Thank you. Yes. At the outset, I would like to thank the organizers and especially Susan and Ashima, who have been so encouraging, and Ashima especially, as she has been watching and looking from the behind about tuberculosis and ovarian cancer, the interesting relationship. And she's encouraged me earlier also to work further into it, and I would thank her. Due to her persistence, my paper on the same topic on tuberculosis and ovarian cancers was published. So why is it important? Why did it interest me? I am from this institution, Christian Medical College, Belleau, and we see about close to 8,000 patients to 9,000 patients per day. So you can imagine the amount of crowding that goes on. It's not a very spread out facility. And where we have people cramming, people are still coming and going around in circles. And what I realized is that to diagnose tuberculosis in a patient who has symptoms and features suggestive of an ovarian cancer, it's quite disturbing for the patient until the day we do a biopsy and negate it and tell them that it's not cancer, but it's TB. So that was actually where I started getting interested. And so I started looking up on those charts and those paper, and the further deliberations were a result of that. But today's topic was actually on the management issues and the dilemmas, some of which we discussed during our case discussion. It has been a very rare, rare combination to have TB and ovarian cancer, and it's good to know that in a short span of time, you could actually see two of those cases in close to 12 years that I've been doing pure oncology. I seriously haven't come upon a case where both are coexisting. It's only from my hearsay and from my knowledge with other cancer treatment that I had discussions with my infectious disease consultants and my medical oncologist that I'll be talking to you today. So thank you, and we'll go into the talk. So tuberculosis and ovarian cancer, the dilemmas actually in management starts with diagnosis. So if one would see this picture on a laparoscopy of bowel with stippling with disease or peritoneum with stipple with such kind of multiple miliary tubercles, for the inexperienced eye, this was always cancer, and it is quite scary. But what I want to stress here is for those of us who have been seeing cancer, miliary seedling of cancer versus miliary seedling of TB, could recognize the gaseous necrosis and also the type of pattern that it spreads over the bowel, the type of the nodules, and we could at one look probably be able to say after some years of looking at it, that this is TB and this is not cancer. So that's why I thought it is of interest to us to look into this. Now, TB itself is very rare, as we all have been talking about, due to better health care or availability in all our countries, though it is coming down, majority of the disease and the global burden of TB is from two-thirds of this is coming from eight countries of which India is a major contributor. So we see a lot of cases still, and interestingly, in the latest statistics, they did see a drop in the cases in the COVID season, but it is still out there and we see up to close to 10 million cases per year, of which about 15% of cases can be extrapulmonary TB, of which a small percentage can be the abdominal TB or the intestinal TB or the peritoneal type of TB that we will be seeing. So where does this, where does one get affected or infected and how does it reach the intraabdominal cavity? It's a complex milieu of things. Some people believe it's from the cough and from the lungs, it gets into the bloodstream and it gets into the, seeded into the abdominal cavity, whereas others believe it could be by ingestion of infected milk and milk products, but however it came, it is there. And it is a combination of immunocompromised status with a poor intake of good food, nutrition, and the whole milieu of things, which ends up, and it is usually a disease of the poorer economic strata. And so it's important to recognize it and have a good clinical suspicion. So extrapulmonary TB itself is quite uncommon. It only contributes to about less than 10% of all tuberculosis cases that we see. And of that only one to 2% presence actually as tuberculosis peritonitis. It is rare, fortunately for us, and hence it is very less studied. And hence, as Ashima said, we do not have very definite guidelines and even literature is very, very scarce on this. And where does these extrapulmonary TBs occur? Extrapulmonary TB in the abdomen, which we will be focusing on, can present in four forms. It could either affect the lymph nodes in the retroperitoneum or inside the placentric lymph nodes, or it could be more commonly affecting the surface of the bowel or a particular segment of the intestine, like the ileocecal region, or it could present as peritoneal TB where it seats the entire peritoneal surface and also the serosal surface of the bowel. And it can sometimes not be associated with ascites, but just be a dry peritoneal TB, where there are just large mid-centric nodules and thickening and fibrosis forming a cocoon or clumping all the bowels together and not having much ascites, but just more of a scarring and stricturing type of peritoneal irritation. So there are difficulties in diagnosing this, as we know, because this is going to look very much like ovarian cancer for the untrained eye. The history is very important, hence in finding out what is behind and be able to have a quick, good suspicion behind the investigation. The examination is also important, which we'll be discussing shortly, and what are the diagnostic tests which will enable us to finally clinch the diagnosis. The differentials that one would think of in this kind of scenarios varies from any advanced bowel disease to hepatobiliary