Response rate specific to bone metastasis of various cancers for immune checkpoint inhibitors: a systematic review.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with cancer, such as melanoma, renal cell carcinoma, head and neck cancer, non-small cell lung cancer (NSCLC), and urothelial carcinoma. The extension of life expectancy has led to an increased incidence of bone metastases (BM) among patients with cancer. BM result in skeletal-related events, including severe pain, pathological fractures, and nerve palsy. Surgery is typically required for the treatment of BM in patients with an impending fracture; however, it may be avoided in those who respond to ICIs. We systematically reviewed studies analyzing BM responses to treatment with ICIs. METHODS: This study was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 statement and registered in the UMIN Clinical Trials Registry (ID: UMIN000053707). Studies reporting response rates based on the Response Evaluation Criteria in Solid Tumors (RECIST) or the MD Anderson Cancer Center (MDA) criteria specific for BM in patients treated with ICIs were included; reports of fewer than five cases and review articles were excluded. Studies involving humans, published in English and Japanese, were searched. The PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched. Ultimately, nine studies were analyzed. The Risk of Bias Assessment tool for Non-randomized Studies was used to assess the quality of studies. RESULTS: Based on the MDA criteria, complete response (CR) or partial response (PR) was observed in 44-78% and 62% patients treated with ICIs plus denosumab for NSCLC and melanoma, respectively. According to the RECIST, CR or PR was recorded in 5% and 7-28% of patients treated with ICIs for renal cell carcinoma and urothelial carcinoma, respectively. CONCLUSION: Although response rates to ICIs for BM are poor, patients treated with ICI plus denosumab for bone metastases with impending fractures from NSCLC and melanoma are likely to avoid surgery to prevent fractures.

Current Concepts in the Treatment of Giant Cell Tumor of Bone: An Update.

Curettage is recommended for the treatment of Campanacci stages 1-2 giant cell tumor of bone (GCTB) in the extremities, pelvis, sacrum, and spine, without preoperative denosumab treatment. In the distal femur, bone chips and plate fixation are utilized to reduce damage to the subchondral bone and prevent pathological fracture, respectively. For local recurrence, re-curettage may be utilized when feasible. En bloc resection is an option for very aggressive Campanacci stage 3 GCTB in the extremities, pelvis, sacrum, and spine, combined with 1-3 doses of preoperative denosumab treatment. Denosumab monotherapy once every 3 months is currently the standard strategy for inoperable patients and those with metastatic GCTB. However, in case of tumor growth, a possible malignant transformation should be considered. Zoledronic acid appears to be as effective as denosumab; nevertheless, it is a more cost-effective option. Therefore, zoledronic acid may be an alternative treatment option, particularly in developing countries. Surgery is the mainstay treatment for malignant GCTB.

A Systematic Review of Adjuvant Chemotherapy in Localized Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma (DDCS) is a high-grade subtype of chondrosarcoma with the bimorphic histological appearance of a conventional chondrosarcoma component with abrupt transition to a high-grade, non-cartilaginous sarcoma. DDCS can be radiographically divided into central and peripheral types. Wide resection is currently the main therapeutic option for localized DDCS. Moreover, the effectiveness of adjuvant chemotherapy remains controversial. Therefore, we performed a systematic review of available evidence to evaluate the effect of adjuvant chemotherapy on localized DDCS. The purpose was to compare the 5-year survival rate among patients treated with surgery plus adjuvant chemotherapy or surgery alone for localized DDCS. The search was conducted in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Of the 217 studies shortlisted, 11 retrospective non-randomized studies (comprising 556 patients with localized DDCS) were selected. The 5-year survival rates were similar between the two treatment groups (28.2% (51/181) vs. 24.0% (90/375), respectively). The overall pooled odds ratio was 1.25 (95% confidence interval: 0.80-1.94; p = 0.324), and heterogeneity I2 was 2%. However, when limited to peripheral DDCS, adjuvant chemotherapy was associated with prolonged survival (p = 0.03). Due to the paucity of included studies and the absence of prospective comparative studies, no conclusions can be drawn regarding the effectiveness or ineffectiveness of adjuvant chemotherapy for localized DDCS.

Is perioperative chemotherapy effective in patients with localized myxoid liposarcoma?

