary tumor size. Compared to patients with a negative (-) pathologic circumferential resection margin, patients with a positive (+) pathologic circumferential resection margin had inferior local regrowth-free survival (29% vs 87%, p < 0.001), regional control (57% vs 94%, p < 0.001), distant metastasis-free survival (43% vs 95%, p < 0.001), and overall survival (86% vs 95%, p < 0.001) at 2 years. However, the (+) and (-) circumferential resection margin by MRI subgroups in patients who had a clinical complete response both had similar regional control, distant metastasis-free survival, and overall survival of more than 90% at 2 years. LIMITATIONS: Retrospective design, modest sample size, short follow-up, and the heterogeneity of treatments. CONCLUSIONS: Circumferential resection margin involvement by MRI at diagnosis is a strong predictor of nonclinical complete response. However, patients who achieve a clinical complete response after short-course radiation therapy and consolidation chemotherapy with nonoperative intent have excellent clinical outcomes regardless of the initial circumferential resection margin status. See Video Abstract at http://links.lww.com/DCR/C190 . EL MARGEN DE RESECCIN CIRCUNFERENCIAL COMO PREDICTOR NO CLNICO DE RESPUESTA COMPLETA EN EL MANEJO CONSERVADOR DEL CNCER DE RECTO: ANTECEDENTES:La radioterapia de corta duración y la quimioterapia de consolidación en el manejo conservador, han surgido como un nuevo paradigma de tratamiento, para los pacientes con cáncer de recto, lastimosamente no hay datos definitivos sobre los predictores de una respuesta clínica completa.OBJETIVO:Evaluar los predictores de respuesta clínica completa y de la sobrevida.DISEÑO:Estudio retrospectivo de cohortes.AJUSTES:Centro oncológico designado por el NCI.PACIENTES:Adenocarcinomas de recto estadio I-III tratados entre 01/2018 y 05/2019 (n = 86).INTERVENCIONES:Radioterapia de corta duración seguida de quimioterapia de consolidación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó una regresión logística para evaluar los predictores de respuesta clínica completa. Los criterios de valoración incluyeron la sobrevida libre de recidiva local, el control regional, la sobrevida libre de metástasis a distancia y la sobrevida general.RESULTADOS:Un margen de resección circunferencial positivo (+) evaluado por imagenes de resonancia magnética nuclear en el momento del diagnóstico fue un predictor no clínico muy significativo de respuesta completa (razón de probabilidades/ OR: 4,1, p = 0,009) al ajustar el nivel de antígeno carcinoembrionario y el tamaño del tumor primario. Comparando con los pacientes que presetaban un margen de resección circunferencial patológico negativo (-), los pacientes con un margen de resección circunferencial patológico positivo (+) tuvieron una sobrevida libre de recidiva local (29% frente a 87%, p < 0,001), un control regional (57% frente a 94%, p < 0,001), una sobrevida libre de metástasis a distancia (43% frente a 95%, p < 0,001) y una sobrevida global (86% frente a 95%, p < 0,001) inferior en 2 años de seguimiento. Sin embargo, los subgrupos de margen de resección circunferencial (+) y (-) evaluados por imágenes de resonancia magnética nuclear en pacientes que tuvieron una respuesta clínica completa tuvieron un control regional similar, una sobrevida libre de metástasis a distancia y una sobrevida general >90% en 2 años de seguimiento.LIMITACIONES:Diseño retrospectivo, tamaño modesto de la muestra, seguimiento corto y heterogeneidad de tratamientos.CONCLUSIONES:La afectación del margen de resección circunferencial evaluado por resonancia magnética nuclear al momento del diagnóstico es un fuerte factor predictivo no clínico de respuesta completa. Sin embargo, los pacientes que logran una respuesta clínica completa después de un curso corto de radioterapia y quimioterapia de consolidación como manejo conservador tienen excelentes resultados clínicos independientemente del estado del margen de resección circunferencial inicial. Consulte Video Resumen en http://links.lww.com/DCR/C190 . (Traducción-Dr. Xavier Delgadillo ).

Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study.

PURPOSE: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. RESULTS: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. CONCLUSIONS: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.

CD23+ mantle cell lymphoma: a clinical pathologic entity associated with superior outcome compared with CD23- disease.

Mantle cell lymphoma (MCL) commonly lacks expression of CD23. However, a significant minority of MCLs express CD23, as assessed by flow cytometric immunophenotyping (FCIP). The aims of our study were to investigate the expression of CD23 by FCIP in patients with MCL and to correlate CD23 expression with pathologic and clinical parameters, including outcome. We studied 53 patients with untreated MCL who had CD23 expression determined by FCIP. At diagnosis, 14 MCLs (26%) were CD23+ at all tissue sites, whereas 33 (62%) were CD23-, and 6 (11%) had discordant CD23 expression among different tissue sites. Patients with CD23- MCL had extranodal disease more commonly compared with patients with CD23+ MCL. Moreover, with 57-month median follow-up, the 4-year event-free and overall survival rates for CD23+ MCL were 45% and 75%, respectively, compared with 19% and 51% for CD23- MCL. In multivariate Cox regression analysis, CD23 status and leukemic-phase MCL were the most important factors predicting outcome.

New therapeutic options in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-alpha tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post-complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.

Molecularly targeted therapies in adult soft tissue sarcomas: present approach and future directions.

BACKGROUND: Sarcomas are rare neoplasms. Given the overwhelming chemotherapy resistance of the disease, patients with progressive and metastatic soft tissue sarcomas are ideal candidates for trials of investigational new drugs. OBJECTIVE: The authors review the molecular mechanisms underlying soft tissue sarcomas and discuss molecularly targeted therapies developed to improve the poor outcome of these uncommon tumors. METHODS: A Medline and American Society of Clinical Oncology abstract search was conducted using the keyword 'soft tissue sarcoma'. Articles and abstracts were reviewed and eligible for inclusion if they used targeted therapies for the treatment of patients with soft tissue sarcomas. RESULTS/CONCLUSION: Phase II clinical trials for patients with soft tissue sarcomas using novel targets and present recognized targets are ongoing and planned.

Adjuvant therapy for colon cancer.

In patients with colon cancer who undergo resection for potential cure, 40% to 60% have advanced locoregional disease and are classified as either stage II or stage III. The role of adjuvant therapy in stage III colon cancer is well defined. The results from the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) and the National Surgical Adjuvant Breast and Bowel Project C-07 trial confirm a definite disease-free survival (DFS) benefit with the addition of oxaliplatin to either infusional or bolus 5-fluorouracil/leucovorin (5-FU/LV). The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial showed capecitabine to be of equivalent clinical benefit to bolus 5-FU/LV. However, adjuvant trials with irinotecan, including Cancer and Leukemia Group B (CALGB 89803), the Pan-European Trial in Adjuvant Colorectal Cancer 3 (PETACC-3), and the French ACCORD trial, have not shown a significant DFS advantage. In contrast, in patients with stage II disease, a small survival benefit of 1% to 5% exists with chemotherapy. Perhaps the analysis of molecular markers in combination with high-risk histopathologic features will help increase patient specificity and identify subsets of patients with stage II colon cancer who will derive a survival benefit with adjuvant therapy. The current Intergroup study stratifying stage II patients based on presence of microsatellite instability and loss of heterozygosity 18q allele will help us better understand the risk versus benefit observed.

Sequence dependent potentiation of gemcitabine by flavopiridol in human breast cancer cells.