malignancies to Crohn's disease. And TB, of course, comes as one, but malignancy features higher in our list, and we are always wanting to disprove or rule in or rule out a malignancy. So these patients generally, if you go into the history, the clinical features could be vague abdominal pain, but there is usually a component of fever, which is most often missed out, so it's important to elicit the history. They may have a vague abdominal distension or a mask, and in rare cases where there is actual involvement of the intestines, there may be blood in stools. Acitis is a very common presentation, which comes to most of our clinics, though it is underreported, and sometimes we do see a patient with intestinal obstruction, for which we are called to see, and there is a lot of stricturing and scarring, and that finally turns out to be TB. So the symptoms are quite vague, and so are the findings. The findings that we commonly see in abdominal TB are extreme amount of malnutrition and cachexia. There may be ascites. The ascites is mostly tense, or there may be an omental cake, which is quite doughy and not… The ascites is also very tense and rigid, and there may be particular deficits, and interestingly, there may be lymphadenopathy, the supraclavicular axillary inguinal. It's very important when you have large lymph nodes with ascites to actually be looking out for tuberculosis. So both history and the examination can actually mimic, very much mimic, ovarian cancer, and so we need to evaluate it along both lines. We would do the routine counts as well as an ESR, which may be elevated quite high in the cases of TB. It can be elevated in malignancy also, but the levels may be much higher in tuberculosis. Tuber markers, interestingly, may be elevated, but what we did find and what we think generally is CA1 to 5, though we call that is not a very sensitive marker, it can be elevated in many other conditions, but the level at which it's elevated can actually tell you that this is probably not TB. It may not be true, but at least it can give you a guidance. So roughly when we say CA1 to 5 is less than 1,000, then we add with a lot of ascites, with a lot of disease, looking on the imaging or for the testing, then you may think that this could probably be TB, because a lot of disease with cirrhosis and not correlating with or a lower level of CA1 to 5 is a definite point which should raise your suspicion. The other diagnostics tests will be a culture imaging, which imaging to do. So we'll go on and discuss those, and of course, diagnostic biopsies and how we take it and where we should take will be our points of discussion. So the tests that are available once we do take, let's say, the ascitic fluid, we do want to do the tests on the ascitic fluid. If you're thinking of TB, we would definitely want to rule out TB using the tests that are available. And to our benefit, we have very good microbiological tests which are available in the form of the expert gene amplification technique test, and its sensitivity is quite high, and we have found it to be very good. Unfortunately, in the cases where there's ascites or an omental biopsy which has been sent for these tests, it hasn't performed well, and when we did discuss this with our microbiologists, they said that extra pulmonary TB tends to be quasi-bacillary, and so these tests do not perform as well as expected. Having said that, you could also offer to do a multiplex PCR testing, which has, again, very good sensitivity, and of late, a lot of interest in adenosine deaminase, which is a potent modulator of the T cell differentiation, and the sensitivity of this also happens to be very high at levels of more than 30 units per liter. So these are some of the microbiological tests, and along with a lymphocytic ascites, which is often the hallmark of tuberculosis or a CA125, which is not so elevated, and an elevated ADA, one could actually clinch the diagnosis of tuberculosis, and it's so important to actually tell the patient, see, you may be having TB and not cancer, and then go on to prove the same by further diagnostic tests. So coming on to the CT scan, CT scan is very…it's not so clear at times. So here are three images. One look at it, at a rough shot, we may say that this is probably a case of disseminated malignancy. So, like, we see a lot of mesentric nodules on the…in the screening image, as well as in the transverse images, we are seeing T-O masses or omental kink. So for the untrained eye, we would call this definitely a case of ovarian malignancy, if it's a lady, and she's come to us with cachexia and weight loss and abdominal distension. But yes, what are the findings, other findings, which can make you think? Kang et al. had, in her…in their study, had said that you could either have ascites, which is actually doculated, or you can have parietal thickening, which is quite a lot of parietal…peritoneal thickening. You could have mesentric nodules, discrete nodules, which we saw in the first picture, or the omentum could be thickened or caked. Again, these all could mimic ovarian cancer on the image. So, image is not really contributory, if you would ask me. Then what does? So, for us, finally, we have to go to get a diagnostic biopsy and the cultures. Unfortunately, without any of these biopsies, our infectious disease consultants are not going to start the ATT, and here in CMC, the practices that we refer them to them, and they have to do the therapy. So, for that, they do need documented AFB in all their biopsies. So that's going to be difficult because we are dealing with post-bacillary type of tuberculosis in the extrapulmonary regions. And these sites in which we take the biopsies are not regular sites to have bacilli identified very easily. But when we do