BACKGROUND: This study aimed to compare the local recurrence, distant metastasis and disease-specific survival rates of patients with localized myxoid liposarcoma in the surgery and adjuvant chemotherapy group versus the surgery alone group. METHODS: A total of 456 patients in the Japanese National Bone and Soft Tissue Tumour Registry database who had localized myxoid liposarcoma and underwent surgery and adjuvant chemotherapy or surgery alone between 2001 and 2019 were included in this retrospective study. The study adjusted for background differences between patients who underwent surgery and adjuvant chemotherapy (n = 228) or surgery alone (n = 228) using propensity score matching. RESULTS: Univariate analysis showed no significant difference in local recurrence rate between the two groups (5-year local recurrence-free survival: 98.6% [95% confidence interval: 95.9-99.6] vs. 94.0% [95% confidence interval: 89.7-96.6], P = 0.052). Univariate analysis showed no difference in the incidence of distant metastases between the two groups (5-year distant metastasis-free survival: 80.5% [95% confidence interval: 73.9-85.8] vs. 75.1% [95% confidence interval: 67.7-81.2], P = 0.508). Univariate analysis showed no difference in disease-specific survival between the two groups (5-year disease-specific survival: 92.6% [95% confidence interval: 86.1-96.2] vs. 93.2% [95% confidence interval: 87.6-96.4], P = 0.804). In the high-risk group (n = 203) with high-grade tumours and tumour size ≥10 cm, there were no significant differences in the local recurrence, distant metastasis and disease-specific survival rates between the surgery and adjuvant chemotherapy group and the surgery alone group. CONCLUSION: The effect of adjuvant chemotherapy on localized myxoid liposarcoma appears to be limited.

Comparison of pre-operative and post-operative radiotherapy in patients with localized myxoid liposarcoma.

BACKGROUND: Myxoid liposarcoma is more radiosensitive than other soft tissue sarcomas, and radiotherapy has been reported to reduce tumour size. This study was performed to compare the rates of local recurrence, survival and wound complications between pre- and post-operative radiotherapy for localized myxoid liposarcoma. METHODS: From the Japanese Nationwide Bone and Soft Tissue Tumor Registry database, 200 patients with localized myxoid liposarcoma who received pre- (range, 30-56 Gy) or post-operative (range, 45-70 Gy) radiotherapy and surgery were included in this retrospective study. Propensity score matching was used to adjust for background differences between patients who received pre- and post-operative radiotherapy. RESULTS: Local recurrence occurred in five (5.0%) and nine (9.0%) patients in the pre- and post-operative radiotherapy groups, respectively (both n = 100). The median follow-up time from diagnosis was 40.5 months (IQR, 26.3-74). Univariate analysis showed a similar risk of local recurrence between the pre- and post-operative radiotherapy groups (5-year local recurrence-free survival 94.9% [95% CI 87.0-98.1] vs. 89.0% [95% CI 79.6-94.3]; P = 0.167). Disease-specific survival was similar between the pre- and post-operative radiotherapy groups (5-year disease-specific survival 88.1% [95% CI 75.5-94.6] vs. 88.4% [95% CI 77.3-94.5]; P = 0.900). The incidence of wound complications was similar between the pre- and post-operative radiotherapy groups (7.0% vs. 12.0%; P = 0.228). CONCLUSIONS: There was no difference in local recurrence, survival or incidence of wound complications between pre- and post-operative radiotherapy for localized myxoid liposarcoma. Therefore, pre-operative radiotherapy for myxoid liposarcoma provides clinical results equivalent to post-operative radiotherapy.

Megaprosthetic reconstruction of the distal femur with a short residual proximal femur following bone tumor resection: a systematic review.

BACKGROUND: To investigate the risk of postoperative function and complications associated with reconstruction methods in patients with short residual proximal femurs (< 12 cm) after resection of distal femoral bone tumors, we performed a systematic review of studies reporting postoperative function and complications in these patients. METHODS: Of the 236 studies identified by systematic searches using the Medline, Embase, and Cochrane Central Register of Controlled Trials databases, eight were included (none were randomized controlled trials). In these studies, 106 (68.4%), 12 (7.7%), and 37 (23.9%) patients underwent reconstruction with custom-made megaprostheses with extracortical plates or cross-pins, allograft prosthetic composite (APC), and Compress® compliant pre-stress (CPS) implants, respectively. RESULTS: Aseptic loosening occurred slightly more frequently in the APC group than in the other reconstruction methods (APC group, 21%; custom-made megaprosthesis group, 0-17%; CPS implant group, 14%). No differences were noted in the frequencies of implant breakage, fractures, or infections between the three reconstruction methods. Mechanical survival, where endpoint was set as implant removal for any reason, was 80% at seven years in the APC group, 70-77% at 10 years in the custom-made megaprosthesis group, and 68% at nine years in the CPS implant group. Therefore, there appeared to be no difference among the three reconstruction methods with respect to mechanical survival. CONCLUSIONS: During megaprosthetic reconstruction of the distal femur with a short residual proximal femur after bone tumor resection, similar results were obtained using custom-made megaprostheses, APCs, and CPS implants.