PURPOSE: Flavopiridol is a novel cyclin dependent kinase (cdk) inhibitor currently in Phase I and II clinical trials. We investigated the interaction between flavopiridol and gemcitabine in two human breast cancer cell lines. Experimental design. MCF-7 [Estrogen receptor (ER) positive] and MDA-MB-231 cells (ER negative) were treated with sub-cytotoxic concentrations of gemcitabine (G), flavopiridol (F), and flavopiridol followed by gemcitabine (F-G), or gemcitabine followed by flavopiridol (G-F) and assayed for biological activity. RESULTS: Growth inhibition assessed by serial cell counting and MTT assay was highest in the G-F group. Significant increase in apoptosis assessed by flow cytometry, poly-ADP-ribose polymerase (PARP) and Caspase-3 degradation was also highest in the G-F group. Expression of pro-apoptotic Bax was up-regulated and anti-apoptotic Bcl-2 was down-regulated in only the G-F treated cells. Significant up regulation of p21(WAF-1) was demonstrated in the G-F group but not in the reverse regimen treated cells. No effect on protein kinase C (PKC) expression was seen in any of the treated cells. CONCLUSIONS: In conclusion, similar to the results in the gastrointestinal cell lines, a sequence dependent potentiation of the effect of gemcitabine by flavopiridol was demonstrated in breast cancer cell lines and it was independent of ER status. This was accompanied by enhanced apoptosis and the up regulation of p21(WAF-1) protein. These results provide rationale for pre-clinical evaluation of this treatment strategy using animal models and in the design of clinical trials of this drug in combination with cytotoxic therapy.

PSA relapse prostate cancer: the importance of tailored therapy.

Prostate specific antigen (PSA) is an invaluable tumor marker in the detection of early prostate cancer as well as a predictor of recurrence after treatment of localized disease. Current practice entails the use of factors such as pretherapy grade, stage and PSA, PSA doubling time, nature of previous therapy and patient age and functional status for a treatment recommendation. For a PSA relapse post radical prostatectomy, radiation therapy to the prostatic fossa is a primary therapeutic consideration. With careful patient selection, about 30 to 40% of patients are rendered disease free using this approach. For patients with radiation therapy as the primary treatment for their prostate cancer, salvage prostatectomy can be considered, but is rarely feasible. Systemic therapy with hormones is standard if patients are not candidates for the above mentioned salvage local therapies or if they relapse after exhaustive local therapies. Unfortunately androgen suppressive therapy is unlikely to induce cure, or prolonged remissions in PSA relapse prostate cancer. The strategy of addition of chemotherapy or biologic therapy to androgen suppressive therapy is under active investigation. The goal of this therapy is to make an impact on the time to progression to metastatic prostate cancer and correspondingly decrease prostate cancer related mortality. Preliminary results of studies incorporating early chemotherapy in combination with androgen suppressive therapy are encouraging, with improvement in time to progression and overall survival. The evaluation of biologic agents and agents with better toxicity profiles is ongoing. This is very important to make therapy widely applicable and to enable prolonged administration especially in a disease such as prostate cancer with a relatively long natural history. Strategies of adjuvant and neoadjuvant therapy in locally advanced prostate cancer are exploring the possibility of reducing the chance of PSA relapse by treating micrometastatic disease. This review discusses the current practices in risk stratification and management of PSA relapse prostate cancer. It also highlights the major clinical trials and areas of active investigation in this field.

Sensitization of human breast cancer cells to gemcitabine by the protein kinase C modulator bryostatin 1.

PURPOSE: Protein kinase C (PKC) plays an important role in cell proliferation, differentiation, and apoptosis. The interaction between the PKC modulator bryostatin 1 (BRYO), and gemcitabine in human breast cancer MCF-7 and MDA-MB-231 cells and in the non-transformed MCF-10A human breast epithelial cells was investigated. METHODS: Immunoblotting was used to determine the expression of PKC isoenzymes and proteins involved in the cell cycle and apoptosis. MTT, ELISA and flow cytometry assays were used to determine cell survival. RESULTS: Treatment of cells with BRYO 200 n M resulted in a significant downregulation of cytoplasmic PKC in all three cell lines. However, the expression of membranous PKC was differentially affected in these cells. BRYO (1-200 n M) had no significant effects on cell viability in any of the cell lines. Nevertheless, BRYO significantly enhanced the antiproliferative and apoptotic effects of gemcitabine in the MCF-7 and MDA-MB-231 cells, but not in the MCF-10A cells. This was associated with significant reduction in the bcl-2/bax ratio. There was a significant upregulation of p53, p21(waf1), and p27 in MCF7 and MCF-10A cells treated with the combination of gemcitabine and BRYO compared to gemcitabine-treated cells. CONCLUSIONS: The potentiation of the effect of gemcitabine by BRYO was demonstrated in MCF-7 and MDA-MB-231 cells and was associated with a specific pattern of PKC modulation. Further investigation of the role of specific isoforms of PKC in the downstream molecular events of gemcitabine-induced cytotoxicity is warranted.

Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells.

Recent results from epidemiology, in vitro cell culture and in vivo (animal and human) studies have suggested the benefits of indole-3-carbinol (I3C) for the prevention of many types of cancer, including breast cancer. However, there are no reports, to the best of our knowledge, on the effect of I3C on isogenic nontumorigenic and tumorigenic breast epithelial cells, and there is a significant void in our understanding of the molecular mechanism(s) by which I3C induces apoptotic cell death in breast cancer cells. To fill this gap in our understanding, we conducted experiments to investigate the effects of I3C on an isogenic nontumorigenic (MCF10A) and tumorigenic (MCF10CA1a [CA1a]) breast epithelial cells. Here we show that CA1a cells are more sensitive to low concentration of I3C in terms of cell growth inhibition compared to MCF10A cells. We further report that I3C upregulates Bax/Bcl-2 ratio and downregulates Bcl-xL expression in CA1a cells but not in MCF10A cells. We also report, for the first time, that I3C induces Bax translocation to the mitochondria, causing mitochondrial depolarization, resulting in the loss of mitochondrial potential leading to the release of cytochrome c and subsequent cell death in CA1a cells but not in MCF10A cells. From these results, we conclude that I3C selectively induces apoptosis in breast cancer cells, but not in nontumorigenic breast epithelial cells, suggesting the potential therapeutic benefit of I3C against breast cancer.

Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis.

For hormone resistant prostate cancer (HRPC), chemotherapy is used but the mortality is 100% with a mean survival time of 7-8 months. Our previous studies have shown the chemotherapeutic effect of ciprofloxacin in bladder cancer. At doses 50-400 micro g/ml ciprofloxacin, the concentrations that are normally achieved at doses currently used for the treatment of anti-bacterial infections, inhibited bladder cancer cell growth and induced S/G2M arrest with modulation of key cell cycle regulatory genes and ultimately activated apoptotic processes. In this study, we investigated the effect of ciprofloxacin on androgen independent prostate carcinoma, PC3 cells and compared our results with non-tumorigenic prostate epithelial cells. The main advantage of this fluroquinolone antibiotic is its relative non-toxicity as compared to current chemotherapy, which is not very effective, for the treatment of advanced hormone resistant prostate cancer. PC3 cells as well as normal prostate epithelial cells (MLC8891) were treated with 25-400 micro g/ml ciprofloxacin, and cell counting was done during 3 days of treatment. The cell death was determined using DAPI staining of cell nuclei, 7AAD-staining followed by flow cytometric analysis as well as by activation of caspase-3, a member of the ICE family of enzymes involved in the apoptotic cascade. The cell lysates were analyzed by immunoblotting techniques for the expression of key genes targeted by ciprofloxacin (p21WAF1, Bax and Bcl-2). Translocation of bax was visualized using a fluorescence staining procedure followed by laser confocal microscopic imaging. Treatment of prostate cancer cells with ciprofloxacin resulted in a dose- and time-dependent inhibition of cell growth (70-100% with 50-400 micro g/ml of the drug). There was a concomitant induction of cell cycle arrest at the S and G2/M phases of the cell cycle as well as induction of apoptosis. The CDK inhibitor p21WAF1 was down-regulated as early as 12 h following ciprofloxacin treatment (100-200 micro g/ml for 12-24 h). There was a significant increase in the Bax/Bcl-2 ratio with translocation of Bax, a pro-apoptotic protein, to mitochondria with concomitant activation of caspase 3. These results suggest the potential usefulness of the fluroquinolone, ciprofloxacin as a chemotherapeutic agent for advanced prostate cancer. The fluroquinolone ciprofloxacin showed anti-proliferative and apoptosis inducing activity on prostate cancer cells but not on non-tumorigenic prostate epithelial cells. These effects of ciprofloxacin were mediated by cell cycle arrest at S-G2/M phase of the cell cycle, Bax translocation to mitochondrial membrane and by increasing the Bax/Bcl-2 ratio in PC3 prostate cancer cells. Based on our in vitro results, further in-depth in vivo animal or human investigations are warranted.