take biopsy, we target the omentum. If omentum has not yielded anything, then we prefer to go for the peritoneal biopsies. If it is possible, we do a laparoscopic biopsy. In difficult cases, we may do open biopsy. We could sometimes target the tubovarian mass, which is solidified and sitting in the pelvis using ultrasound-guided procedures, or we could go for the powdered Douglas nodules, either an FNAC or an aspiration of fluid. So these are some of the ways which we can obtain material. And these are then further sent on for the cultures that we just discussed. And we could also send even tissues for culture, like the omentum and peritoneum, can also be subjected to various microbiological tests. But again, as I mentioned, the yield is very poor. So what is the gold standard for diagnosing them? Yes, of course, it is biopsy, which shows the gaseous necrosis, the Langehans type of giant cells, the lymphocytic infiltration, and the zeal-neosense cleaning and the detection of the AFB. That would clinch the diagnosis. We have come to terms with also saying that if the PCR is positive or a quantifier on gold is positive, we would also call that as positive and carry on with the treatment. So these are some of the ways that we would be able to clinch our diagnosis finally. So this was one study which quoted the correlation of various diagnostic modalities in clinching the diagnosis of abdominal, or here it was the case of intestinal TB. And here we saw that the 100% sensitivity was on the MGIT test, and they have also included a response to tuberculosis therapy as a good specificity. But if you look at the test in the form of imaging, or if you call it as the biopsy about presence of a granuloma or a TB-PCR, so all of them perform more or less almost the same. Some are specific, some are sensitive. So it is a very dicey. No test is so particularly good that we can go for it. And so it makes it all the more difficult as clinicians for us. The laparoscopy, why is it important early in the diagnosis is, as I mentioned, a lot of the workup wastes a lot of the time for the patient. So if we could very early, if you think there is suspicion of a TB, if we perform a laparoscopy for the trained, I'm supposing that we will be able to actually get a diagnosis either of the scarring and white patches, ascites, and this malaria TB nodules, which you can see on the peritoneum. These could be easily picked up for us who routinely see disseminated malignancy in our procedures. And so it would be a good option for us to perform a diagnostic laparoscopy. And this is why I put up this slide. Having diagnosed them, how do we treat this extra pulmonary TB? We offer them nine months of therapy, two months with isoniazid, rifampicin, ethambutol, pyrazinamide, and seven months of consolidation with dextrofampicin and isoniazid and ethambutol. And in cases where you're doing anti-TB therapy with anti-cancer drugs, as I mentioned earlier, because rifampicin may enhance the metabolism, you could change this to levoflox instead during the course of the chemotherapy. So this picture here actually tells us, it summarizes how you could be misled by an extra pulmonary TB, which would either arise from the endopatrium or anywhere in the female genital tract, or it could be in the peritoneum. It can be misdiagnosed quite easily, and it's asymptomatic because it's post-bacillary, so it presents quite delayed or in a very advanced form, like with excess of ascites, and it quite goes on for some time before it gets diagnosed. But the lack of sensitivity of diagnostic tests could lead to its late diagnosis and late treatment, and it's quite a difficult condition to treat. And above all, we are worried, like we were discussing in some of our cases, will there be a flare-up of those TB if we put it aside and go ahead and treat, let's say we're going to do a chemotherapy, is it going to flare up? Is the TB going to be pushed up because of immunosuppression following the chemotherapy? Or are we affecting the malignancy because we're giving the TB? So these are the dilemmas that we face. And what is more complicating is that these, as I mentioned, the sanctuary of these TB bacilli are in the organs, which are not so easily accessible through the bloodstream, and so they tend to reside in the body for a longer period and are very difficult to eradicate both ways. And cancer only complicates the therapy, which goes on. So with that, I thought I'll just share our little experience. So the aim of this study was to see how, like I mentioned, I was interested in seeing how we went about diagnosing these cases. It was the small case series of 23 patients in the years 2014 to 2017. I went through all the diagnostic tests and how we confirmed them and what treatment they took. And most of our patients for us come from, interestingly, they are from West Bengal. They travel a lot and they come here. So it is very important that we do the diagnosis at the earliest for them, because they have spent a lot of money and they come here and stay. And we went through all the history, which is almost similar to what we just discussed. And on imaging, the same omental caking, pelvic masses and SIDs and peritoneal ticking, there was a combination of all of these in most of the cases. So I would just straight go on to say, yes, the cultures which we took out and analyzed were not much informative. A lot of them were present in both or not present in both. Some were positive for TB and still they would not be picked up on culture. So finally, we ended up doing even ascitic tabs and ultrasound-guided biopsies. The yield, the positivity, though it said that ascitic tab was positive for lymphocytic, when if you consider lymphocytosis as positivity for TB, yes, it was all lymphocytic, but