Reconstruction after Talar Tumor Resection: A Systematic Review.

This systematic review investigated the functional outcomes and complications of reconstruction methods after talar tumor resection. A systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases identified 156 studies, of which 20 (23 patients) were ultimately included. The mean Musculoskeletal Tumor Society scores in the groups reconstructed using tibiocalcaneal fusion (n = 17), frozen autograft (n = 1), and talar prosthesis (n = 5) were 77.6 (range 66-90), 70, and 90 (range 87-93), respectively. Regarding complications, sensory deficits were observed in one patient (6%) and venous thrombosis in two patients (12%) in the tibiocalcaneal fusion group, while osteoarthritis was observed in one patient (100%) in the frozen autograft group. No complications were observed in the talar prosthesis group. Reconstruction with talar prosthesis seems preferable to conventional tibiocalcaneal fusion after talar tumor resection because it offers better function and fewer complications. However, as this systematic review included only retrospective studies with a small number of patients, its results require re-evaluation in future randomized controlled trials with larger numbers of patients.

Outcome of Reoperation for Local Recurrence Following En Bloc Resection for Bone Giant Cell Tumor of the Extremity.

En bloc resection is typically performed to treat giant cell tumors of bone (GCTB), particularly when curettage can be challenging owing to extensive bone cortex destruction with soft tissue extension. Few reports have addressed the clinical outcomes after reoperation for local recurrence in patients with GCTB who underwent en bloc resection. In this multicenter retrospective study, we investigated local recurrence, distant metastasis, malignant transformation, mortality, and limb function in patients treated for local recurrence following en bloc resection for GCTB. Among 205 patients who underwent en bloc resection for GCTB of the extremities between 1980 and 2021, we included 29 with local recurrence. En bloc resection was performed for large tumors with soft tissue extension, pathological fractures with joint invasion, complex fractures, and dispensable bones, such as the proximal fibula and distal ulna. Local re-recurrence, distant metastasis, malignant transformation, and mortality rates were 41.4% (12/29), 34.5% (10/29), 6.9% (2/29), and 6.9% (2/29), respectively. The median Musculoskeletal Tumor Society score was 26 (interquartile range, 23-28). The median follow-up period after surgery for local recurrence was 70.1 months (interquartile range, 40.5-123.8 months). Local recurrence following en bloc resection for GCTB could indicate an aggressive GCTB, necessitating careful follow-up.

Effect of adjuvant chemotherapy on periosteal osteosarcoma: a systematic review.

BACKGROUND AND OBJECTIVE: The effects of adjuvant chemotherapy on periosteal osteosarcoma are controversial. Therefore, we conducted a systematic review of studies comparing mortality, local recurrence, distant metastasis and secondary malignancy incidence among patients who underwent surgery and (neo-) adjuvant chemotherapy or surgery alone for periosteal osteosarcoma without distant metastases at diagnosis. METHODS: Of the 210 studies identified in the search, 13 were included in this study, involving 291 patients with periosteal osteosarcoma in total. RESULTS: The mortality rates in the surgery and (neo-) adjuvant chemotherapy and surgery alone groups were 11.3% (8/71) and 16.3% (16/98), respectively. The overall pooled odds ratio was 0.89 (P = 0.800). The local recurrence rate in the surgery and (neo-) adjuvant chemotherapy group was 12.1% (8/66), while that in the surgery alone group was 17.6% (13/74). The overall pooled odds ratio was 1.31 (P = 0.601). The distant metastasis rate in the surgery and (neo-) adjuvant chemotherapy group was 15.2% (10/66) and that in the surgery alone group was 10.8% (8/74). The overall pooled odds ratio was 1.51 (P = 0.444). The incidence of secondary malignancy in the surgery and (neo-) adjuvant chemotherapy group was 7.6% (9/118) and that in the surgery alone group was 2.7% (2/74). The overall pooled odds ratio was 2.29 (P = 0.187). CONCLUSIONS: Adjuvant chemotherapy did not appear to improve the prognosis of patients with periosteal osteosarcoma. No association was found between the use of adjuvant chemotherapy and development of secondary malignancies.

Endosialin/CD248 may be a potential therapeutic target to prevent the invasion and metastasis in osteosarcoma.

Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane receptor, found on the plasma membrane of activated mesenchymal cells, which binds to fibronectin. Although endosialin is expressed at high levels in stem-like cells of sarcomas, its role has not been fully uncovered. The present study aimed to determine whether endosialin expression is associated with tumor progression and metastasis, and whether endosialin has the potential to act as a novel therapeutic target in osteosarcoma (OS) using MORAb-004/ontuxizumab, a humanized monoclonal antibody, which targets the type C lectin domain of endosialin. The results demonstrated that endosialin was highly expressed in OSs with metastatic disease. Furthermore, MORAb-004 had no cytostatic effect on OS cells in vitro and did not change the expression of stem cells and differentiation markers; however, it inhibited migration of OS cells. Taken together, these results suggest that endosialin may play a role in migration, and may be involved in the metastatic process of OSs. Furthermore, MORAb-004 reduces the motility of OS cells, and suppresses invasion and the development of metastatic lesions.

Effect of Adjuvant Chemotherapy on Localized Malignant Giant Cell Tumor of Bone: A Systematic Review.

A malignant giant cell tumor of the bone (GCTB) is a rare primary malignant tumor classified as primary or secondary. Wide resection of the primary tumor is recommended for localized malignant GCTB, but the effect of adjuvant chemotherapy is unclear. A systematic review was performed to compare the mortality associated with wide resection with that of wide resection plus adjuvant chemotherapy for primary and secondary localized malignant GCTB. Among the 745 studies identified, 9 were included. A total of 112 cases of localized malignant GCTB were included, with 39 and 73 cases being primary and secondary malignant GCTB. In primary localized malignant GCTB, the mortality rates were 40% (6/15 patients) and 33% (8/24 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. Overall pooled odds ratio was 1.07 (95% confidence interval, 0.26-4.37; p = 0.92). In secondary localized malignant GCTB, the mortality rates were 30.6% (11/36 patients) and 62.2% (23/37 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. The overall pooled odds ratio was 0.31 (95% confidence interval, 0.10-0.95; p = 0.04). The effect of adjuvant chemotherapy remains unclear for primary localized malignant GCTB, but adjuvant chemotherapy improved the survival of patients with secondary localized malignant GCTB.

Anti-Stem Cell Property of Pterostilbene in Gastrointestinal Cancer Cells.

Pterostilbene (PTE) is a natural sterbenoid contained in blueberries that has an antioxidant effect. In contrast, PTE also generates oxidative stress in cancer cells and provides an antitumor effect. Here, we examined the potential mechanism of this contrasting effect of PTE using three gastrointestinal cancer cell lines, namely CT26, HT29, and MKN74. PTE showed a dose-dependent inhibition of cell proliferation, sphere-forming ability, and stem cell marker expression in all three cell lines. Furthermore, the cells treated with PTE showed an increase in mitochondrial membrane potential and an increase in mitochondrial oxidative stress and lipid peroxide. Upon concurrent treatment with vitamin E, N-acetyl-L-cysteine, and PTE, the PTE-induced mitochondrial oxidative stress and growth inhibition were suppressed. These findings indicate that PTE induces oxidative stress in cancer cells, suppresses stemness, and inhibits proliferation. These antitumor effects of PTE are considered to be useful in cancer treatment.

Integrative assessment of clinicopathological parameters and the expression of PD-L1, PD-L2 and PD-1 in tumor cells of retroperitoneal sarcoma.

Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue sarcoma subtypes. The aim of the present study was to describe the clinical significance and prognostic implications of PD-L1, PD-L2, and PD-1 in patients with retroperitoneal sarcoma (RSar). In this retrospective, multicenter, collaborative study, medical charts were reviewed and the immunohistochemical staining results of resected tissue specimens from 51 patients with RSar were examined. Immunohistochemical staining was performed with primary antibodies against PD-L1, PD-L2, PD-1, and Ki-67. The correlations between the baseline clinical parameters and expression levels of the four molecules in sarcoma cells were evaluated, and their prognostic values after tumor resection were assessed. Dedifferentiated liposarcoma (41%), leiomyosarcoma (20%), and undifferentiated pleomorphic sarcoma (16%) were the three major types identified. Dedifferentiated liposarcoma and leiomyosarcoma showed higher levels of PD-L1 expression than did other sarcomas. The Spearman correlation analysis revealed that baseline serum lactate dehydrogenase levels were moderately and positively correlated with PD-L1 (P=0.02, r=0.41) and PD-L2 (P=0.006, r=0.47) expression. The median recurrence-free and disease-specific survival was 58 and 16 months, respectively, during the 29-month median follow-up after surgery. On univariate analysis, a higher expression level of PD-1 was associated with a higher risk of recurrence, whereas multivariate analyses revealed that independent predictors of recurrence-free and disease-specific survival indicated a high expression of Ki-67 (P=0.03; hazard ratio, 2.29 vs. low expression) and prognostic stage IIIB (P=0.04; hazard ratio, 5.11 vs. stage I-II), respectively. Findings of the current study provide novel insights about the prognostic value of PD-L1, PD-L2, and PD-1 expression in RSar. Serum lactate dehydrogenase levels constitute a potential predictor of PD-L1 and PD-L2 expression levels in RSar. Further investigations are needed to determine the immunologic landscape of RSar and provide a foundation for therapeutic intervention using immune checkpoint inhibitors.

