Two5 62 Molecular genetics and cancer biology - Oncology, tissue engineering

• R0 - no residual tumor 
• R1 - microscopic residual 
• R2 - macroscopic residual 
• R3 - Gross spillage or dissemination during resection

Response evaluation criteria in solid tumors

Target lesions: 

• Complete response (CR): Disappearance of all target lesions, confirmed at 4 weeks 
• Partial response (PR): At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter, confirmed at 4 weeks 
• Stable disease (SD): Neither PR nor PD criteria met
• Progressive disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
• [@ CP SP - complete, partial, stable, progressive] 

Non target lesions:

CVD - Cyclophosphamide, Vincristine, Dacarbazine 

In Malignant pheo if MIBG treatment fails

Mitotane - Derivative of DDT

Combination of Mitotane with streptozotocin

M-EDP - Mitotane - Etoposide, doxorubicin, cisplatin

A. Drugs directly acting on cells (Cytotoxic drugs)

• 1. Alkylating agents -Cyclophosphamide, Dacarbazine, Ifosfamide, Busulfan, Melphalan, Cisplatin, Temozolomide [AI 12]
• 2. Antimetabolites
• - Folate antagonist - Methotrexate
• - Purine antagonist: Cladribine, Fludarabine, Azathioprine, 6-Mercaptopurine
• - Pyrimidine antagonist: Ftorafur,5-Fluorouracil, Cytarabine (cytosine arabinoside)
• 3. Vinca alkaloids -  VINCristine (OnCoVIN),  Vinblastine, vinflunine (for UTUC) 
• 4. Taxanes - Paclitaxel, docetaxel, Cabazitaxel 
• 5. Epipodophyllotoxin - Etoposide
• 6. Antibiotics - Actinomycin D (Dactinomycin), Doxorubicin (adriamicin), Daunorubicin, Mitomycin, Mitoxantrone
• [@ अल्की आन्टी ले 2 ta  etro भेन्ता - alky, anti *2,  etRo vin, ta) - total 6]

B. Drugs altering hormonal milieu - Glucocorticoids, Tamoxifen, Flutamide, Finasteride

• Peripheral neuropathy 
• Cr - Renal 
• Can - Ototoxicity 
• Cardiac - 
• Myelosuppression

• disruption of microtubule function - induce apoptosis . Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division as depolymerization is prevented. Thus, in essence, taxanes are mitotic inhibitors.
• In contrast to the taxanes, the vinca alkaloids prevent mitotic spindle formation through inhibition of tubulin polymerization. Both taxanes and vinca alkaloids are, therefore, named spindle poisons or mitosis poisons, but they act in different ways.

Docetaxel - myelosuppression, fatigue, neuropathy, nail dystrophy 

Cabazitaxel - Neutropenia

Liquid biopsies are non-invasive blood tests that detect circulating tumour cells (CTCs) and fragments of tumor DNA that are shed into the blood from the primary tumour and from metastatic sites.

• The sampling and analysis of non-solid biological tissue, primarily blood.
• Like traditional biopsy this type of technique is mainly used as a diagnostic and monitoring tool for diseases such as cancer, with the added benefit of being largely non-invasive. Therefore, it can also be done more frequently which can better track tumors and mutations over a duration of time.

• There are several types of liquid biopsy methods; method selection depends on the condition that is being studied.
• - In cancer studies, circulating tumor cells (CTCs) and/or circulating tumor DNA (ctDNA) are collected.
• - In heart attack diagnosis, circulating endothelial cells (CECs) are sampled.
• - In prenatal diagnosis, cell-free fetal DNA (cffDNA) is extracted from maternal blood. Amniotic fluid can also be extracted and analysed.
• 

How it works - When tumor cells die, they release ctDNA into the blood. Cancer mutations in ctDNA mirror those found in traditional tumor biopsies, which allows them to be used as molecular biomarkers to track the disease.

Liquid biopsies can detect changes in tumor burden months or years before conventional imaging tests can, making them suitable for early tumor detection, monitoring, and detection of resistance mutations. 

• Is this the end of tissue biopsies?
• - Tissue biopsy will remain the gold standard for the next couple of years. As scientific knowledge advances, researchers are learning more about the potential of liquid biopsies to detect mutations

• Bladder cancer
• 1. Diagnosis
• - Bladder cancer antigen (BTA)
• - Nuclear matrix protein 22
• - Immunocytochemistry
• - Fluorescent in situ hybridization (FISH)
• - DNA methylation combined with the mutation status of FGFR3
• 2. Chemotherapy prediction - Molecular subtyping of bladder tumors
• 3. Predicting the efficacy of BCG therapy - High concentration of urinary IL‐2, IL‐8, and IL‐18 -low recurrence probability after BCG treatment
• 4. Treatment
• - PI3K–AKT–MTOR(42%)
• - Receptor tyrosine kinase (RTK)–MAPK (45% )
• - Erdafitinib -FGFR3 Inhibitor
• - Afatinib- ERBB family inhibitor
• - High levels of PDL1 expression (>5% of tumour-infiltrating lymphocytes expressing PDL1) - objective response rate higher (27% for atezolizumab/22% for pembrolizumab vs 10% for chemotherapy)
• - Gene therapy - Ad5CMV‐P53: adenovirus vector mediating dp53 gene transfer, 7 CG‐0700-recombinant adenovirus specifically targeting Rb pathway