the biopsies, there were only about 70% of them, which were positive. So laparoscopy and laparotomy yielded better biopsies. Laparoscopies were higher as compared to laparotomy. And expert PCR also did not perform as well as we thought. And the explanation there was that we were not probably sending the right culture or the post-bacillary was not being picked up. So this was what our microbiologist could tell us. The perioperative findings of our patients were miliary tubercles, ascites, adnexal mass, cocoon abdomen adhesions in some of them. Again, there was a combination of these findings in most of our patients, but miliary TBs when seen and the clumping of the bowels was so pathognomic of TB and one could easily diagnose. So this was our algorithm for diagnosis. And a majority of our patients, 15 of the 23, had some form of a laparoscopy or a laparotomy biopsy, which needed to be done to confirm the diagnosis of AFB on the biopsies. The things which aided in that diagnosis was to put together the age, the clinical symptoms, see a one to five year static fluid, and the extensive nature of the peritoneal disease. And of course, even we sometimes include a trial of ATD in one or two of these cases. And the fact that they did not have cancer or negative for malignant actually clinched the diagnosis for us as TB also. So we did use this Lingenfenster's criteria to say that one has to have a clinical manifestation suggestive of TB, imaging needs to have evidence of abdominal TB and histopathological or microbiological evidence of TB. And there has to be a therapeutic response to TB. So these criteria are essential to label it as abdominal tuberculosis. So this was the one that we went for. And so in conclusion, for my study, what we did for our study from CMC, what we did say is being an endemic region in India, we need to think of TB with a high degree of clinical suspicion and isolation of AFB is the gold standard for diagnosis of pulmonary TB, but has a very low yield in abdominal TB as mentioned. So ultrasound guided procedure can be a reasonable first type of test, which is not so time consuming, but you could do it, but go for a diagnostic laparoscopy or a laparotomy early in the workup, save time and anxiety for the patients. So after that, because our talk and the cases today involved patients who already had malignancy and now diagnosed with TB along, I looked up some literature, but it was very difficult to find articles. So I did look up for a patient with him on chemotherapy for lung cancer and coexistence TB, though it's not related to us, but generally what they have said that the concurrent anti-TB and chemotherapy treatment did not increase the hematological toxicity or the hepatic dysfunction as we think. So in TB, in patients with pulmonary, in patients with tuberculosis on tuberculosis therapy for pulmonary TB, even if they had lung cancer, they could carry on with both. This is just to correlate with us. And in another study where I looked up where they had put a mix of cancers, like lung cancers, and then we had some colorectal cancer, then we had some sigmoid cancers, transverse colon cancers and other GI malignancies, breast cancer, total of about 30 patients. And here they too found a good success of anti-TB chemotherapy, sorry, anti-TB therapy. And there was 70% of resolution of the same therapy and there was no MTB related treatment failures. The survival was not affected. So they could continue both the treatment and the conclusion was that concurrent chemotherapy is effective and safe for treating cancer patients with active MTB. And so it goes on to support what we've earlier discussed that need not hold back one therapy for the other. The only article that I could come upon with treatment of advanced ovarian cancer with co-existent peritoneal TB, which is what was put by Manisha too, is from Japan. And here they were trying to study the fact that rifampicin may enhance the metabolism of paclitaxel. So whether to administer it differently or to avoid it. And in that particular study, they had done the serum assay of paclitaxel and they had drawn a curve as to what is the values. And for the days that they gave the chemo, they gave the weekly chemo with paclitaxel carbopactin. They discontinued the therapy on day one, eight and 15 with rifampicin and they would wait for the paclitaxel to finish and then they would go back to the therapy. So they found that there was good response to both the chemotherapy. So this was the only study that I could get my hands on. But in summary, I guess it is safe to continue both therapies together. The take home from, at least from our institution is that we do not stop one for the other. They are under close surveillance and they preferably need to be supervised in the same institution where they're taking the therapy and they need to be around. And it needs a multi-departmental, like a multi-unit input as like infectious disease, medical oncology, and us who have been monitoring the ovarian cancer, if it is also there. With that, I would like to end my talk. Thank you once again for this opportunity. Also would like to share that we see a lot of patients with granulomas in the lymph nodes in cases of endometrium and cervical cancer from whom we take out the retropaternal lymph nodes. And those, when we send them to ID for ATT thinking that case use necrosis and Langen cells is enough, they often get sent back saying, this is not TB, we need to see AFB. So I would like any of your comments on that. I mean, so we just kind of get such saying, it's nothing, just keep them on follow-up. It's part of your malignancy. So, yes.

Tuberculosis

Ovarian cancer

Diagnosis challenges

Diagnostic tests

Abdominal TB treatment

Concurrent TB and cancer therapies