Impairment-driven cancer rehabilitation in patients with neoplastic spinal cord compression using minimally invasive spine stabilization.

BACKGROUND: Neoplastic spinal cord compression is a cause of severe disability in cancer patients. To prevent irreversible paraplegia, a structured strategy is required to address the various impairments present in cancer patients. In this study, we aimed to identify the status where rehabilitation with minimally invasive spine stabilization (MISt) effectively improves ADL. METHODS: We retrospectively reviewed 27 consecutive patients with neoplastic spinal compression who were treated with MISt. We classified the impairments of patients through our multidisciplinary tumor board based on spine-specific factors, skeletal instability, and tumor growth. The neurological deficits, progress of pathological fracture, incidence of vertebral collapse, and postoperative implant failure were examined. Changes of the Barthel index (BI) scores before and after surgery were investigated throughout the clinical courses. RESULTS: The average duration to ambulation was 7.19 ± 11 days, and we observed no collapse or progression of paralysis except in four cases of complete motor paraplegia before the surgery. Neurological deficiency was improved to or maintained at Frankel's grade E in 16 patients, remained unchanged in 6 patients (in grades B, C, D), and worsened in 5 patients. BI score comparisons before and after surgery in all patients showed statistically significant increments (p < 0.05). On further analysis, we noted good functional prognosis in patients capable of ambulation within 7 days (p < 0.05) and in patients who could survive longer than 3 months after the surgery (p < 0.05). CONCLUSIONS: In various cancer patients with neoplastic spinal cord compression, skeletal instability as the primary impairment is a good indication for MISt, as the patients showed early ambulation with improved BI scores.

Miscorrelation of Functional Outcome and Sociooccupational Status of Childhood, Adolescent, and Young Adult Generation With Bone and Soft Tissue Sarcoma Patients.

Few studies have examined the relationship between functional outcome and sociooccupational or psychological status in adolescent and young adults (AYA) generation and childhood sarcoma patients. We retrospectively analyzed clinical (prognostic and functional) and sociooccupational outcomes in 50 patients; 22 children aged under 14 years and 28 AYAs generation (15 to 29 y). There were 35 cases of bone sarcomas and 15 of soft tissue sarcomas. Limb-sparing surgery was performed in 30 of 37 extremity cases. The most prevalent problems among patients were as follows: limited activities; drop-out or delayed studies among high school and college students; limitation in job searching; and changes in social relationships. These problems were unaffected by limb-sparing. Regression analysis between functional and sociooccupational disability showed that the correlation coefficient was significant (P=0.005) in all limb-salvaged patients, but there was no significant correlation among osteosarcoma patients (P=0.07). These findings suggest that quality of life is a multidimensional measure: it depends on physical status, spiritual health, and social well-being of both patients and family members. To overcome the disadvantages of this type of disease, it is essential to provide comprehensive care at the earliest convenience using multidimensional approaches.

Mesenchymal stem cells up-regulate the invasive potential of prostate cancer cells via the eotaxin-3/CCR3 axis.

This study aimed to clarify the role of mesenchymal stem cells (MSCs) as a component of the cancer microenvironment. We investigated the homing-related chemokine expression levels of MSCs treated with a prostate cancer cell line (PC-3) -conditioned medium. Among several homing chemokines, an antibody array revealed that expression of eotaxin-3 (but not eotxin-1 and -2) was highly enhanced in MSCs treated with PC-3-conditioned medium. A gene expression array showed significantly increased expression of CCR3, a receptor of eotaxin-3, in PC-3. In a matrigel invasion assay, interferon-gamma, a specific inhibitor of eotaxin-related homing, significantly reduced the transmigration of PC-3 cells, under co-cultured condition with MSCs, in a dose-dependent manner (P < 0.05). Consistent with these results, anti-CCR3 antibody successfully reduced PC-3 migration under the co-cultured condition. These findings suggest that MSCs to modulation of the invasive potential of prostate cancer cells via the eotaxin-3/CCR3 axis.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Broad targeting of resistance to apoptosis in cancer.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Therapeutic targeting of replicative immortality.

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.

Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition.

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.