Ciprofloxacin inhibits cell growth and synergises the effect of etoposide in hormone resistant prostate cancer cells.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer related deaths in men in the United States. Ciprofloxacin is a relatively non-toxic antibiotic that can be easily administered orally with large volume of distribution and good tissue penetration. Studies from others and our laboratory have recently reported its anti-tumor activity in a variety of human tumor cells. In our current experiment, we studied the effect of ciprofloxacin on a hormone resistant prostate cancer (HRPC) cell line, PC-3. Our study shows significant in vitro cell growth inhibition of PC-3 cell line (p=0.0001) and also shows that there is a synergistic increase in the antiproliferative effect of etoposide when these cells are pretreated with ciprofloxacin for 24 h, prior to etoposide exposure (p=0.0001). Western blot analysis of the protein extracts from these cells showed down-regulation of Bcl-2, altering the ratio of Bax:Bcl-2 favoring apoptosis. In our study no significant effect was seen on p21WAF1 expression by the combination of ciprofloxacin and etoposide but there was down-regulation of p21WAF1 gene by ciprofloxacin alone. Ciprofloxacin also inhibited NF-kappaB binding to DNA. Further studies in this area are warranted as the roles of p21WAF1, Bax/Bcl-2 and NF-kappaB may be important molecular events in mediating the antiproliferative and apoptosis inducing effect of etoposide in combination with ciprofloxacin in HRPC cells.

Role of mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells.

PURPOSE: In our earlier series we showed that ciprofloxacin inhibits bladder tumor cell growth with concomitant S/G2M cell cycle arrest and reported an increased Bax-to-Bcl-2 ratio in cells undergoing cell death. In the current series we elucidated the molecular mechanisms by which ciprofloxacin induces apoptotic processes. MATERIALS AND METHODS: Ciprofloxacin mediated mitochondrial depolarization was detected by flow cytometry in HTB9 cells. Mitochondrial permeability transition was measured by spectrophotometry in isolated mitochondria treated with ciprofloxacin in the presence and absence of cyclosporin. The consequential decrease in mitochondrial calcium, cytochrome c release and Bax translocation to mitochondria, which resulted in the activation of caspase 3 leading to apoptotic cell death, was measured by biochemical and confocal microscopy. RESULTS: Mitochondrial depolarization was observed during ciprofloxacin induced apoptotic processes. Cyclosporin A, a known inhibitor of the mitochondrial permeability transition pore, protected cells against decreased mitochondrial potential. Also, ciprofloxacin induced an alteration of mitochondrial calcium as early as 5 minutes and this disruption of intracellular calcium homeostasis was prevented by cyclosporin. Ciprofloxacin also had a direct effect on swelling of isolated mitochondria, which was absent in the presence of cyclosporin. Mitochondrial changes were accompanied by cytochrome c release and caspase 3 activation. Our findings also showed Bcl-2 dependent subcellular redistribution of Bax to the mitochondrial membrane in ciprofloxacin treated bladder tumor cells. CONCLUSIONS: The disruption of calcium homeostasis, mitochondrial swelling and redistribution of Bax to the mitochondrial membrane are key events in the initiation of apoptotic processes in ciprofloxacin treated bladder cancer cells.