• Prostate cancer
• 1. Diagnosis
• - PHI, 4K score
• - Gene fusion - TMPRSS2–ERG fusions
• - AMACR: alpha methylacyl CoA racemase - Tissue based marker
• - - Liquid biospy - Circulating tumor cells (CTCs), Circulating tumor DNA (ctDNA), Cell free DNA (cfDNA), MicroRNAs (miRNAs)- Liquid biospy - Circulating tumor cells (CTCs), Circulating tumor DNA (ctDNA), Cell free DNA (cfDNA), MicroRNAs (miRNAs)
• 2. Treatment
• - Targetting PSMA-Theranostics: Diagnosis-68Ga-PSMA PET/CT, therapetics-177Lu-PSMA
• - AR- V7 in circulating tumour cells (CTCs) and tissue biopsy samples
• - BRCA mutation - PARP
• - Microsattelite instability - CPI

• Renal cell carcinoma
• - PDL1 - CPI

• Talk about tumor markers in 
• - adrenal
• - kidney 
• - bladder 
• - prostate 
• - testis 
• -

• Tissue engineering is a technology similar to regenerative medicines.
• Regenerative medicines mean the use of stem cells. Stem cells can be
• - Embryonic stem cells
• - Adult stem cells

Progenitor cells reside within each organ, have limited self-renewal capacity, and differentiate into only one defined cell type. They are responsible for new cell differentiation and tissue formation during the normal process of tissue regeneration due to natural turnover, aging, and tissue injury.

• Epithelial Cells
• 1. Autologous urothelial cells - obtained from urinary bladder, often been used in urethral and bladder reconstruction
• 2. Autologous epidermal cells - harvested from penile foreskin because of its abundant resources
• 3. Autologous oral keratinocytes - buccal keratinocytes and lingual keratinocytes

Smooth Muscle Cells - Autologous SMCs offer the potential for improved ECM compliance and tissue elasticity, in addition to angiogenesis and epithelial maturation. In bladder, SMCs are essential to allow for contraction of the engineered tissue for urine expulsion

Stem cells are undifferentiated cells that have self-renewal potential and are able to differentiate into mature nonregenerative cells and effector cells. 

• Sources 
• - Bone marrow stem cells (BMSCs)
• - Adipose-derived stem cells (ADSCs)
• - Urine-derived stem cells (USCs)

Cells are implanted or seeded into an artificial structure capable of supporting three-dimensional tissue formation. These structures typically are called scaffolds.

Scaffolds facilitate the delivery of cells to desired sites in the body, define a three-dimensional space for the formation of new tissues with appropriate structure, and provide mechanical support for the newly regenerated tissues

Carbon nanotubes are among the numerous types for tissue engineering scaffolds They are biocompatible and can be functionalized with biomolecules.

• Requirements for scaffolds
• - High porosity and an adequate pore size
• - Biodegradability
• - rate at which degradation occurs has to coincide as much as possible with the rate of tissue formation
• - Inject ability

Stress urinary incontinence (SUI) - Assuming that mechanical injury/ dysfunction due to menopause or childbirth to be an important component of SUI, various investigators have injected bone marrow-derived, mesenchymal or human amniotic fluid-derived stem cells into the sphincter with varying results.

Bladder outlet obstruction - Bladder outlet obstruction causes inflammation, hypertrophy and later fibrosis (10). Reports suggest that mesenchymal stem cells injected into the bladder reduce hypoxia, markers of inflammation with the remodeling of collagen in rat models. However, the mechanism by which these changes occur has yet to be elucidated completely

• Urethral reconstruction - Attempts have been made to treat urethral stricture with stem cell therapy. This has been attempted either by engineered grafts (with or without scaffolds) using stem cells or with a tissue-engineered autologous tabularized urethra. 
• 

Bladder augmentation, detrusor interactivity, and the neurogenic bladder - Both overactive bladder and underactive detrusor have reported having improved outcomes in preclinical studies with local injections of adipose-derived stem cells. Bladder augmentation using a tissue-engineered bladder has been described in many trials and perhaps is most likely to be adopted clinically. The prerequisites of an ideal synthetic bladder material are two-fold. After integration in the host bladder, it should increase the compliance, and second, there should be a urinary barrier similar to the urothelium. Most tissue-engineered synthetic polymer bladders where it was hoped that there will be ingrowth of bladder cells fail in this regard.


Erectile dysfunction - In a rat model of post radiation erectile dysfunction, Qiu et al. reported significant improvement in the erectile function after injection of fat derived stem cells. Intracavernosal injection of stem cells resulted in their migration in to the major pelvic ganglia in rats with cavernosal nerve injury. While this holds promise in post prostatectomy erectile dysfunction, human trials have not yet been reported

In November 2017, the Food and Drug Administration has issued guidelines regarding stem cell use. Stem cells from most sources are now classified as drugs and therefore will be subject to the same scrutiny in this attempt to establish a “clear and modern” framework for regenerative medicine. An exception to this regulation is “same surgical procedure” wherein a procedure where stem cells use is in an autologous manner and is completed in a single surgery. In such a case the stem cells used is not called a biological drug